Method for modulating amount of virus, method for treating or preventing virus infections, method for estimating amount of virus, and method for predicting prognosis of virus infection in subject, as well as composition and system for these methods

Abstract

To provide means for modulating the amount of virus in a subject.SOLUTION: Provided herein is a method comprising administering to a subject a component for modulating an indicator associated with D-amino acid in the subject.SELECTED DRAWING: Figure 2

Description

[Technical field]

[0001] The present invention relates to methods for adjusting the viral load in a subject, for treating or preventing a viral infection in a subject, for estimating the viral load in a subject, and for predicting the prognosis of a viral infection in a subject, as well as compositions and systems for these methods. [Background technology]

[0002] Infection refers to the settlement, invasion, and proliferation of pathogens (pathogenic microorganisms) such as viruses in the cells, tissues, and organs of a host through various infection routes. In many cases, pathogens that invade a host are eliminated from the host without being able to infect the host by the host's defense mechanism, but a state in which infection is established and some symptoms or signs such as fever appear (onset) is called an infectious disease. Infections caused by viruses such as coronaviruses and influenza viruses and the resulting infectious diseases may pose a threat to the medical and economic health due to pandemics. Genetic tests (PCR method, etc.), immunological tests (antigen detection method, etc.), antibody and antigen tests, etc. have been put to practical use to detect the presence and amount of viruses in a host. In addition, urinary liver fatty acid binding protein (L-FABP) (Patent Document 1) has been proposed as a biomarker for predicting the risk of aggravation of viral infections.

[0003] In recent years, quantitative research has progressed in identifying trace amounts of D-amino acids and L-amino acids in living organisms, including mammals, due to the advancement of technology for identifying and analyzing chiral amino acids. As a result, the existence and functions of some D-amino acids, which have traditionally been treated as total amino acids (D-amino acids + L-amino acids) or conveniently as L-amino acids due to technical limitations, have become clear. It has been shown that in the mammalian intestine, the D-amino acid metabolism of D-amino acid oxidase (DAO) regulates the intestinal immunity of the host against Vibrio bacteria (Non-Patent Document 1). It has also been reported that the %D values ​​({D-amino acids / (D-amino acids + L-amino acids)} x 100) of D-asparagine, D-serine, D-alanine, and D-proline in the blood of humans infected with human immunodeficiency virus (HIV) and receiving antiretroviral therapy correlate with the age and renal function marker (eGFR) of the subjects, but no changes due to HIV infection were observed (Non-Patent Document 2). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent No. 6933834 [Patent Document 2] Patent No. 6868878 [Patent Document 3] Patent No. 6993654 [Patent Document 4] International Publication No. 2020 / 196436 [Patent Document 5] International Publication No. 2013 / 140785 [Non-patent literature]

[0005] [Non-Patent Document 1] Sasabe J, Miyoshi Y, Rakoff-Nahoum S, Zhang T, Mita M, Davis BM, Hamase K, Waldor MK. Interplay between microbial D-amino acids and host D-amino acid oxidase modifies murine mucosal defense and gut microbiota. Nat Microbiol. 2016 Jul 25;1(10):16125. doi: 10.1038 / nmicrobiol.2016.125.

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[0006] In normal life activities, the balance of D-amino acids in the body is controlled within a certain range. If there is a variation in the balance of D-amino acids accompanied by a viral infection or a change in the subject's viral load, the risk of harming health increases, so it is necessary to correct and adjust it. [Means for solving the problem]

[0007] The present inventors comprehensively and highly precisely quantified and analyzed chiral amino acids (amino acids that can be distinguished between D-amino acids and L-amino acids) in the blood of subjects infected with a virus, and discovered a phenomenon in which the amount of D-amino acids in the blood fluctuates (decreases and increases) in subjects infected with a virus, and found that this fluctuation is related to the amount of virus in the subject and the symptoms and pathology of the viral infection. Furthermore, as a result of intensive research into the effect and mechanism of artificially varying the amount of D-amino acids in the body of a subject, the inventors developed a technology that suppresses the worsening of viral infection and improves the prognosis by adjusting the amount of virus in the subject by controlling the amount of D-amino acids in the body, and thus completed the present invention, which provides a solution to the above-mentioned problems.

[0008] That is, the gist of the present invention relates, for example, to the following: [Item 1] A method for adjusting a viral load in a subject, comprising: A method comprising administering to the subject a composition for controlling an indicator relating to D-amino acids in the subject. [Item 2] The method according to Item 1, wherein the indicator for D-amino acids is a measured value for D-amino acids in blood or a corrected value or correction formula thereof. [Item 3] The method according to Item 1 or 2, wherein the component for controlling the D-amino acid-related indicator of the subject is a D-amino acid. [Item 4] The method according to any one of Items 1 to 3, wherein the D-amino acid is one or more D-amino acids selected from the group consisting of D-proline, D-serine, D-alanine, and D-asparagine. [Item 5] The method according to any one of Items 1 to 4, wherein the virus is a virus belonging to a family selected from orthomyxovirus, coronavirus, paramyxovirus, rhabdovirus, arenavirus, bunyavirus, filovirus, retrovirus, togavirus, flavivirus, picornavirus, astrovirus, calicivirus, reovirus, parvovirus, adenovirus, papillomavirus, polyomavirus, herpesvirus, hepadnavirus, and poxvirus. [Item 6] The method according to any one of Items 1 to 5, further comprising treating or preventing viral infection in the subject by controlling an indicator of D-amino acids in the subject that has changed due to the viral infection. [Item 7] The method according to Item 6, wherein the fluctuation in the subject's D-amino acid indicator due to viral infection is a fluctuation indicating a decrease in the amount of D-amino acid in the blood. [Item 8] The method according to Item 6 or 7, wherein the control of the D-amino acid indicator in the subject is a supplement to D-amino acids in the blood that have decreased due to a viral infection. [Item 9] A method for estimating viral load in a subject, comprising: The method comprises determining the viral load in the subject using an index related to D-amino acids in the subject. [Item 10] The method according to Item 9, wherein the viral load in the subject is determined to be increased when the indicator for D-amino acids shows that the amount of D-amino acids in the blood is decreased or is below a predetermined threshold. [Item 11] The method according to any one of Items 9 and 10, wherein when the indicator for D-amino acids shows that the decrease in the amount of D-amino acids in the blood has stopped or is increasing, it is determined that the increase in the amount of virus in the subject has stopped or is decreasing. [Item 12] The method according to any one of Items 9 to 11, further comprising predicting the prognosis of the subject's viral infection based on the result of the determination of the viral load in the subject. [Item 13] The method according to Item 12, wherein the prognosis of the subject is determined to be a worsening or aggravation of the viral infection when the indicator for the D-amino acid shows that the amount of D-amino acid in the blood is reduced or is below a predetermined threshold. [Item 14] The method according to item 12 or 13, wherein the prognosis of the subject is determined to be improvement of the viral infection when the indicator for the D-amino acid shows that the decrease in the amount of D-amino acid in the blood has stopped or is increasing. [Item 15] The method according to any one of Items 12 to 14, wherein the viral load in the subject is determined to have decreased to a curative level when the indicator for the D-amino acid shows that the amount of D-amino acid in the blood has returned to within the standard range or above. [Item 16] The method according to any one of Items 12 to 15, wherein the prognosis of the subject is determined to be cured of the viral infection when the indicator for D-amino acids indicates that the amount of D-amino acids in the blood has returned to within the standard range. [Item 17] The method according to any one of Items 9 to 16, wherein the indicator for a D-amino acid is a measured value for a D-amino acid in blood or a corrected value or correction formula thereof. [Item 18] The method according to any one of Items 9 to 17, wherein the D-amino acid is one or more D-amino acids selected from the group consisting of D-proline, D-serine, D-alanine, and D-asparagine. [Item 19] The method according to any one of Items 9 to 18, wherein the virus is a virus belonging to a family selected from orthomyxovirus, coronavirus, paramyxovirus, rhabdovirus, arenavirus, bunyavirus, filovirus, retrovirus, togavirus, flavivirus, picornavirus, astrovirus, calicivirus, reovirus, parvovirus, adenovirus, papillomavirus, polyomavirus, herpesvirus, hepadnavirus, and poxvirus. [Item 20] A composition for regulating a viral load in a subject, comprising: A composition comprising an ingredient for adjusting an index related to D-amino acids in a subject. [Item 21] The composition according to Item 20, wherein the indicator for D-amino acids is a measured value for D-amino acids in blood or a corrected value or correction formula thereof. [Item 22] The composition according to item 20 or 21, wherein the component for controlling the D-amino acid-related indicator of the subject is a D-amino acid. [Item 23] The composition according to any one of Items 20 to 22, wherein the D-amino acid is one or more D-amino acids selected from the group consisting of D-proline, D-serine, D-alanine, and D-asparagine. [Item 24] The composition according to any one of Items 20 to 23, wherein the virus is a virus belonging to a family selected from orthomyxoviruses, coronaviruses, paramyxoviruses, rhabdoviruses, arenaviruses, bunyaviruses, filoviruses, retroviruses, togaviruses, flaviviruses, picornaviruses, astroviruses, caliciviruses, reoviruses, parvoviruses, adenoviruses, papillomaviruses, polyomaviruses, herpesviruses, hepadnaviruses, and poxviruses. [Item 25] The composition according to any one of Items 20 to 24, for treating or preventing a viral infection in a subject by controlling an indicator of D-amino acids in the subject that varies due to the viral infection. [Item 26] The composition described in Item 25, wherein the fluctuation in the subject's D-amino acid indicator due to viral infection is a fluctuation indicating a decrease in the amount of D-amino acid in the blood. [Item 27] ​​The composition described in Item 25 or 26, wherein the adjustment of the subject's D-amino acid indicator is by supplementing D-amino acids in the blood that have decreased due to a viral infection. [Item 28] A system for carrying out the method according to any one of items 9 to 19, The system includes an input unit, an analysis and measurement unit, a memory unit, a data processing unit, and an output unit. The input unit inputs information from a subject, the analysis and measurement unit obtains an index for D-amino acids of the subject by analyzing and measuring information from the subject inputted from the input unit; The storage unit stores a determination value regarding a virus infection and / or a virus infectious disease, The data processing unit processes the indicator of the subject acquired by the analysis and measurement unit based on the determination value stored in the memory unit, thereby determining the amount of virus in the subject and / or the prognosis of the subject's viral infection; The output unit outputs the result of the determination by the data processing unit as information regarding the amount of virus in the subject and / or the prognosis of the viral infection in the subject. The system is configured as follows. Effect of the Invention

[0009] According to one aspect of the present invention, by controlling a subject's D-amino acid indicators that fluctuate due to viral infection or that may fluctuate in the future, it is possible to adjust the amount of virus in the subject and efficiently treat or prevent viral infection.

[0010] Furthermore, according to one embodiment of the present invention, by making an assessment using an index related to a subject's D-amino acid, it becomes possible to efficiently estimate the viral load in a subject and efficiently predict the prognosis of a viral infection in a subject. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 is a schematic diagram showing the experimental protocol for administering D-alanine to influenza virus-infected model mice in Example 1. [Diagram 2] FIG. 2 is a graph showing the rate of weight change in influenza virus-infected model mice after administration of D-alanine in Example 1. [Diagram 3] Fig. 3A is a graph showing the results of a viral plaque quantification assay of lung tissues 5 days after D-Ala administration in each of the Mock, IAV, and IAV+D-Ala groups in Example 1. Fig. 3B is a graph analyzing the correlation between BD-Ala and the viral load in the IAV+D-Ala group in Example 1. [Figure 4] FIG. 4 is a survival rate curve for the administration of D-alanine to influenza virus-infected model mice in Example 1. [Diagram 5] FIG. 5 is a graph showing the relationship between body weight and blood D-amino acid level in influenza virus-infected model mice administered D-alanine in Example 1. [Figure 6-1] FIG. 6-1 is a graph showing BD-Ala, BD-Ser, BD-Asn, and BD-Pro 48 to 72 hours after infection in each of the Mock(-) and IAV(+) groups in Example 1. [Figure 6-2] FIG. 6-2 is a graph showing B% D-Ala, B% D-Ser, B% D-Asn, and B% D-Pro 48 to 72 hours after infection in each of the Mock(-) and IAV(+) groups in Example 1. [Figure 7] FIG. 7 is a graph showing the rate of change in body weight of influenza virus-infected model mice in Example 1. [Figure 8] FIG. 8 shows survival rate curves for the administration of D-serine or D-alanine to influenza virus-infected model mice in Example 1. [Figure 9] FIG. 9 is a graph showing the rate of weight change in influenza virus-infected model mice following administration of D-serine or D-alanine in Example 1. [Figure 10] FIG. 10 is a schematic diagram showing the experimental protocol for the coronavirus-infected mouse model in Example 2. [Figure 11-1] FIG. 11-1 is a graph showing the changes over time in BD-Ala, BD-Ser, BD-Pro, and BD-Asn in a coronavirus-infected model mouse in Example 2. [Figure 11-2] Figure 11-2 is a graph showing the changes over time in B%D-Ala, B%D-Ser, B%D-Pro, and B%D-Asn in a coronavirus-infected model mouse in Example 2. [Figure 12] FIG. 12 is a schematic diagram showing an experimental schedule for administering D-alanine to coronavirus-infected model mice in Example 2. [Figure 13] FIG. 13 is a graph showing the dose and rate of change in body weight when D-alanine was administered to a coronavirus-infected model mouse group in Example 2. [Figure 14] FIG. 14 is a survival curve for administration of D-alanine to a coronavirus-infected model mouse in Example 2. [Figure 15-1] FIG. 15-1 is a graph showing the changes over time in BD-Ala, BD-Ser, BD-Asn, and BD-Pro for the SCV (Vehicle) and SCV+D-Ala groups in Example 2. [Figure 15-2] FIG. 15-2 is a graph showing the changes over time in B % D-Ala, B % D-Ser, B % D-Asn, and B % D-Pro for the SCV (Vehicle) and SCV+D-Ala groups in Example 2. [Figure 16-1] FIG. 16-1 is a graph showing BD-Ala, BD-Ser, BD-Asn, and BD-Pro for the SCV+D-Ala group in Example 2, classified into two groups based on a body weight maintenance rate of 90% (body weight loss rate of 10%) (-: group whose body weight was maintained at 90% or more, +: group whose body weight was reduced by 10% or more). [Figure 16-2]FIG. 16-2 is a graph showing B% D-Ala, B% D-Ser, B% D-Asn, and B% D-Pro for the SCV+D-Ala group in Example 2, classified into two groups based on a body weight maintenance rate of 90% (body weight loss rate of 10%) (-: group whose body weight was maintained at 90% or more, +: group whose body weight was reduced by 10% or more). [Figure 17] FIG. 17 is a graph showing the rate of weight change over time for D-alanine administration to coronavirus-infected model mice in Example 2. [Figure 18] FIG. 18 is a survival curve for the coronavirus-infected mouse model administered D-alanine in Example 2, with weight loss and death as combined endpoints. [Figure 19] FIG. 19 is a survival rate curve classified by blood D-alanine amount in coronavirus-infected model mice in Example 2. [Figure 20] FIG. 20 is a block diagram showing a schematic example of a configuration of a system according to the present invention. [Figure 21] FIG. 21 is a flow chart that illustrates an example of processing by the system of the present invention (the method of the present invention). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The present invention will be described in detail below with reference to specific embodiments. However, the present invention is not limited to the following embodiments, and can be embodied in any form without departing from the spirit of the present invention.

[0013] All patent documents (such as published patent applications and patent publications) and non-patent documents cited in this specification are hereby incorporated by reference in their entirety into this specification.

[0014] In the following description, the "first method of the present invention," "second method of the present invention," and "third method of the present invention" described below may be collectively referred to as the "method of the present invention" as appropriate.

[0015] [Definition] In the present specification, amino acids and their residues may be represented by three-letter abbreviations well known to those skilled in the art. The main abbreviations used in the present specification are shown in the following table. [Table 1]

[0016] ·D-amino acids ·L-amino acids In this specification, "D-amino acids" (abbreviated as "D form" where appropriate) and "L-amino acids" (abbreviated as "L form" where appropriate) refer to stereoisomers of amino acids based on the D / L notation system of IUPAC nomenclature. D and L forms are enantiomers. It is known that the majority of proteinogenic amino acids in living organisms are L forms. Although glycine does not have D and L isomers, for the sake of convenience, glycine will be treated as the D form in this specification unless otherwise specified.

[0017] In the present specification, specific examples of D-amino acids include, but are not limited to, glycine, D-alanine, D-histidine, D-isoleucine, D-allo-isoleucine, D-leucine, D-lysine, D-methionine, D-phenylalanine, D-threonine, D-allo-threonine, D-tryptophan, D-valine, D-arginine, D-cysteine, D-glutamine, D-proline, D-tyrosine, D-aspartic acid, D-asparagine, D-glutamic acid, and D-serine. Among them, neutral aliphatic amino acids, glucogenic amino acids related to energy metabolism and sugar metabolism pathways, and D-proline, D-serine, D-alanine, and D-asparagine, which are relatively abundant in blood, are preferred. Any one of these D-amino acids may be used alone, or any combination of two or more of them may be used.

[0018] In addition, D-cysteine ​​contained in a biological sample is oxidized outside the body and converted to D-cystine, so by measuring an indicator (e.g., amount) of D-cystine instead of D-cysteine, an indicator (e.g., amount) of D-cysteine ​​contained in a biological sample can be calculated.

[0019] ·D-amino acid indicators As used herein, "D-amino acid indicator" refers to any indicator obtained from a living body and having some relationship to D-amino acids (measurement values ​​or test values ​​of D-amino acid indicators obtained from a subject may be simply abbreviated as "D-amino acid test values" or the like.) Examples of D-amino acid indicators include measurement values ​​of D-amino acids in blood or their corrected values ​​or correction formulas.

[0020] An example of a measured value of an index related to D-amino acids in blood is the amount of D-amino acids in blood. In this specification, "amount of D-amino acids in blood" means the amount of D-amino acids contained in a specific amount of blood. The amount of D-amino acids in blood may be expressed as a concentration. The amount of D-amino acids in blood is measured as the amount in a sample of collected blood that has been centrifuged, sedimented, or pretreated for analysis. Therefore, the amount of D-amino acids in blood can be measured as the amount of D-amino acids in a blood sample derived from collected blood, such as whole blood, serum, or plasma. As an example, in the case of analysis using HPLC, the amount of D-amino acids contained in a specified amount of blood is represented by a chromatogram, and can be quantified by comparison with a standard product for peak height, area, and shape, or by analysis using calibration.

[0021] Correction values ​​or correction formulas for measured values ​​relating to the amount of D-amino acids include any value or formula obtained by correcting the amount of D-amino acids. Specific examples include the corrected D / L ratio of the amount of D-amino acids, %D ({D-amino acid / (D-amino acid+L-amino acid)}×100) representing the ratio of D-amino acids in a specific amino acid, D-amino acid clearance, D-amino acid excretion rate (Non-Patent Documents 3 and 4), and further formulas or values ​​corrected according to the purpose using the amount of D-amino acids as an explanatory variable, and values ​​calculated by a preset formula, etc.

[0022] Another example of the correction value of the D-amino acid amount is a value obtained by adjusting the D-amino acid amount according to physiological fluctuation factors, such as age, sex, BMI, etc. In addition, when the dynamics of D-amino acids are affected by the function of the kidney, a value obtained by adjusting the D-amino acid amount according to an index of renal function may be used as the correction value of the D-amino acid amount. Such an index of renal function may be selected from, but is not limited to, creatinine, cystatin C, inulin clearance, creatinine clearance, urinary protein, urinary albumin, β2-MG, α1-MG, NAG, L-FABP, NGAL, glomerular filtration rate, estimated glomerular filtration rate (eGFR), renal function measurements and estimation formulas using D-amino acids (Patent Documents 2, 3, 4), etc. Specific examples include correction to obtain the ratio of the amount of D-amino acids in blood to the amount of creatinine in blood (amount of D-amino acids in blood / amount of creatinine in blood). Furthermore, since it is known that D-amino acids in the body fluctuate due to neurodegenerative diseases (such as ALS), autoimmune diseases (such as multiple sclerosis), metabolic diseases (such as diabetes) and the like (Patent Document 5, Non-Patent Document 5), it is also possible to correct the amount of D-amino acids based on the fluctuating factors or markers of each disease.

[0023] Another example of an index related to D-amino acids may be a value or formula obtained by correcting the amount of D-amino acids in the blood of a subject with an index related to a substance in the subject's body (e.g., an L-amino acid). The substance in the subject's body used for correction is not limited to, but may be, for example, the amount of L-amino acids in the blood of the subject or the total amount of amino acids.

[0024] When a value obtained by correcting the amount of D-amino acids using other test values ​​or the like is used as an index for D-amino acids, the criteria for judging the viral load and / or symptoms and pathology of viral infections based on the fluctuation (e.g., decrease or increase) of the amount of D-amino acids and the methods for judging and analyzing the same can be appropriately set or changed according to the correction content for the amount of D-amino acids. As an example, when a value obtained by correcting the amount of D-amino acids using a reciprocal (e.g., [1 / amount of D-amino acid]) or a multiplier is used as an index for D-amino acids, the criterion set based on the fluctuation (e.g., decrease or increase) of the amount of D-amino acids in blood can be used as a reciprocal (e.g., a decrease in the amount of D-amino acids in blood indicates an increase in the value, and an increase in the amount of D-amino acids indicates a decrease in the value) or logarithm.

[0025] In the method of the present invention, any one of D-amino acid indicators (e.g., blood D-amino acid amount, corrected D / L ratio, %D ({D-amino acid / (D-amino acid+L-amino acid)}×100), D-amino acid clearance, D-amino acid excretion rate, etc.) may be used alone or any two or more of them may be used in combination. In the latter case, a panel test in which multiple D-amino acid indicators are combined simultaneously may be used.

[0026] In the method of the present invention, the sample for measuring the indicators related to the D-amino acid of the subject may be one or more samples obtained in a single test, or may be two or more samples obtained in multiple tests. When multiple samples are used, the samples may be obtained at the same time point, or may be obtained at multiple different time points. The form of these samples may be appropriately selected according to various aspects described below.

[0027] The amount of D-amino acids and / or L-amino acids in a sample such as blood can be measured by any method, for example, chiral column chromatography, enzyme methods, or immunological methods using monoclonal antibodies that distinguish optical isomers of amino acids. The amount of D-amino acids and / or L-amino acids in a sample can be measured by any method known to those skilled in the art. Examples include the following chromatographic and enzymatic methods (Y. Nagata et al., Clinical Science, 73 (1987), 105. Analytical Biochemistry, 150 (1985), 238., A. D'Aniello et al., Comparative Biochemistry and Physiology Part B, 66 (1980), 319. Journal of Neurochemistry, 29 (1977), 1053., A. Berneman et al., Journal of Microbial & Biochemical Technology, 2 (2010), 139., WG Gutheil et al., Analytical Biochemistry, 287 (2000), 196., G. Molla et al., Methods in Molecular Biology, 794 (2012), 273., T. Ito et al., Analytical Biochemistry, 371 (2007), 167, etc.), antibody method (T. Ohgusu et al., Analytical Biochemistry, 357 (2006), 15, etc.), gas chromatography (GC) (H. Hasegawa et al., Journal of Mass Spectrometry, 46 (2011), 502., MC Waldhier et al., Analytical and Bioanalytical Chemistry, 394 (2009), 695., A. Hashimoto, T. Nishikawa et al., FEBS Letters, 296 (1992), 33., H.Bruckner and A. Schieber, Biomedical Chromatography, 15 (2001), 166., M. Junge et al., Chirality, 19 (2007), 228., M. C. Waldhier et al., Journal of Chromatography A, 1218 (2011), 4537, etc.), capillary electrophoresis (CE) (H. Miao et al., Analytical Chemistry, 77 (2005), 7190., D. L. Kirschner et al., Analytical Chemistry, 79 (2007), 736., F. Kitagawa, K. Otsuka, Journal of Chromatography B, 879 (2011), 3078., G. Thorsen and J. Bergquist, Journal of Chromatography B, 745 (2000), 389, etc.), high performance liquid chromatography (HPLC) (N. Nimura and T. Kinoshita, Journal of Chromatography, 352 (1986), 169., A. Hashimoto et al., Journal of Chromatography, 582 (1992), 41., H. Bruckner et al., Journal of Chromatography A, 666 (1994), 259., N. Nimura et al., Analytical Biochemistry, 315 (2003), 262., C. Muller et al., Journal of Chromatography A, 1324 (2014), 109., S. Einarsson et al., Analytical Chemistry, 59 (1987), 1191., E. Okuma and H. Abe, Journal of Chromatography B, 660 (1994), 243., Y. Gogami et al., Journal of Chromatography B, 879 (2011), 3259., Y. Nagata et al., Journal of Chromatography, 575 (1992), 147., S. A. Fuchs et al., Clinical Chemistry, 54 (2008), 1443., D. Gordes et al., Amino Acids, 40 (2011), 553., D. Jin et al., Analytical Biochemistry, 269 (1999), 124., J. Z. Min et al., Journal of Chromatography B, 879 (2011), 3220., T. Sakamoto et al., Analytical and Bioanalytical Chemistry, 408 (2016), 517., W. F. Visser et al., Journal of Chromatography A, 1218 (2011), 7130., Y. Xing et al., Analytical and Bioanalytical Chemistry, 408 (2016), 141., K. Imai et al., Biomedical Chromatography, 9 (1995), 106., T. Fukushima et al., Biomedical Chromatography, 9 (1995), 10., R. J. Reischl et al., Journal of Chromatography A, 1218 (2011), 8379., R. J. Reischl and W. Lindner, Journal of Chromatography A, 1269 (2012), 262., S. Karakawa et al., Journal of Pharmaceutical and Biomedical Analysis, 115 (2015), 123., Hamase K, et al.,Chromatography 39 (2018) 147-152 etc.) can be mentioned.

[0028] The optical isomer separation and analysis system of the present invention may combine a plurality of separation and analysis. As a specific example, the method for analyzing optical isomers includes the steps of passing a sample containing components having optical isomers through a first column packing material as a stationary phase together with a first liquid as a mobile phase to separate the components of the sample, individually retaining each of the components of the sample in a multi-loop unit, supplying each of the components of the sample individually retained in the multi-loop unit through a flow path to a second column packing material having an optically active center as a stationary phase together with a second liquid as a mobile phase to separate the optical isomers contained in each of the components of the sample, and detecting the optical isomers contained in each of the components of the sample, thereby measuring the amount of D-amino acids and / or L-amino acids in a sample (Japanese Patent No. 4291628). In HPLC analysis, D- and L-amino acids may be derivatized in advance with a fluorescent reagent such as o-phthalaldehyde (OPA) or 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F), or diastereomerized using N-tert-butyloxycarbonyl-L-cysteine ​​(Boc-L-Cys) or the like (Kenji Hamase and Kiyoshi Zaitsu, Analytical Chemistry, Vol. 53, pp. 677-690 (2004)). Alternatively, the amount of D-amino acids and / or L-amino acids in a sample can be measured by an immunological method using a monoclonal antibody that distinguishes optical isomers of amino acids, for example, a monoclonal antibody that specifically binds to D-amino acids or L-amino acids. In addition, when the total amount of D-amino acids and L-amino acids is used as an index, it is not necessary to separate and analyze D-amino acids and L-amino acids, and amino acids can be analyzed without distinguishing between D-amino acids and L-amino acids. In that case, separation and quantification can be performed by an enzyme method, an antibody method, GC, CE, or HPLC.

[0029] In this specification, the amounts of biomolecules such as D-amino acids, L-amino acids, creatinine, proteins, and drugs are expressed not only in terms of simple mass, weight, or amount of substance (mol), but also in any physical quantity that can be measured, such as the mass, weight, or amount of substance (mol) per tissue, cell, organ, or molecular unit, volume, or weight, or the mass, weight, or amount of substance (mol) in a liquid such as blood or urine, concentration, specific gravity, or density.

[0030] Viruses and viral infections As used herein, the term "virus" refers to a minute infectious structure whose minimum components are nucleic acid carrying genetic information and a protein shell that covers the nucleic acid, and which replicates itself using the cells of other organisms. The viruses to which the present invention can be applied are not particularly limited as long as they infect humans, and may be any virus, including viruses that cause infectious diseases in host organisms through infection.

[0031] Examples of viruses include, but are not limited to, orthomyxoviruses (influenza A virus, influenza B virus, influenza C virus, etc.), coronaviruses (SARS coronavirus (SARS-CoV), MERS coronavirus (MERS-CoV, SARS coronavirus 2 (SARS-CoV-2)), paramyxoviruses (measles virus, mumps virus, etc.), rhabdoviruses, arenaviruses, bunyaviruses, filoviruses, retroviruses (human immunodeficiency virus (HIV)), etc.), togaviruses, flaviviruses (hepatitis C virus, Examples of viruses that can be identified include viruses belonging to various families, such as human adenoviruses (HCV), picornaviruses (rhinovirus types A to C, etc.), astroviruses, caliciviruses, reoviruses, parvoviruses, adenoviruses (human adenovirus types A to G, etc.), papillomaviruses, polyomaviruses, herpesviruses (herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), varicella-zoster virus (VZV), etc.), hepadnaviruses (hepatitis B virus (HBV), etc.), and poxviruses (variola virus, cowpox virus, monkeypox virus, camelpox virus, etc.).

[0032] As used herein, "infection" refers to a state in which a pathogen such as a virus adheres to, settles, invades, or grows in the host's cells, tissues, or organs through various infection routes, and includes overt infection, asymptomatic infection, and persistent infection (latent infection). As used herein, "infectious disease" refers to a state in which infection is established and some symptoms or signs appear (for example, fever, chills, headache, muscle pain, joint pain, etc. for influenza, and pneumonia, etc. for COVID-19). The amount of virus in a subject can be measured by a method such as a test (biochemical test, serological test, endocrine test, microbiological test, virological test, culture test, microscopic test, genetic test (PCR method, hybridization, etc.), immunological test (antigen / antibody detection method), pathological test, etc.) of a collected specimen (pharyngeal secretion, sputum / respiratory secretion, urine, vaginal secretion, feces, blood, cerebrospinal fluid, tissue, cell, organ, etc.), an imaging test (endoscopic test, contrast agent test, ultrasound test, CT test, MRI test, etc.), and is expressed not only as a simple mass, weight, amount of substance, or quantity, but also as any measurable physical quantity such as mass, weight, amount of substance, quantity, volume, area per tissue / cell / organ / molecule unit, culture colony / plaque unit, volume / weight, mass, weight, amount of substance, quantity, concentration, specific gravity, and density in a liquid such as blood or urine. It may also be expressed qualitatively, such as more, less, increase, decrease, etc., by comparing with an arbitrary standard.

[0033] Examples of viral infections include, but are not limited to, the common cold, influenza, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), COVID-19, mumps, other viral pneumonias, chickenpox, shingles, measles, herpes labialis, genital herpes, hepatitis B, hepatitis C, smallpox, and monkeypox.

[0034] ·subject In the present specification, the term "subject" is not limited to, but includes, for example, vertebrates. Examples of vertebrates include mammals, birds, reptiles, amphibians, and fish. Examples of mammals include humans, as well as non-human mammals such as mice, rats, guinea pigs, monkeys, rabbits, cows, horses, pigs, sheep, camels, goats, dogs, and cats. Examples of birds include chickens. Among them, humans or non-human mammals are preferred as subjects, and humans are particularly preferred. In addition, various animals in which virus infection and / or virus infection are induced by transplantation of virus-infected and / or virus-infected cells, genetic modification, or drugs (DNA, RNA, various vaccines, etc.) may be used as subjects. Furthermore, individuals, cells, tissues, organoids, etc. of various animals that serve as a specific virus infection model may be used as subjects.

[0035] ·Judgment criteria In the second and third methods of the present invention, as described below, an index relating to a subject's D-amino acid is compared with a predetermined judgment criterion to estimate the amount of virus in the subject's body and to predict the prognosis of the subject's viral infection.

[0036] As used herein, the term "criterion" refers to any criterion for estimating the amount of virus in a subject's body or judging the prognosis of a viral infection in a subject using an index related to a D-amino acid in the subject. Examples include, but are not limited to, a predetermined reference value consisting of a single numerical value (referred to as a "criterion value" as appropriate; it may also be referred to as a judgment value or clinical judgment value) and a predetermined reference range defined by an upper limit and a lower limit (referred to as a "criterion range" as appropriate). That is, as used herein, the term "criterion" encompasses "reference value" and "reference range". The reference value (clinical judgment value) and reference range can be set in advance by analysis of a target reference individual or a target reference population. A healthy subject can be used as the reference individual, and a group of healthy subjects can be used as the reference population.

[0037] The method of comparing the target D-amino acid index with a predetermined criterion is not particularly limited. When a criterion value is used as the criterion, for example, the criterion value is used as the upper limit of the D-amino acid index, and the criterion can be whether the target D-amino acid index is equal to or greater than the criterion value, or whether it exceeds the criterion value. Alternatively, the criterion value is used as the lower limit of the D-amino acid index, and the criterion can be whether the target D-amino acid index is equal to or less than the criterion value, or whether it falls below the criterion value. On the other hand, when a criterion range is used as the criterion, for example, the criterion can be whether the target D-amino acid index is within the criterion range, exceeds the criterion range, or falls below the criterion range. Alternatively, the judgment can be made based on whether the indicator for the target D-amino acid fluctuates over time from outside the judgment criteria range to within the judgment criteria range, fluctuates from within the judgment criteria range to outside the judgment criteria range, remains outside the judgment criteria range, or remains within the judgment criteria range.

[0038] In the method of the present invention, a single judgment reference value or judgment reference range may be used as the judgment criterion, or multiple judgment reference values ​​or judgment reference ranges may be used in combination, or one or more judgment reference values ​​and one or more judgment reference ranges may be used in combination.

[0039] [Method for adjusting viral load and treating or preventing viral infection by controlling indicators related to D-amino acids in a subject (first method of the present invention)] One aspect of the present invention relates to a method for adjusting the amount of virus in a subject, comprising administering to the subject a component for controlling an index related to D-amino acids of the subject (hereinafter, may be appropriately referred to as a "regulator of D-amino acid amount"). The correlation between the amount of virus in a subject and the index related to D-amino acids of the subject is utilized, and the index related to D-amino acids of the subject is controlled using the regulator of D-amino acid amount to adjust the amount of virus in the subject. In one embodiment, the amount of D-amino acids in blood, which is one of the indexes related to D-amino acids, can be increased and the amount of virus in the lungs of the subject can be reduced by administering D-alanine or D-serine, which are regulators of D-amino acid amount, to the subject. The control and adjustment include changing the index related to D-amino acids of the subject toward a target or a predetermined value, and a preset reference range from a subject or a group of subjects in a healthy state, or changing the amount of virus in the subject toward a target or a predetermined value, and a preset reference range from a subject or a group of subjects in a healthy state. Real-time monitoring of a subject's D-amino acid indicators enables the efficient setting of the type, dosage, and administration timing of the D-amino acid amount control agent, which is effective for precise control of D-amino acid indicators and contributes to improving the accuracy of adjusting the viral load in a subject.

[0040] The type of D-amino acid used as an agent for controlling the amount of D-amino acid may be any type as long as it is capable of controlling an indicator related to a specified D-amino acid. However, neutral aliphatic amino acids and glucogenic amino acids related to the energy metabolism and sugar metabolic pathways are preferred, and one type may be used alone or multiple types of amino acids may be used in combination.

[0041] In association with an increase in the viral load in a subject, the subject may exhibit symptoms and pathologies such as fever, headache, sore throat, myalgia, general malaise, chills, gastrointestinal symptoms (diarrhea, etc.), cough, dyspnea, weight change, and death, or these symptoms and pathologies may worsen. The adjustment of the viral load in a subject may be evaluated based on these test values ​​and changes in symptoms and pathologies that can be quantitatively and / or qualitatively determined in clinical practice. As a specific example, when fever or weight loss continues in a viral infection, it can be evaluated that the viral load in a subject is maintained and / or increased, and when fever or weight loss is suppressed by administration of a regulator of D-amino acid load, it can be evaluated that the viral load is decreased. Furthermore, the respective values ​​may be calculated, estimated, and evaluated using correlations, regression equations, etc., with the parameters consisting of the viral load in a subject, indicators related to D-amino acids, related clinical test values, symptoms, and pathologies as objective variables and / or explanatory variables. When adjusting the viral load in a subject corresponds to the treatment and / or prevention of a viral infection, reducing the viral load in a subject and / or not allowing it to increase, and / or suppressing the rate of increase can be referred to as prevention before the onset of viral infection and / or treatment after the onset of viral infection.

[0042] The first method of the present invention provides a completely new approach to the treatment or prevention of viral infections, focusing on the correlation between the viral load in a subject and an index related to D-amino acids (e.g., blood D-amino acid level), by administering a component for controlling and regulating them to the subject. That is, by controlling the index related to D-amino acids in a subject by any means, it becomes possible to regulate the viral load in the subject.

[0043] The component for controlling the D-amino acid-related indicators of a subject (D-amino acid amount control agent) is not limited, and may be, for example, a composition such as a drug or food that can increase or decrease the amount of D-amino acids inside and outside cells, tissues, organs, and body fluids by administering D-amino acids from the outside, adding or removing D-amino acids to food, or adding or removing D-amino acids to a culture medium. For example, the D-amino acid concentration in blood, cells, and tissues can be increased by drinking an aqueous solution containing D-amino acids (Non-Patent Document 6), and the D-amino acid concentration in blood can be decreased by ingesting food from which D-amino acids have been removed. For example, D-serine is administered orally or intravenously to the kidney, and thus the amount of D-serine in the kidney can be controlled by utilizing the fact that D-serine is directed to the kidney (Non-Patent Document 7). In addition, the amount of another D-amino acid may be controlled by changing the metabolic system by administering any D-amino acid. As a specific example, the amount of D-serine in the blood of a subject can be increased by administering D-alanine to the subject. The D-amino acid used here may contain a modified or derivative D-amino acid, or a pharma- ceutically acceptable salt thereof, as long as it can increase or decrease the amount of the D-amino acid in the subject. It may further contain a therapeutic agent for viral infection in the subject. The drug of the present invention can be formulated by selecting a dosage form suitable for its administration route. For oral administration, tablets, capsules, liquids, powders, granules, chewable agents, etc., and for parenteral administration, injections, powders, infusions, etc., can be designed. In addition, these preparations may contain various adjuvants used in medicine, i.e., carriers and other adjuvants, such as stabilizers, preservatives, soothing agents, flavorings, corrigents, fragrances, emulsifiers, fillers, pH adjusters, etc., and can be blended within a range that does not impair the effects of the drug (composition) of the present invention. The optical purity of drugs and D-amino acids as raw materials is preferably 50% or more, and more preferably 90% or more, but is not limited and any optical purity can be selected as long as the effect is observed.However, the amount of D-amino acid as an active ingredient must be designed so as to be capable of controlling the indicators related to the D-amino acid.

[0044] The component for controlling the indicators related to the target D-amino acid (the regulator of the D-amino acid amount) may be one that controls the amount of the target D-amino acid by utilizing any physiological mechanism. In one embodiment, the amount of the target D-amino acid can be controlled by the expression (promotion, inhibition, etc.) and activity (activation, inhibition, stimulation, etc.) of proteins related to the absorption, transport, distribution, metabolism (synthesis and decomposition), excretion, action, etc. of D-amino acids, such as enzymes (D-amino acid oxidase (DAO), D-aspartate oxidase (DDO), serine isomerase (SRR), etc.), transporters, and receptors (N-methyl-D-aspartate glutamate receptors (NMDAR), etc.). DAO inhibitors increase the amount of D-amino acids at the site of action by suppressing the oxidation of D-amino acids, and inhibitors and activators of D-amino acid transporters increase or decrease the amount of D-amino acids at the transport source and destination. Drugs acting on proteins such as enzymes and transporters may not directly produce an effect, but may indirectly change the amount or action of D-amino acids, for example, by competitive reactions of substrates, agonists, or antagonists, or by actions due to scaffold sharing. Non-Patent Document 8 discloses, without intending to be limiting, that the SMCT family, ASCT family, and the like expressed in the brain and kidney as D-amino acid transporter proteins change the local amount of D-amino acids by agonists / inhibitors. These transporters are affected by cooperation / competition through cotransport substances (e.g., sodium ions) and scaffolds, so that the transport activity of D-amino acids can be controlled by, for example, sodium / glucose cotransporter (e.g., SGLT2) inhibitors. Patent Document 4 also discloses that angiotensin 2 receptor antagonists (ARBs) change the amount of D-amino acids in the blood. For example, it is possible to screen for drugs and candidates that can control indicators related to D-amino acids (D-amino acid amount, etc.) by measuring the amount of D-amino acids in culture media, cells, tissues, and body fluids before and after administration of a drug for treating a viral infection, and evaluating the effect. In such cases, the effect can be evaluated by measuring the amount of D-amino acids in the body fluids, cells, and tissues at the site of action.

[0045] When administering an agent for controlling D-amino acid amount, efficacy may be confirmed and decisions regarding continuation or discontinuation of administration, or the dosage and timing of administration may be determined by temporarily or over time monitoring indicators related to D-amino acids (e.g., blood D-amino acid levels) and / or virus load and / or test values, symptoms, and pathological conditions related to infectious diseases for any sample from the subject.

[0046] By applying the present invention, it is possible to control indicators related to D-amino acids by varying the amount of D-amino acids in the living body of a subject using any physiological mechanism, and as a result, the amount of viruses in the subject is adjusted, and symptoms and pathology of viral infections can be controlled. In one embodiment, the amount of D-amino acids in the living body can be varied by controlling the expression (promotion, inhibition, etc.) and / or activity (activation, inhibition, stimulation, etc.) of proteins related to the absorption, transport, distribution, metabolism (synthesis and / or decomposition), excretion, action, etc. of D-amino acids, or the transporters or receptors of D-amino acids, thereby making it possible to adjust the amount of viruses.

[0047] Therefore, the D-amino acid amount regulator that can be used in the present invention may be one that directly or indirectly promotes gene expression of a protein related to the absorption, transport, distribution, metabolism or excretion of D-amino acids, and may be, for example, the protein or a vector that expresses it, or a factor that promotes the activity upstream of the cascade that promotes the expression of the protein or a vector that expresses it.

[0048] Furthermore, for example, the D-amino acid amount regulator that can be used in the present invention may be one that directly or indirectly suppresses gene expression of a protein associated with the absorption, transport, distribution, metabolism or excretion of D-amino acids, and may be, for example, one selected from a small molecule compound, an aptamer, an antibody, an antibody fragment, as well as an antisense RNA or DNA molecule, an RNAi-inducing nucleic acid, a microRNA (miRNA), a ribozyme, a genome-editing nucleic acid, and an expression vector thereof.

[0049] [Method for estimating viral load in a subject's body (second method of the present invention)] One aspect of the present invention relates to a method for estimating the viral load in a subject's body, the method comprising determining the viral load in the subject's body using an indicator related to a D-amino acid in the subject (suitably abbreviated as the "second method of the present invention").

[0050] By utilizing the correlation between the viral load in a subject and the D-amino acid index of the subject, the viral load of the subject can be estimated and determined from the test value of the D-amino acid index, which is also called a viral load test. As a specific example, if the amount of D-amino acids in the blood (D-amino acid index) is increased, it can be estimated and determined that the viral load of the subject is decreased, and if the amount of D-amino acids in the blood is decreased, it can be estimated and determined that the viral load of the subject is increased. By setting any judgment reference value (clinical judgment value) and judgment reference range for the D-amino acid index regarding the viral load and viral infection, the viral load and viral infection of the subject can be estimated and determined from the test value of the D-amino acid index of the subject. Since the D-amino acid index and the viral load are correlated, the following formula (I): Y=a1·X1+a2·X2+···+an·Xn+b···(I) [In the formula, a1 to an represent constants obtained by the regression analysis, X1 to Xn represent variables of indicators related to D-amino acids selected by the regression analysis, b represents a constant obtained by the regression analysis. is obtained in advance. In one embodiment, the viral load in a subject can be estimated and determined or examined by using the above formula (I).

[0051] In this specification, "regression analysis" refers to a method of estimating an equation showing the relationship between explanatory variables (also referred to as "independent variables") and response variables (also referred to as "dependent variables") by a statistical method, for example, a method of solving the equation by least squares method, moving average method, regression using a kernel, etc. Regression analysis is a well-known technique, and any regression analysis can be adopted in the present invention. The regression used in the regression analysis of the present invention may be linear regression or nonlinear regression (e.g., n-th order polynomial regression analysis). In addition, the regression used in the present invention may be simple regression or multiple regression. In the present invention, an equation for determining the value Y is obtained by regression analysis using an index related to D-amino acids obtained from any subject or subject group (e.g., an index corrected by D, L-amino acid amount, and if necessary, creatinine amount, etc.) as an explanatory variable and the viral load in the subject as a response variable. Depending on the regression analysis applied, it can be expressed as a variable of a power that is a linear function, a quadratic function, a cubic function, or an n-th order function (n is a natural number).

[0052] The indicators relating to the viral load and any D-amino acid used in the regression analysis of formula (I) are preferably data with a correlation coefficient R of ≧0.5, more preferably data with a correlation coefficient R of ≧0.6, even more preferably data with a correlation coefficient R of ≧0.7, and most preferably data with a correlation coefficient R of ≧0.8.

[0053] [Method for predicting the prognosis of a viral infection in a subject (third method of the present invention)] One aspect of the present invention relates to a method for predicting the prognosis of a viral infection in a subject, the method comprising determining the prognosis of a viral infection in the subject using an indicator for a D-amino acid in the subject (suitably abbreviated as the "third method of the present invention").

[0054] In this specification, "prediction of prognosis" refers to predicting or estimating the subsequent course and outlook for a disease or treatment. When expressing a prediction of prognosis, units such as hours, days, weeks, months, and years may be used, and Kaplan-Meier analysis may be used as a representative prognosis prediction tool. Prognosis includes functional prognosis of organs, etc. (pneumonia, renal failure, etc.), life prognosis of estimated death, and prognosis of symptoms and pathology such as fever, headache, sore throat, muscle pain, general fatigue, chills, gastrointestinal symptoms (diarrhea, etc.), cough, dyspnea, weight, viral load, and recurrence, and can be expressed quantitatively or qualitatively (e.g., worsening, aggravation, improvement, etc.) using the variables (parameters) and units of each evaluation item, and prediction of prognosis is important information for selecting a treatment method. In one aspect, by comparing a subject's D-amino acid indicator with a reference value (clinical judgment value) or reference range determined from the amount of D-amino acids in the blood of a subject or a group of subjects having a viral infection with prognosis information, information on the prognosis of the viral infection in the subject can be provided.

[0055] According to one embodiment, the method of the present invention can provide information to assist in the selection of a treatment for a viral infection using an index related to a D-amino acid in a subject. The correlation between the amount of D-amino acid in the blood of a subject and the amount of virus in the subject in relation to the amount of virus in the subject and the response or change of the viral infection to the viral infection or treatment is utilized, and the test value of the index related to the D-amino acid in the subject is compared with a predetermined prognostic criterion (reference range or clinical judgment value) to select the optimal treatment from drug therapy, oxygen therapy (nasal cannula, HFNC, CPAP, NPPV, etc., respiratory failure), surgical treatment, artificial respiratory management (artificial ventilator, etc.), ECMO (extracorporeal membrane oxygenation), blood purification therapy (dialysis, plasma exchange, apheresis, etc.), thrombosis countermeasures, renal disorder countermeasures, symptomatic treatment (antipyretic, antitussive, etc.), dietary therapy, etc., or to assist in the determination of the priority. Even during the treatment stage, the index related to the D-amino acid in the subject is monitored in real time to predict the prognosis, thereby providing information to assist in the selection of the next stage of treatment. Furthermore, in the event of a pandemic or bioterrorism, prognostic predictions and assessments based on D-amino acid indicators can be used for triage, which determines and selects the priority of medical care and treatment for the target, and for risk assessment in each pandemic phase, including the alert, pandemic, and transitional stages. Antiviral drugs, which are mainly used in drug therapy, are drugs that have effects such as inhibiting the adsorption and invasion of viruses into host cells, inhibiting intracellular uncoating, nucleic acid synthesis, protein synthesis, and extracellular release, and oxygen therapy, the use of artificial ventilators, and ECMO are used for severely ill subjects.

[0056] According to one embodiment, the method of the present invention can provide information to select an optimal drug such as an antiviral drug as a means of treating a viral infection, or to assist in determining the priority of the drug, based on the prediction or judgment of the prognosis using an index related to the D-amino acid of a subject. As a specific example, the index related to the D-amino acid of a subject can be used to set a judgment criterion (reference range or clinical judgment value) for the effect, side effects, and adverse reactions of a given drug in advance, and to compare the judgment criterion with the test value of the subject to consider whether or not to administer the drug. According to one embodiment, the index related to the D-amino acid of a subject can be used to predict and judge the effect, side effects, and adverse reactions after drug administration, and to provide information to assist in determining whether or not to continue or stop administration, or the dosage and timing of administration. Furthermore, the index related to the D-amino acid of a subject can be used to provide information to assist in screening and / or determining a means for adjusting the value of an index related to the D-amino acid of a subject.

[0057] Specific examples of drugs that can be used as a means of treating viral infections include, but are not limited to, the following: Drugs for treating viral infections include neuraminidase inhibitors (oseltamivir, zanamivir, peramivir, laninamivir, etc.), M2 protein inhibitors (amantadine, etc.), RNA polymerase inhibitors (favipiravir, molnupiravir, etc.), cap-dependent endonuclease inhibitors (baloxavir, marboxil, etc.), anti-herpes virus drugs (acyclovir, valacyclovir, famciclovir, amenamevir, etc.), anti-cytomegalovirus drugs (anti-mycobacterial drugs, anti ... Antiviral drugs (ganciclovir, foscarnet, valganciclovir, etc.), anti-hepatitis B virus drugs (entecavir, tenofovir, lamivudine, adefovir, etc.), anti-hepatitis C virus drugs (sofosbuvir, ribavirin, redibasvir, etc.), nucleoside reverse transcriptase inhibitors (tenofovir, emtricitabine, etc.), non-nucleoside reverse transcriptase inhibitors (rilpipridine, efavirenz, etc.), integrase inhibitors (elvitegravir, dolutegravir, vir, etc.), protease inhibitors (darunavir, ritonavir, etc.), CCR5 inhibitors (maraviroc, etc.), antibiotics, herbal medicines (kakkonto, shoseiryuto, maoto, etc.), acetaminophen, NSAIDs, antihistamines, immunosuppressants (steroids, baricitinib, etc.), neutralizing antibody drugs (remdesivir, casirivimab, imdevimab, sotrovimab, etc.), Janus kinase inhibitors (baricitinib), RNA polymerase inhibitors (remdesivir), biologically active peptides Antibodies that may be used include peptides (adrenomedullin, etc.), GM-CSF preparations (sargramostim, etc.), anticoagulants (heparin, etc.), antiparasitic drugs (ivermectin, etc.), humanized anti-human IL-6 receptor monoclonal antibodies (tocilizumab, sarilumab, etc.), serine protease inhibitors (nafamostat, etc.), vaccines (DNA vaccines, RNA vaccines, attenuated vaccines, adenovirus vector vaccines, etc.), oral fluid replacement, infusions, blood transfusions, etc.

[0058] ·others The method of the present invention can be used to provide various other information. For example, according to one embodiment, the method of the present invention can provide information on screening for viral infection and / or viral infection and diagnosis of the pathology based on the aforementioned information and judgment results on the viral load and prognosis performed based on the test value of an indicator related to the D-amino acid of the subject. In addition, according to one embodiment, the method of the present invention can provide information on screening of efficacy, side effects, and adverse reactions in drug development, judgment of clinical trials, alternative endpoints, etc., based on the information and judgment results on the viral load and prognosis performed based on the test value of an indicator related to the D-amino acid of the subject. The multiple pieces of information may be provided individually or simultaneously depending on the purpose.

[0059] [System for Providing Information on Viral Load and / or Prognosis of Viral Infection (System of the Present Invention)] One aspect of the present invention relates to a system (suitably abbreviated as the "system of the present invention") for predicting the prognosis of a viral infection in a subject and / or estimating and / or determining the amount of virus in the subject's body by carrying out the second method of the present invention and / or the third method of the present invention.

[0060] FIG. 20 is a block diagram showing a schematic example of the configuration of the system of the present invention. However, the configuration shown in FIG. 20 is merely an example, and the configuration of the system of the present invention is not limited thereto. The system 10 shown in FIG. 20 includes a memory unit 11, an input unit 12, an analysis and measurement unit 13, a data processing unit 14, and an output unit 15. The memory unit 11 is configured to store various information including criteria for the prognosis of the viral load and / or viral infection. The input unit 12 is configured to input various information including information from the subject. The analysis and measurement unit 13 is configured to perform various analysis and measurement such as obtaining an index for the D-amino acid of the subject by analyzing and measuring the information from the subject. The data processing unit 14 is configured to perform various calculation processes such as performing a judgment on the viral load and / or prognosis of the viral infection of the subject by processing the index for the D-amino acid of the subject based on the criteria. The output unit 15 is configured to output various information including information on the prognosis of the viral load and / or viral infection.

[0061] Specifically, the storage unit 11 is configured with, for example, a memory device such as a RAM, a ROM, or a flash memory, a fixed disk device such as a hard disk drive, or a portable storage device such as a flexible disk or an optical disk. The storage unit 11 is configured to store various information such as data and instructions input from the input unit 12, data measured by the analysis and measurement unit 13, the results of arithmetic processing performed by the data processing unit 14, and computer programs and databases used for various processes of the information processing device that realizes the sample analysis system 10. The computer program may be installed from a computer-readable recording medium such as a CD-ROM or a DVD-ROM, or via the Internet. The computer program is installed in the storage unit 11 using a known setup program or the like.

[0062] The input unit 12 is an interface with the outside of the sample analysis system 10, and also includes an operation unit such as a keyboard and a mouse. This allows the input unit 12 to input data measured by the analysis and measurement unit 13, instructions for arithmetic processing to be performed by the data processing unit 14, and the like. Furthermore, when the analysis and measurement unit 13 is located externally, the input unit 12 may include an interface unit that can input the measured data, etc. via a network or a storage medium, separate from the operation unit.

[0063] The analysis and measurement unit 13 is configured to obtain an index related to the D-amino acid of the subject by analyzing and measuring information from the subject. For example, the analysis and measurement unit 13 can be configured to measure at least the amount of D-amino acid from a blood sample of the subject. Therefore, the analysis and measurement unit 13 may have a configuration that enables separation and measurement of D- and L-isomers of amino acids. The amino acids may be configured to analyze one by one, or may be configured to analyze some or all types of amino acids together. The analysis and measurement unit 13 is not intended to be limited to the following, but may be, for example, a chiral chromatography system equipped with a sample introduction unit, an optical resolution column, and a detection unit, preferably a high performance liquid chromatography system. From the viewpoint of detecting only the amount of a specific amino acid, quantification may be performed by an enzyme method or an immunological method. The analysis and measurement unit 13 may be configured separately from the evaluation system of the test value, and the measured data, etc. may be input via the input unit 12 using a network or a storage medium.

[0064] The data processing unit 14 can select information on the viral load and / or prognosis of a viral infection in a subject by comparing the indicator for D-amino acids measured by the analysis and measurement unit 13 with the criteria stored in the storage unit. The indicator for D-amino acids may be a formula or value corrected by the amount of a substance in the subject's body (e.g., the amount of D-amino acids or an index of a test), or may be a formula or value corrected by physiological fluctuation factors such as age, sex, BMI, etc. The data processing unit 14 executes various arithmetic processing on the data measured by the analysis and measurement unit 13 and stored in the storage unit 11 according to a program stored in the storage unit. The arithmetic processing is performed by a CPU included in the data processing unit. This CPU includes a functional module that controls the analysis and measurement unit 13, the input unit 12, the storage unit 11, and the output unit 15, and can perform various controls. Each of these units may be composed of an independent integrated circuit, microprocessor, software, etc.

[0065] The output unit 15 is configured to output information on the viral load and / or prognosis of a viral infection in a subject, which is a result of arithmetic processing performed by the data processing unit. The output unit 15 may be an output means such as a display device such as a liquid crystal display that directly displays the results of arithmetic processing, or a printer, or may be an interface unit for outputting to an external storage device or via a network.

[0066] FIG. 21 is a flow chart showing an example of the processing by the system of the present invention (the method of the present invention). However, the processing shown in FIG. 21 is merely an example, and the processing by the system of the present invention is not limited thereto. First, the criteria for the prognosis of the viral load and / or viral infection are read from the input unit 12 and stored in the memory unit 11 (step S1). Next, information on the D-amino acid of the subject is read from the input unit 12 and stored in the memory unit 11 (step S2). Next, the analysis and measurement unit 13 analyzes and measures the information from the subject stored in the memory unit 11 to obtain an index for the D-amino acid of the subject (step S3). Next, the data processing unit 14 processes the index for the D-amino acid of the subject obtained by the analysis and measurement unit 13 based on the criteria stored in the memory unit 11 to perform a judgment on the viral load and / or the prognosis of the viral infection of the subject (step S4). Next, the determination results of the subject's viral load and / or prognosis of the viral infection by the data processing unit 14 are stored in the memory unit 11 as information regarding the subject's viral load and / or prognosis of the viral infection, and output from the output unit 15 (step S5).

[0067] [others] Although the present invention has been described in detail above with reference to specific embodiments, the present invention is not limited to these embodiments. Those skilled in the art can derive various other inventive concepts from the above description, and all of these are included in the technical scope of the present invention.

[0068] For example, it is possible to provide a computer program (appropriately referred to as the "program of the present invention") for implementing the system of the present invention using a general-purpose information processing device. Specifically, the program of the present invention can be configured as a program including computer instructions that can cause the information processing device and external devices such as an input / output interface and an analyzer connected thereto to function as a sample analysis system 10 including a memory unit 11, an input unit 12, an analysis and measurement unit 13, a data processing unit 14, and an output unit 15, for example, as shown in FIG. 20, by installing and executing the program of the present invention on a general-purpose information processing device. Such a program of the present invention can be realized by knowledge of computer programming well known to those skilled in the art. Such a program of the present invention and a recording medium such as a CD-ROM including the program are also included in the technical scope of the present invention.

[0069] Since the present invention can be carried out by comparing the test value of an indicator related to D-amino acids in a subject with a predetermined judgment standard (reference range or clinical judgment value), it can be carried out by persons other than physicians, such as clinical testing, health examination, and data processing companies, or by analysis and analysis systems and analysis and analysis programs, without the need for judgment by a physician, and thus does not fall under so-called medical procedures, etc. In other words, since the present invention provides a judgment result for the detection and / or stage classification of a viral infection and / or viral infection in a subject based on an indicator related to the D-amino acids in the subject, it does not replace medical procedures such as diagnosis and treatment by a physician, but has extremely high technical usefulness as a preliminary or auxiliary method for improving the accuracy and efficiency of such diagnosis and treatment. EXAMPLES

[0070] The present invention will be described in more detail below with reference to examples, but these examples are merely illustrative and are not intended to limit the present invention in any way. Those skilled in the art can easily modify and alter the present invention based on the description in this specification, and all such modifications and alterations are within the technical scope of the present invention.

[0071] In the examples, the symbols have the following meanings: D-AA: D-amino acid L-AA: L-amino acid BD-AA: D-amino acid concentration in blood (serum or plasma) (nmol / mL or μM) BL-AA: L-amino acid concentration in blood (serum or plasma) (nmol / mL or μM) B%D-AA:(BD-AA / BD-AA+BL-AA)×100(%) Mock: Non-infected mice (control group) IAV: Influenza virus (influenza A virus)-infected mice SCV: coronavirus (SARS-CoV-2) infected mice +D-AA: D-amino acid administration group

[0072] All experiments were approved by the Animal Committee of the National Institutes of Biomedical Innovation, Health and Nutrition and conducted in accordance with the guidelines of the Animal Protection and Management Act of Japan.

[0073] [Example 1: Influenza model mouse test] 1 is a schematic diagram showing the experimental protocol for administering D-AA to IAV and Mock (+D-AA) in Example 1. C57BL6 mice (SLC, Tokyo, Japan) bred in a specific pathogen control facility were used, and in order to increase the amount of virus in the mice bodies in a short period of time, 10 L of water containing 50 times the TCID50 (median tissue culture infectious dose, 50% infectious dose) of H1N1 influenza A / Puerto Rico / 8 / 34 (PR8 influenza virus strain (ATCC, Manassas, USA) was intranasally administered to anesthetized 4-week-old mice to infect them. After infection, the weights of the mice in each group were measured and blood samples were taken according to a predetermined schedule, and chiral amino acids (D-amino acids and L-amino acids) in the plasma were quantitatively analyzed by 2D-HPLC.

[0074] 2 is a graph showing the rate of change in body weight in each of the Mock, Mock+D-Ala, IAV, and IAV+D-Ala groups (n=3-10) in Example 1. The values ​​in the graph indicate the number of mice whose body weight was measured at each time point. The virus-infected mice lost weight, but the rate of weight loss was suppressed in the IAV+D-Ala group (*P<0.05), indicating that administration of D-Ala (a regulator of D-amino acid amount) resists and protects against viral infection and increases in viral load.

[0075] 3A is a graph showing the results of a viral plaque quantification assay of lung tissue 5 days after D-Ala administration in each of the Mock, IAV, and IAV+D-Ala groups (n=3 to 7) in Example 1. The amount of virus in the infected body increased, but the increase in the amount of virus in the IAV+D-Ala group was suppressed compared to the IAV group, and the amount of virus in the body was adjusted by controlling BD-Ala (an indicator for D-amino acids) through administration of D-Ala (a regulator of D-amino acid amount).

[0076] 3B is a graph analyzing the correlation between BD-Ala and the viral load in the IAV+D-Ala group in Example 1. BD-Ala and the viral load have a negative correlation, and the viral load can be decreased by increasing or controlling the BD-Ala of a subject to a high level, or the viral load can be increased by decreasing or controlling the BD-Ala of a subject to a low level. In the regression equation obtained from these data: Y (viral load) = -96.5 [BD-Ala] + 9110, the correlation coefficient R = 0.627, and the viral load in the body can be estimated or determined by measuring BD-Ala and substituting it into the regression equation.

[0077] FIG. 4 shows survival curves by Kaplan-Meier analysis with death as the endpoint for each of the Mock, Mock+D-Ala, IAV, and IAV+D-Ala groups (n=3-10) in Example 1. Aggravation accompanied by an increase in the amount of virus in the body reduced the survival rate of influenza virus-infected mice, but the mortality rate was suppressed by administration of D-Ala, and the life prognosis could be changed by controlling the amount of D-amino acids in the mouse blood with a regulator of D-amino acid amount and adjusting the amount of virus in the body. In addition, it can be predicted that the prognosis will improve when the amount of D-Ala in the body increases, and the selection, dosage, and administration timing of the regulator of D-amino acid amount can be appropriately determined.

[0078] FIG. 5 is a graph showing BD-Ala, BD-Asn, BD-Pro, and BD-Ser in two groups (-: group whose body weight was maintained at 80% or more, +: group whose body weight was reduced by 20% or more) classified based on a body weight maintenance rate of 80% (body weight reduction rate of 20%) for the IAV+D-Ala group (n=9) in Example 1. The - group maintained a higher level of BD-AA than the + group, and the body weight change, which is a symptom associated with an increase in the amount of virus, was adjusted by controlling the amount of D-amino acid in the blood through administration of D-Ala (a regulator of the amount of D-amino acid). In addition, BD-AA can be estimated from the degree of weight reduction.

[0079] FIG. 6-1 and FIG. 6-2 are graphs showing the indices of D-amino acids 48 to 72 hours after infection in each of the Mock(-) and IAV(+) groups in Example 1. Specifically, FIG. 6-1 is a graph showing BD-Ala, BD-Ser, BD-Asn, and BD-Pro, and FIG. 6-2 is a graph showing B%D-Ala, B%D-Ser, B%D-Asn, and B%D-Pro. BD-AA and B%D-AA, which are indices of D-amino acids, are decreased as the amount of virus in the IAV(+) group increases compared to the Mock(-) group, which is the reference population group. Since the indices of D-amino acids may vary due to viral infection, it is found that it is useful to appropriately monitor BD-AA in order to control the indices.

[0080] Fig. 7 is a graph showing the rate of body weight change (%) after infection in each of the Mock(-) and IAV(+) groups in Example 1. The data in Figs. 6 and 7 show that there is a correlation between an increase in the amount of virus in the body, symptoms of viral infection (weight loss), and an index related to D-amino acids (BD-AA).

[0081] 8 shows survival curves by Kaplan-Meier analysis with death as the endpoint for each of the IAV (Vehicle), IAV+D-Ser, and IAV+D-Ala groups in Example 1. Aggravation accompanied by an increase in the amount of virus in the body reduced the survival rate of influenza virus-infected mice, but administration of D-Ser and D-Ala suppressed the mortality rate, indicating that the regulator of D-amino acid content regulates the amount of virus in the body and changes the prognosis. It can also be predicted that the prognosis will improve if the amount of D-Ser and D-Ala in the body is increased.

[0082] 9 is a graph showing the rate of change in body weight in each of the IAV (Vehicle), IAV+D-Ser, and IAV+D-Ala groups in Example 1. Although the body weight of each virus-infected group decreased, the rate of weight loss was suppressed in the IAV+D-Ser and IAV+D-Ala groups, indicating that administration of D-amino acid amount regulators, D-Ser or D-Ala, resisted and protected against virus infection and an increase in the viral load.

[0083] [Example 2: COVID-19 model mouse test] Figure 10 is a schematic diagram showing the protocol of the coronavirus-infected mouse experiment in Example 2. Using CAG-hACE2 mice, which are highly susceptible to SARS-CoV-2 and were developed by the National Institutes of Biomedical Innovation, Health and Nutrition, 2 × 10 TCID50 of SARS-CoV-2 was administered. 2 ~10 4 Anesthetized 8- to 12-week-old mice were infected with a dose equivalent to 100 mg of the virus through the bronchus to create a coronavirus infection model mouse (Non-Patent Document 9).

[0084] 11-1 and 11-2 are graphs showing the indices related to D-amino acids in the SCV group in Example 2. Specifically, FIG. 11-1 is a graph showing the time-dependent changes in BD-Ala, BD-Ser, BD-Pro, and BD-Asn, and FIG. 11-2 is a graph showing the time-dependent changes in B%D-Ala, B%D-Ser, B%D-Pro, and B%D-Asn. Immediately after SARS-CoV-2 infection, both BD-AA and B%D-AA are observed to increase due to the supply of D-AA from the body, but they decrease as the disease worsens due to an increase in the amount of virus, indicating that the supply of D-AA is insufficient compared to a healthy state. As such, since the indices related to D-amino acids can fluctuate due to viral infection, it is useful to appropriately monitor BD-AA and B%D-AA in order to control the indices.

[0085] 12 is a schematic diagram showing the experimental schedule for administering D-Ala to coronavirus-infected mice in Example 2. A predetermined dose of D-Ala was administered intraperitoneally twice a day to 8-12 week-old male and female CAG-hACE2 mice starting two days before the experiment. The mice were then infected with SARS-CoV-2 via the respiratory tract.

[0086] 13 is a graph showing the rate of change in body weight in each of the SCV (saline) and SCV+D-Ala (dosage amounts of 0.04 g, 0.2 g, and 1 g / kg body weight) groups in Example 2. It can be seen that each of the SCV+D-Ala groups suppressed weight loss, a symptom caused by viral increase, compared to the SCV group.

[0087] FIG. 14 shows survival curves by Kaplan-Meier analysis with death as the endpoint for each of the SCV (Vehicle) and SCV+D-Ala groups in Example 2. Aggravation accompanied by an increase in the amount of virus in the body reduces the survival rate of coronavirus-infected mice, but the mortality rate was suppressed by administration of D-Ala. It was shown that the amount of virus was adjusted and the life prognosis changed by controlling the amount of D-amino acid in the mouse body with a regulator of the amount of D-amino acid. It can also be predicted that the prognosis will improve if the amount of D-Ala in the body is increased.

[0088] Figures 15-1 and 15-2 are graphs showing the indices related to D-amino acids for the SCV (Vehicle) and SCV+D-Ala groups in Example 2. Specifically, Figure 15-1 is a graph showing the time course of BD-Ala, BD-Ser, BD-Asn, and BD-Pro, and Figure 15-2 is a graph showing the time course of B%D-Ala, B%D-Ser, B%D-Asn, and B%D-Pro. By administering D-Ala (a regulator of D-amino acid amount), an increase in each BD-AA and B%D-AA was observed, indicating that each BD-AA and B%D-AA, which are indices related to D-amino acids, can be controlled.

[0089] Figures 16-1 and 16-2 are graphs showing D-amino acid-related indexes for two groups (-: group whose body weight was maintained at 90% or more, +: group whose body weight was reduced by 10% or more) classified based on a body weight maintenance rate of 90% (body weight reduction rate of 10%) in the SCV+D-Ala group in Example 2. Specifically, Figure 16-1 is a graph showing BD-Ala, BD-Ser, BD-Asn, and BD-Pro, and Figure 16-2 is a graph showing B%D-Ala, B%D-Ser, B%D-Asn, and B%D-Pro. The - group maintained higher BD-AA and B%D than the + group, indicating that the change in body weight associated with an increase in the amount of virus is adjusted by controlling the amount of D-amino acids in blood with a regulator of the amount of D-amino acids. In addition, BD-AA and B%D can be estimated from the degree of weight reduction.

[0090] 17 is a graph showing the rate of weight change over time for the SCV (Vehicle) and SCV+D-Ala groups in Example 2. The SCV+D-Ala group had a smaller rate of weight loss compared to the SCV (Vehicle), indicating that administration of D-Ala (a regulator of D-amino acid amount) alleviated the symptoms of viral infection.

[0091] 18 shows survival curves by Kaplan-Meier analysis with weight loss and death as composite endpoints for the SCV (Vehicle) and SCV+D-Ala groups in Example 2. Aggravation due to an increase in the amount of virus in the body reduces the survival rate of coronavirus-infected mice, but weight loss and mortality are suppressed by administration of D-Ala, indicating that a regulator of D-amino acid content adjusts the amount of virus in the body and changes the prognosis. It can also be predicted that the prognosis will improve if the amount of D-Ala in the body increases.

[0092] 19 shows survival curves by Kaplan-Meier analysis with death as the endpoint for each group classified into high (≧4.72 μM) and low (<4.72 μM) BD-Ala levels in the SCV+D-Ala group in Example 2. When the prognostic criterion value for in vivo BD-Ala is set at 4.72 μM, it can be predicted that the high BD-Ala group will have a better prognosis than the low BD-Ala group.

[0093] All of the survival rate curves described above in Example 2 show that administration of D-Ala (a regulator of D-amino acid levels) had a preventive effect on alleviating symptoms of viral infections. [Industrial Applicability]

[0094] The present invention is extremely useful in the fields of diagnosis and treatment of viral infection and / or viral infectious diseases.

Claims

1. 1. A method for modulating viral load in a subject, comprising: A method comprising administering to a subject a composition for controlling an index related to D-amino acids in the subject.

2. The method described in claim 1, wherein the D-amino acid is one or more D-amino acids selected from the group consisting of D-proline, D-serine, D-alanine, and D-asparagine.

3. The method according to claim 1 or 2, wherein the index for D-amino acids is a measured value for D-amino acids in blood, or a corrected value or correction formula thereof.

4. The method according to claim 1 or 2, wherein the component for controlling the D-amino acid-related indicators of the subject is a D-amino acid.

5. 3. The method of claim 1 or 2, wherein the virus is a virus belonging to a family selected from orthomyxoviruses, coronaviruses, paramyxoviruses, rhabdoviruses, arenaviruses, bunyaviruses, filoviruses, retroviruses, togaviruses, flaviviruses, picornaviruses, astroviruses, caliciviruses, reoviruses, parvoviruses, adenoviruses, papillomaviruses, polyomaviruses, herpesviruses, hepadnaviruses, and poxviruses.

6. The method of claim 1 or 2, further comprising treating or preventing a viral infection in the subject by controlling the subject's D-amino acid indicators that have been altered by the viral infection.

7. The method according to claim 6, wherein the change in the subject's D-amino acid indicator due to viral infection is a change that indicates a decrease in the amount of D-amino acid in the blood.

8. The method according to claim 6, wherein the control of the D-amino acid-related indicators in the subject is by supplementing blood D-amino acids that have decreased due to viral infection.

9. 1. A method for estimating viral load in a subject, comprising: The method comprises determining the viral load in the subject using an index related to D-amino acids in the subject.

10. The method of claim 9, wherein the D-amino acid is one or more D-amino acids selected from the group consisting of D-proline, D-serine, D-alanine, and D-asparagine.

11. The method of claim 9 or 10, wherein the viral load in the subject is determined to be increased when the index for D-amino acids indicates that the amount of D-amino acids in the blood is reduced or is equal to or lower than a predetermined threshold.

12. The method according to claim 9 or 10, wherein the increase in the viral load in the subject is determined to have stopped or is decreasing when the index related to the D-amino acid shows that the decrease in the amount of D-amino acid in the blood has stopped or is increasing.

13. The method according to claim 9 or 10, further comprising predicting the prognosis of the subject's viral infection based on the determination result of the viral load in the subject.

14. The method of claim 13, wherein the prognosis of the subject is determined to be a worsening or severe viral infection when the index for D-amino acids indicates that the amount of D-amino acids in the blood is reduced or is equal to or lower than a predetermined threshold.

15. The method of claim 13, wherein the prognosis of the subject is determined to be improvement of the viral infection when the index for D-amino acids shows that the decrease in the amount of D-amino acids in the blood has stopped or is increasing.

16. The method of claim 13, wherein the viral load in the subject is determined to have decreased to a curative level when the index related to the D-amino acid indicates that the amount of D-amino acid in the blood has returned to within the reference range.

17. The method according to claim 13, wherein the prognosis for the subject is determined to be recovery from the viral infection when the index for D-amino acids indicates that the amount of D-amino acids in the blood has returned to within the reference range.

18. The method according to claim 9 or 10, wherein the index for D-amino acids is a measured value for D-amino acids in blood, or a corrected value or correction formula thereof.

19. 11. The method of claim 9 or 10, wherein the virus is a virus belonging to a family selected from orthomyxoviruses, coronaviruses, paramyxoviruses, rhabdoviruses, arenaviruses, bunyaviruses, filoviruses, retroviruses, togaviruses, flaviviruses, picornaviruses, astroviruses, caliciviruses, reoviruses, parvoviruses, adenoviruses, papillomaviruses, polyomaviruses, herpesviruses, hepadnaviruses, and poxviruses.

20. 1. A composition for modulating viral load in a subject, comprising: A composition comprising components for adjusting the D-amino acid index of the subject.

21. The composition described in claim 20, wherein the D-amino acid is one or more D-amino acids selected from the group consisting of D-proline, D-serine, D-alanine, and D-asparagine.

22. The composition according to claim 20 or 21, wherein the indicator for D-amino acids is a measured value for D-amino acids in blood, or a corrected value or correction formula thereof.

23. The composition according to claim 20 or 21, wherein the component for adjusting the D-amino acid-related index of the subject is a D-amino acid.

24. 22. The composition of claim 20 or 21, wherein the virus is a virus belonging to a family selected from orthomyxoviruses, coronaviruses, paramyxoviruses, rhabdoviruses, arenaviruses, bunyaviruses, filoviruses, retroviruses, togaviruses, flaviviruses, picornaviruses, astroviruses, caliciviruses, reoviruses, parvoviruses, adenoviruses, papillomaviruses, polyomaviruses, herpesviruses, hepadnaviruses, and poxviruses.

25. The composition according to claim 20 or 21, for treating or preventing a viral infection in a subject by adjusting the D-amino acid indicators of the subject that fluctuate due to the viral infection.

26. The composition according to claim 25, wherein the change in the subject's D-amino acid indicator due to viral infection is a change that indicates a decrease in the amount of D-amino acid in the blood.

27. The composition according to claim 25, wherein the adjustment of the subject's D-amino acid indicators is by supplementing D-amino acids in the blood that have decreased due to a viral infection.

28. A system for carrying out the method according to claim 9 or 10, comprising: The system includes an input unit, an analysis and measurement unit, a memory unit, a data processing unit, and an output unit; The input unit inputs information from a subject, the analyzing and measuring unit analyzes and measures the information from the subject inputted via the input unit to obtain an index related to the D-amino acid of the subject; the storage unit stores a determination value regarding a virus infection and / or a viral infection disease, the data processing unit processes the indicators of the subject acquired by the analysis and measurement unit based on the determination values ​​stored in the storage unit, thereby determining the amount of virus in the subject and / or the prognosis of the subject's viral infection; The output unit outputs the result of the determination by the data processing unit as information regarding the amount of virus in the subject and / or the prognosis of the viral infection in the subject. The system is configured as follows:

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