Methods and compositions for impairing multiplication of HIV-1

a technology of compositions and compositions, applied in the field of methods and compositions for impairing the multiplication of hiv1, can solve the problems of nullifying the proposed mechanism of action for therapeutic benefit in hiv infection, affecting the clinical effect of the infection, and causing serious side effects in some patients, so as to reduce the viral level of hiv-1, impair the multiplication of the virus, and reduce the viral multiplication

Inactive Publication Date: 2006-11-16
THYMON
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Unfortunately, however, this type of treatment is associated with serious side effects in some patients.
However, the specification also shows that these reagents do not block uptake of functional Tat by cells (see Example 9 in WO92 / 14755), thus nullifying the proposed mechanism of action for therapeutic benefit in HIV infection.

Method used

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  • Methods and compositions for impairing multiplication of HIV-1
  • Methods and compositions for impairing multiplication of HIV-1
  • Methods and compositions for impairing multiplication of HIV-1

Examples

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example 1

Immunological Studies on Minimal Tat Protein Amino Acid Sequences Necessary for Binding to Antibody for Epitope I in HIV-1 Tat Protein

[0151] A peptide corresponding to amino acids 4-16 of SEQ ID NO: 1 illustrated in FIG. 1 was synthesized as described below. This sequence is among the most frequent sequence representation at these positions in 31 Tat protein sequences of the common B subtype reported in the NIAID HIV database. This sequence was chosen as a putative immunogen, named Epitope I.

[0152] A. Peptide Synthesis—Immunizing Peptides

[0153] The amino acid sequence of this immunogen -Val-Asp-Pro-Arg-Leu-Glu-Pro-Trp-Lys-His-Pro-Gly-Ser- (SEQ ID NO: 28) was synthesized by solid phase methodology on polypropylene pegs according to the methods of H. M. Geysen et al., J. Immunol. Meth., 102:259 (1987), with an N-terminal cysteinyl being incorporated to facilitate coupling to a carrier protein. The N-terminus was left as a free amine and the C-terminus was amidated in the immunizing...

example 2

Sequence Variations in Epitope I of HIV-1 Tat Protein and Immunological Cross-Reactivities of Antiserums to These Sequences

[0174] Variations in the sequence of Tat protein AA 5-10 of SEQ ID NO: 1 were analyzed in sequences available in HUMAN RETROVIRUSES and AIDS 1996, published by the Theoretical Biology and Biophysics Group of the Los Alamos National Laboratory, Los Alamos, N. Mex., and additional sequences kindly obtained from GenBank by Esther Guzman of the Los Alamos Laboratory.

[0175] A. Variations in Sequences

[0176] 399 aa 5-10 Tat hexapeptide sequences of the common B subtype of HIV-1 were obtained, as were 18 from the non-B subtypes (6 from subtype A, 2 from subtype C, 7 from subtype D, 2 from subtype F and 1 from subtype U).

[0177] For the B subtype, 386 of the total 399 (97%) hexapeptides had either Arg (289, 74%), or Lys (45, 11%), or Ser (36, 9%) or Asn (16, 4%) in position 3 as the only variation in the hexapeptides. The remaining variations (3%) comprised:

-Gly-Pro...

example 3

Defining an Antibody Binding Amino Acid Sequence (Epitope II) Within the Linear 18 Amino Acid Sequence Following Cys37 of HIV-1 Tat Protein

[0196] A peptide corresponding to amino acids 38-55 of SEQ ID NO: 1 illustrated in FIG. 1 was synthesized as described in Example 1. Using the methods described in Example 1, a low titer antibody response in rabbits was detected and Table 28 summarizes studies defining the sequence involved in this antibody binding. The geometric mean titer (GMT) is reported as percentage of self-titer.

TABLE 13Antiserum to SEQ ID NO:105:Phe-Ile-Thr-Lys-Gly-Leu-Gly-Ile-Ser-Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-ArgGMT (% selfDetector Peptidestiter)SEQ ID NO.Phe-Ile-Thr-Lys-Gly-Leu-Gly-Ile-Ser-Tyr-Gly- 947 (100)105Arg-Lys-Lys-Arg-Arg-Gln-ArgPhe-Ile-Thr-Lys-Gly-Leu-Gly-Ile-Ser-Tyr-Gly-1141 (115)(amino acids 1-15 of SEQ IDArg-Lys-Lys-ArgNO:105)Lys-Gly-Leu-Gly-Ile-Ser-Tyr-Gly- 895 (95)(amino acids 41-55 of SEQArg-Lys-Lys-Arg-Arg-Gln-ArgID NO:1)Leu-Gly-Ile-Ser-Tyr-Gly- 986...

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Abstract

A composition which elicits antibodies to greater than 95%, and even greater than 99%, of the known variants of HIV-1 Tat protein contains at least one peptide or polypeptide of the formula of Epitope I (based on amino acids 2-10 of HIV-1 Tat consensus sequence) and optionally one or more of a peptide or polypeptide of Epitope II (based on amino acids 41 to 51 of that sequence), of Epitope III (based on amino acids 52-62 of that sequence), or of Epitope IV (based on amino acids 62 through 72 of that sequence with a C-terminal Pro). Vaccinal and pharmaceutical compositions can contain the antibodies induced by the peptide compositions for use in passive therapy. Diagnostic compositions and uses are described for assessing the immune status of vaccinated patients.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This is a continuation of U.S. patent application Ser. No. 10 / 262,435, filed Sep. 30, 2002, which is a divisional of U.S. patent application Ser. No. 09 / 451,067, filed Nov. 30, 1999, now U.S. Pat. No. 6,525,179, issued Feb. 25, 2003, which is a divisional of U.S. patent application Ser. No. 09 / 113,921, filed Jul. 10, 1998, now U.S. Pat. No. 6,193,981, issued Feb. 27, 2001, which is a continuation-in-part of U.S. patent application Ser. No. 08 / 893,853, filed Jul. 11, 1997, now U.S. Pat. No. 5,891,994, issued Apr. 6, 1999.BACKGROUND OF THE INVENTION [0002] The present invention relates generally to compositions and methods useful for inhibiting the multiplication of human immunodeficiency virus-1 (HIV-1) in infected patients, symptomatic or asymptomatic, and for attenuating HIV-1 multiplication during primary infection in previously uninfected subjects, thus minimizing progression to AIDS. [0003] High plasma levels of human immunodeficien...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/10A61K38/00C12N15/09A61K39/00A61K39/12A61K39/395A61P31/18C07K1/00C07K5/00C07K7/00C07K14/00C07K14/16C07K16/00C07K17/00C12N1/21C12N5/10C12N7/00C12P21/08C12Q1/70G01N33/53
CPCA61K38/10A61K39/00A61K39/21A61K2039/6037C07K14/005C07K16/1072A61K2039/55566C07K2319/60C12N2740/15022C12N2740/16322C12N2740/16334A61K2039/545C07K2317/34A61K39/12A61P31/18
Inventor GOLDSTEIN, GIDEON
Owner THYMON
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