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Cmv glycoproteins and recombinant vectors

Inactive Publication Date: 2013-06-06
OREGON HEALTH & SCI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to recombinant vectors that express human cytomegalovirus (HCMV) glycoproteins, particularly US2, US3, US6, and US11, or rhesus cytomegalovirus (RCMV) glycoproteins, Rh182, Rh184, Rh185, and Rh189. These vectors can be used for the purpose of inducing a protective CD8+ T cell response against challenge with the corresponding glycoproteins. The invention also includes methods for making and using these vectors, as well as methods for determining the efficacy of HCMV vaccines. The technical effects of the invention include providing improved methods for preventing and treating CMV infections, as well as better understanding the immunology of CMV infections.

Problems solved by technology

Although HCMV is generally benign in healthy individuals, the virus may cause devastating disease in immunocompromised populations resulting in high morbidity and mortality (for review, see (Pass, R. F. 2001.
HCMV therefore remains a major cause of mortality in multiple patient populations emphasizing the need for new antiviral pharmacologic and vaccine strategies.
Paradoxically, the high levels of CMV-specific immunity are unable to either eradicate the virus from the healthy infected individual, or confer protection of the CMV sero-positive individual against re-infection.

Method used

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  • Cmv glycoproteins and recombinant vectors
  • Cmv glycoproteins and recombinant vectors
  • Cmv glycoproteins and recombinant vectors

Examples

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example 1

Evasion of CD8+ T Cells is Critical for Superinfection by Cytomegalovirus

[0214]Cytomegalovirus (CMV) may superinfect persistently infected hosts despite CMV-specific humoral and cellular immunity; however, how it does so remains undefined. Applicants have demonstrated that superinfection of rhesus CMV-infected rhesus macaques (RM) requires evasion of CD8+ T cell immunity by virally encoded inhibitors of major histocompatibility complex class I (MHC-I) antigen presentation, particularly the homologs of human CMV US2, 3, 6, and 11. In contrast, MHC-I interference was dispensable for primary infection of RM, or for the establishment of a persistent secondary infection in CMV-infected RM transiently depleted of CD8+ lymphocytes. These findings demonstrate that US2-11 glycoproteins promote evasion of CD8+ T cells in vivo, thus supporting viral replication and dissemination during superinfection, a process that complicates the development of preventive CMV vaccines but that may be exploit...

example 2

[0240]In this Example, Applicants develop a number of attenuated RhCMV-vaccines to examine the highest level of attenuation that may still achieve protection against ΔUS2-11-Gag. A limitation of Applicants' preliminary data was that Applicants had only shown that natural infection with RhCMV was protective against re-infection with ΔUS2-11, but Applicants had yet to demonstrate that experimental infection with recombinant RhCMV would be protective. Applicants now demonstrate that a recombinant virus lacking the major tegument proteins pp65a and pp65b or pp71 protects against re-infection by ΔUS2-11-Gag.

[0241]PP65 is one of the most abundant proteins in HCMV particles and the most abundant component of the viral tegument, an amorphous protein structure layered between the capsid and the envelope. In addition to its role in evading innate immune responses, pp65 is one of the most immunogenic proteins encoded by HCMV and it is therefore included in most experimental vaccines and pp65-s...

example 3

A Systematic Evaluation of Cytomegalovirus Vaccine Efficacy

[0257]Although human cytomegalovirus (HCMV) causes a mostly benign, unnoticed persistent infection in immunocompetent individuals, it may cause disease in immunocompromised individuals such as transplant or AIDS patients. HCMV is also the most frequent infectious cause of birth defects, with an estimated 0.7% of babies in the APPLICANTS being born with congenital infection, and approximately 10% of these infections resulting in long-term sequelae (primarily sensorineural defects) (Dollard, S. C. et al. 2007. Rev Med Virol 17:355-63). The annual health costs to care for these children is estimated to be about $1-2 billion (Cannon, M. J., and K. F. Davis. 2005. BMC Public Health 5:70). For these reasons, the development of a CMV vaccine has been given high priority by the Institute of Medicine and the National Vaccine Advisory Committee (Arvin, A. M. et al. 2004. Clin Infect Dis 39:233-9). However, the development of a vaccine...

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Abstract

This invention also relates to recombinant vectors expressing one or more of the human CMV (HCMV) glycoproteins US2, US3, US6 and US11 or corresponding functional rhesus CMV (RhCMV) homologues Rh182, Rh184, Rh185 or Rh189, methods of making them, uses for them, expression products from them, and uses for the expression products. This invention also relates to recombinant cytomegalovirus vectors vectors lacking one or more of the glycoproteins, methods of making them, uses for them, expression products from them, and uses for the expression products.

Description

RELATED APPLICATIONS AND INCORPORATION BY REFERENCE[0001]This application is a continuation-in-part application of international patent application Serial No. PCT / US2011 / 029930 filed Mar. 25, 2011, which published as PCT Publication No. WO 2011 / 119920 on Sep. 29, 2011, which claims priority to U.S. provisional patent application Ser. No. 61 / 317,647 filed Mar. 25, 2010. Reference is made to U.S. patent application Ser. No. 11 / 597,457 filed Apr. 28, 2008.FEDERAL FUNDING LEGEND[0002]This invention was supported, in part, by the National Institutes of Health grant numbers RO1 AI059457 and RO1 AI060392), the National Center for Research Resources grant numbers RR016025, RR18107 and RR00163 supporting the Oregon National and the Ruth L. Kirschstein National Research Service Awards grant numbers T32 AI007472 and T32 HL007781. The federal government may have certain rights to this invention.[0003]The foregoing applications, and all documents cited therein or during their prosecution (“appln...

Claims

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Application Information

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IPC IPC(8): A61K39/245A61K39/00A61K39/02C12Q1/02A61K39/12
CPCA61K39/21G01N33/56972A61K2039/5254C12N7/00C12N2710/10343C12N2710/16134C12N2710/16143C12N2710/24143C12N2740/10034C12N2740/15043A61K39/00A61K39/0011A61K39/02A61K39/12C12Q1/025A61K39/245C07K14/005C12N15/86A61K2039/5256C12N2710/16121C12N2710/16122C12N2710/16162C12N2740/15034C12N2800/24C12N2710/16131C12N2710/16171A61K39/4611A61K39/464838
Inventor PICKER, LOUISFRUEH, KLAUSHANSEN, SCOTT G.POWERS, COLIN
Owner OREGON HEALTH & SCI UNIV
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