Vaccine-Elicited Memory Cytotoxic T Lymphocytes Contribute to Mamu-A*01-Associated Control of Simian/Human Immunodeficiency Virus 89.6P Replication in Rhesus Monkeys

Beth Israel Deaconess Medical Center, Division of Viral Pathogenesis, 330 Brookline Ave. RE-113, Boston, MA 02215, USA.
Journal of Virology (Impact Factor: 4.44). 05/2005; 79(8):4580-8. DOI: 10.1128/JVI.79.8.4580-4588.2005
Source: PubMed


The expression of particular major histocompatibility complex (MHC) class I alleles can influence the rate of disease progression following lentiviral infections. This effect is a presumed consequence of potent cytotoxic T-lymphocyte (CTL) responses that are restricted by these MHC class I molecules. The present studies have examined the impact of the MHC class I allele Mamu-A*01 on simian/human immunodeficiency virus 89.6P (SHIV-89.6P) infection in unvaccinated and vaccinated rhesus monkeys by exploring the contribution of dominant-epitope specific CTL in this setting. Expression of Mamu-A*01 in immunologically naive monkeys was not associated with improved control of viral replication, CD4+ T-lymphocyte loss, or survival. In contrast, Mamu-A*01+ monkeys that had received heterologous prime/boost immunizations prior to challenge maintained higher CD4+ T-lymphocyte levels and better control of SHIV-89.6P replication than Mamu-A*01- monkeys. This protection was associated with the evolution of high-frequency anamnestic CTL responses specific for a dominant Mamu-A*01-restricted Gag epitope following infection. These data indicate that specific MHC class I alleles can confer protection in the setting of a pathogenic SHIV infection by their ability to elicit memory CTL following vaccination.

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Available from: Sampa Santra, May 20, 2014
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    • "The studies also showed that RM that express the Class I Mamu-A*01 molecule control viremia after infection by a chimeric lentivirus composed of elements from both HIV and SIV, referred to as SHIV, more effectively than Mamu-A*01 negative animals (Mothe et al., 2003). This improved control of viral replication correlated with the development of a high-frequency dominant epitope Gag-specific CTL response following infection (Seaman et al., 2005). Similarly, the Mamu B*17 alleles also has been associated with slower disease progression in SIV-infected RM (Allen et al., 1998;Evans et al., 2000;Loffredo et al., 2007;Loffredo et al., 2008). "
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    ABSTRACT: We have developed a murine model expressing the rhesus macaque (RM) Mamu-A01 MHC allele to characterize immune responses and vaccines based on antigens of importance to human disease processes. Towards that goal, transgenic (Tg) mice expressing chimeric RM (alpha1 and alpha2 Mamu-A01 domains) and murine (alpha3, transmembrane, and cytoplasmic H-2K(b) domains) MHC Class I molecules were derived by transgenesis of the H-2K(b)D(b) double MHC Class I knockout strain. After immunization of Mamu-A01/K(b) Tg mice with rVV-SIVGag-Pol, the mice generated CD8(+) T-cell IFN-gamma responses to several known Mamu-A01 restricted epitopes from the SIV Gag and Pol antigen sequence. Fusion peptides of highly recognized CTL epitopes from SIV Pol and Gag and a strong T-help epitope were shown to be immunogenic and capable of limiting an rVV-SIVGag-Pol challenge. Mamu-A01/K(b) Tg mice provide a model system to study the Mamu-A01 restricted T-cell response for various infectious diseases which are applicable to a study in RM.
    Virology 03/2009; 387(1):16-28. DOI:10.1016/j.virol.2009.01.041 · 3.32 Impact Factor
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    • "virus. The Mamu-A*01 status of these animals was determined as recently described (Seaman et al., 2005). "
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    Virology 07/2006; 349(2):276-89. DOI:10.1016/j.virol.2006.01.043 · 3.32 Impact Factor
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    • "This variability among animals could be due, in part, to differences in the major histocompatibility complex (MHC) alleles present among the macaques used. Consistent with this idea, previous studies have demonstrated that MHC allelic composition, including such alleles as Mamu A*01 and B*17, is associated with CTL response, CTL escape and the rate of SIV disease progression in macaques (Bontrop and Watkins, 2005; Loffredo et al., 2004; O'Connor et al., 2003; Seaman et al., 2005a). The implications of these findings are that differences in MHC allelic composition of nonhuman primates in preclinical immunogenicity studies as well as humans in clinical trials may influence the immunological responses noted and the success or failure of HIV-1 vaccine candidates. "
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