MHC Heterozygote Advantage in Simian Immunodeficiency Virus–Infected Mauritian Cynomolgus Macaques

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Simian immunodeficiency virus (SIV)-infected macaques are the preferred animal model for human immunodeficiency virus (HIV) vaccines that elicit CD8؉ T cell responses. Unlike humans, whose CD8 ؉ T cell responses are restricted by a maximum of six HLA class I alleles, macaques express up to 20 distinct major histocompatibility complex class I (MHC-I) sequences. Interestingly, only a subset of macaque MHC-I sequences are transcriptionally abundant in peripheral blood lymphocytes. We hypothesized that highly transcribed MHC-I sequences are principally responsible for restricting SIV-specific CD8 ؉ T cell responses. To examine this hypothesis, we measured SIV-specific CD8؉ T cell responses in MHC-I homozygous Mauritian cynomolgus macaques. Each of eight CD8 ؉ T cell responses defined by full-proteome gamma interferon (IFN-␥) enzyme-linked immunospot (ELISPOT) assay were restricted by four of the five transcripts that are transcriptionally abundant (>1% of total MHC-I transcripts in peripheral blood lymphocytes). The five transcriptionally rare transcripts shared by these animals did not restrict any detectable CD8؉ T cell responses. Further, seven CD8 ؉ T cell responses were defined by identifying peptide binding motifs of the three most frequent MHC-I transcripts on the M3 haplotype. Combined, these results suggest that transcriptionally abundant MHC-I transcripts are principally responsible for restricting SIV-specific CD8 ؉ T cell responses. Thus, only a subset of the thousands of known MHC-I alleles in macaques should be prioritized for CD8 ؉ T cell epitope characterization.

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Transcriptionally Abundant Major Histocompatibility Complex Class I Alleles Are Fundamental to Nonhuman Primate Simian Immunodeficiency Virus-Specific CD8⁺T Cell Responses

Budde

Lhost

Burwitz

et al. 2011

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“…All animals were used in previous studies (9,11,12). They were purchased from Charles River Laboratories or Bioculture Group, and cared for by the Wisconsin National Primate Research Center (WNPRC) according to protocols approved by the University of Wisconsin Graduate School Animal Care and Use Committee.…”

Section: Animalsmentioning

confidence: 99%

Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

Gellerup

Balgeman

Nelson

et al. 2016

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Anti-HIV CD8 T cells included in therapeutic treatments will need to target epitopes that do not accumulate escape mutations.Identifying the epitopes that do not accumulate variants but retain immunogenicity depends on both host major histocompatibility complex (MHC) genetics and the likelihood for an epitope to tolerate variation. We previously found that immune escape during acute SIV infection is conditional; the accumulation of mutations in T cell epitopes is limited, and the rate of accumulation depends on the number of epitopes being targeted. We have now tested the hypothesis that conditional immune escape extends into chronic SIV infection and that epitopes with a preserved wild-type sequence have the potential to elicit epitope-specific CD8 T cells. We deep sequenced simian immunodeficiency virus (SIV) from Mauritian cynomolgus macaques (MCMs) that were homozygous and heterozygous for the M3 MHC haplotype and had been infected with SIV for about 1 year. When interrogating variation within individual epitopes restricted by M3 MHC alleles, we found three categories of epitopes, which we called categories A, B, and C. Category B epitopes readily accumulated variants in M3-homozygous MCMs, but this was less common in M3-heterozygous MCMs. We then determined that chronic CD8 T cells specific for these epitopes were more likely preserved in the M3-heterozygous MCMs than M3-homozygous MCMs. We provide evidence that epitopes known to escape from chronic CD8 T cell responses in animals that are homozygous for a set of MHC alleles are preserved and retain immunogenicity in a host that is heterozygous for the same MHC alleles. IMPORTANCEAnti-HIV CD8 T cells that are part of therapeutic treatments will need to target epitopes that do not accumulate escape mutations. Defining these epitope sequences is a necessary precursor to designing approaches that enhance the functionality of CD8 T cells with the potential to control virus replication during chronic infection or after reactivation of latent virus. Using MHChomozygous and -heterozygous Mauritian cynomolgus macaques, we have now obtained evidence that epitopes known to escape from chronic CD8 T cell responses in animals that are MHC homozygous are preserved and retain immunogenicity in a host that is heterozygous for the same MHC alleles. Importantly, our findings support the conditional immune escape hypothesis, such that the potential to present a greater number of CD8 T cell epitopes within a single animal can delay immune escape in targeted epitopes. As a result, certain epitope sequences can retain immunogenicity into chronic infection.

“…These results indicate the association of MHC-I haplotypes with AIDS progression. There has been a number of reports describing SIV infections in macaques sharing a single or a couple of MHC-I alleles, but few studies have examined SIV infection in macaques sharing an MHC-I haplotype (10,11,40). SIV infection induces multiple epitope-specific CD8 ϩ T-cell responses, and CD8 ϩ T-cell responses specific for some MHC-I-restricted epitopes can be affected by those specific for other MHC-I-restricted epitopes due to CTL immunodominance (16,29,52).…”

Section: Discussionmentioning

confidence: 99%

Association of Major Histocompatibility Complex Class I Haplotypes with Disease Progression after Simian Immunodeficiency Virus Challenge in Burmese Rhesus Macaques

Nomura

Yamamoto

Shiino

et al. 2012

Nonhuman primate AIDS models are essential for the analysis of AIDS pathogenesis and the evaluation of vaccine efficacy. Multiple studies on human immunodeficiency virus and simian immunodeficiency virus (SIV) infection have indicated the association of major histocompatibility complex class I (MHC-I) genotypes with rapid or slow AIDS progression. The accumulation of macaque groups that share not only a single MHC-I allele but also an MHC-I haplotype consisting of multiple polymorphic MHC-I loci would greatly contribute to the progress of AIDS research. Here, we investigated SIVmac239 infections in four groups of Burmese rhesus macaques sharing individual MHC-I haplotypes, referred to as A, E, B, and J. Out of 20 macaques belonging to A + ( n = 6), E + ( n = 6), B + ( n = 4), and J + ( n = 4) groups, 18 showed persistent viremia. Fifteen of them developed AIDS in 0.5 to 4 years, with the remaining three at 1 or 2 years under observation. A + animals, including two controllers, showed slower disease progression, whereas J + animals exhibited rapid progression. E + and B + animals showed intermediate plasma viral loads and survival periods. Gag-specific CD8 + T-cell responses were efficiently induced in A + animals, while Nef-specific CD8 + T-cell responses were in A + , E + , and B + animals. Multiple comparisons among these groups revealed significant differences in survival periods, peripheral CD4 + T-cell decline, and SIV-specific CD4 + T-cell polyfunctionality in the chronic phase. This study indicates the association of MHC-I haplotypes with AIDS progression and presents an AIDS model facilitating the analysis of virus-host immune interaction.