Two MHC Class I Molecules Associated with Elite Control of Immunodeficiency Virus Replication, Mamu-B*08 and HLA-B*2705, Bind Peptides with Sequence Similarity

Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53706, USA.
The Journal of Immunology (Impact Factor: 4.92). 06/2009; 182(12):7763-75. DOI: 10.4049/jimmunol.0900111
Source: PubMed


HLA-B27- and -B57-positive HIV-infected humans have long been associated with control of HIV replication, implying that CD8(+) T cell responses contribute to control of viral replication. In a similar fashion, 50% of Mamu-B*08-positive Indian rhesus macaques control SIVmac239 replication and become elite controllers with chronic-phase viremia <1000 viral RNA copies/ml. Interestingly, Mamu-B*08-restricted SIV-derived epitopes appeared to match the peptide binding profile for HLA-B*2705 in humans. We therefore defined a detailed peptide-binding motif for Mamu-B*08 and investigated binding similarities between the macaque and human MHC class I molecules. Analysis of a panel of approximately 900 peptides revealed that despite substantial sequence differences between Mamu-B*08 and HLA-B*2705, the peptide-binding repertoires of these two MHC class I molecules share a remarkable degree of overlap. Detailed knowledge of the Mamu-B*08 peptide-binding motif enabled us to identify six additional novel Mamu-B*08-restricted SIV-specific CD8(+) T cell immune responses directed against epitopes in Gag, Vpr, and Env. All 13 Mamu-B*08-restricted epitopes contain an R at the position 2 primary anchor and 10 also possess either R or K at the N terminus. Such dibasic peptides are less prone to cellular degradation. This work highlights the relevance of the Mamu-B*08-positive SIV-infected Indian rhesus macaque as a model to examine elite control of immunodeficiency virus replication. The remarkable similarity of the peptide-binding motifs and repertoires for Mamu-B*08 and HLA-B*2705 suggests that the nature of the peptide bound by the MHC class I molecule may play an important role in control of immunodeficiency virus replication.

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Available from: Dominic R Beal, Oct 07, 2015
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    • "Studies in the SIV model add further weight to the hypothesis that Nef responses can contribute to disease control. In the rhesus macaque, Mamu-B*08, which has a peptide-binding motif so similar to HLA-B*27 that it can bind the same peptides [33], is also associated with elite viraemic control [34–36]. However, unlike HLA-B*27 [25], the immunodominant responses are within accessory/regulatory proteins, and a vaccine induced Mamu-B*08-restricted response to the Nef RL10 epitope (SIV Nef 137–146, RRHRILDIYL) is correlated with viraemic control [34]. "
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    ABSTRACT: Recent studies in the SIV-macaque model of HIV infection suggest that Nef-specific CD8+ T-cell responses may mediate highly effective immune control of viraemia. In HIV infection Nef recognition dominates in acute infection, but in large cohort studies of chronically infected subjects, breadth of T cell responses to Nef has not been correlated with significant viraemic control. Improved disease outcomes have instead been associated with targeting Gag and, in some cases, Pol. However analyses of the breadth of Nef-specific T cell responses have been confounded by the extreme immunogenicity and multiple epitope overlap within the central regions of Nef, making discrimination of distinct responses impossible via IFN-gamma ELISPOT assays. Thus an alternative approach to assess Nef as an immune target is needed. Here, we show in a cohort of >700 individuals with chronic C-clade infection that >50% of HLA-B-selected polymorphisms within Nef are associated with a predicted fitness cost to the virus, and that HLA-B alleles that successfully drive selection within Nef are those linked with lower viral loads. Furthermore, the specific CD8+ T cell epitopes that are restricted by protective HLA Class I alleles correspond substantially to effective SIV-specific epitopes in Nef. Distinguishing such individual HIV-specific responses within Nef requires specific peptide-MHC I tetramers. Overall, these data suggest that CD8+ T cell targeting of certain specific Nef epitopes contributes to HIV suppression. These data suggest that a re-evaluation of the potential use of Nef in HIV T-cell vaccine candidates would be justified.
    PLoS ONE 09/2013; 8(9):e73117. DOI:10.1371/journal.pone.0073117 · 3.23 Impact Factor
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    • "In macaques, Mamu-B*17 and Mamu-B*08 correlate with control of viral replication and delayed progression to AIDS [18]–[19]. In humans, HLA-B*27 and HLA-B*57 expression is correlated with control of viral loads, while HLA-B*35 expression is correlated with rapid AIDS development [17], [20], [21]. "
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    ABSTRACT: The presence of certain MHC class I alleles is correlated with remarkable control of HIV and SIV, indicating that specific CD8 T cell responses can effectively reduce viral replication. It remains unclear whether epitopic breadth is an important feature of this control. Previous studies have suggested that individuals heterozygous at the MHC class I loci survive longer and/or progress more slowly than those who are homozygous at these loci, perhaps due to increased breadth of the CD8 T cell response. We used Mauritian cynomolgus macaques with defined MHC haplotypes and viral inhibition assays to directly compare CD8 T cell efficacy in MHC-heterozygous and homozygous individuals. Surprisingly, we found that cells from heterozygotes suppress viral replication most effectively on target cells from animals homozygous for only one of two potential haplotypes. The same heterozygous effector cells did not effectively inhibit viral replication as effectively on the target cells homozygous for the other haplotype. These results indicate that the greater potential breadth of CD8 T cell responses present in heterozygous animals does not necessarily lead to greater antiviral efficacy and suggest that SIV-specific CD8 T cell responses in heterozygous animals have a skewed focus toward epitopes restricted by a single haplotype.
    PLoS ONE 08/2012; 7(8):e43690. DOI:10.1371/journal.pone.0043690 · 3.23 Impact Factor
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    • "Both of the Mamu-A1⋆065:01-restricted SIVmac239 Gag241-249 epitope and the HLA-B⋆57-restricted HIV TW10 epitope are considered to have the same anchor residues, S at position 2 and tryptophan (W) at the carboxyl terminus. Additionally, anchor residues of CTL epitopes presented by Mamu-B⋆17/Mamu-B⋆08 were indicated to be similar to those restricted by HLA-B⋆57/HLA-B⋆27 (Loffredo et al., 2009; Wu et al., 2011). "
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    ABSTRACT: Virus-specific cytotoxic T lymphocytes (CTLs) are major effectors in acquired immune responses against viral infection. Virus-specific CTLs recognize specific viral peptides presented by major histocompatibility complex class-I (MHC-I) on the surface of virus-infected target cells via their T cell receptor (TCR) and eliminate target cells by both direct and indirect mechanisms. In human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections, host immune responses fail to contain the virus and allow persistent viral replication, leading to AIDS progression. CTL responses exert strong suppressive pressure on HIV/SIV replication and cumulative studies have indicated association of HLA/MHC-I genotypes with rapid or slow AIDS progression.
    Frontiers in Microbiology 06/2012; 3:234. DOI:10.3389/fmicb.2012.00234 · 3.99 Impact Factor
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