Patterns of CD8+ Immunodominance May Influence the Ability of Mamu-B*08-Positive Macaques To Naturally Control Simian Immunodeficiency Virus SIVmac239 Replication

Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, 555 Science Dr., Madison, WI 53711, USA.
Journal of Virology (Impact Factor: 4.44). 03/2008; 82(4):1723-38. DOI: 10.1128/JVI.02084-07
Source: PubMed


Certain major histocompatibility complex (MHC) class I alleles are strongly associated with control of human immunodeficiency
virus and simian immunodeficiency virus (SIV). CD8+ T cells specific for epitopes restricted by these molecules may be particularly effective. Understanding how CD8+ T cells contribute to control of viral replication should yield important insights for vaccine design. We have recently identified
an Indian rhesus macaque MHC class I allele, Mamu-B*08, associated with elite control and low plasma viremia after infection with the pathogenic isolate SIVmac239. Here, we infected
four Mamu-B*08-positive macaques with SIVmac239 to investigate why some of these macaques control viral replication. Three of the four macaques
controlled SIVmac239 replication with plasma virus concentrations below 20,000 viral RNA copies/ml at 20 weeks postinfection;
two of four macaques were elite controllers (ECs). Interestingly, two of the four macaques preserved their CD4+ memory T lymphocytes during peak viremia, and all four recovered their CD4+ memory T lymphocytes in the chronic phase of infection. Mamu-B*08-restricted CD8+ T-cell responses dominated the acute phase and accounted for 23.3% to 59.6% of the total SIV-specific immune responses. Additionally,
the ECs mounted strong and broad CD8+ T-cell responses against several epitopes in Vif and Nef. Mamu-B*08-specific CD8+ T cells accounted for the majority of mutations in the virus at 18 weeks postinfection. Interestingly, patterns of viral
variation in Nef differed between the ECs and the other two macaques. Natural containment of AIDS virus replication in Mamu-B*08-positive macaques may, therefore, be related to a combination of immunodominance and viral escape from CD8+ T-cell responses.

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    • "and Mamu-B * 08 exhibit low to undetectable viral loads without experimental interventions, so much so that 50% of Mamu-B * 08-positive rhesus macaques of Indian origin were shown to effectively control SIVmac239 replication to become EC (Loffredo et al., 2008). Such parallels between human and rhesus MHC alleles contributing for virus control, defined as significantly lower set-point viral load and prolonged survival time, were noted specifically for HLA-B "

    Full-text · Article · Mar 2013 · Frontiers in Immunology
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    • "Elucidation of the mechanisms of viral control associated with individual protective MHC-I alleles would contribute to HIV cure and vaccine-based prevention. Because CD8+ T-cell responses specific for some MHC-I-restricted epitopes can be affected by those specific for other MHC-I-restricted epitopes due to immunodominance [29], [46], [47], macaque groups sharing MHC-I genotypes at the haplotype level are useful for the analysis of cooperation of multiple epitope-specific CD8+ T-cell responses. Previously, we reported a group of Burmese rhesus macaques sharing MHC-I haplotype 90-120-Ia (A), which dominantly induce Gag-specific CD8+ T-cell responses and tend to show slower disease progression after SIVmac239 challenge [21]. "
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    ABSTRACT: Several major histocompatibility complex class I (MHC-I) alleles are associated with lower viral loads and slower disease progression in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections. Immune-correlates analyses in these MHC-I-related HIV/SIV controllers would lead to elucidation of the mechanism for viral control. Viral control associated with some protective MHC-I alleles is attributed to CD8(+) T-cell responses targeting Gag epitopes. We have been trying to know the mechanism of SIV control in multiple groups of Burmese rhesus macaques sharing MHC-I genotypes at the haplotype level. Here, we found a protective MHC-I haplotype, 90-010-Id (D), which is not associated with dominant Gag-specific CD8(+) T-cell responses. Viral loads in five D(+) animals became significantly lower than those in our previous cohorts after 6 months. Most D(+) animals showed predominant Nef-specific but not Gag-specific CD8(+) T-cell responses after SIV challenge. Further analyses suggested two Nef-epitope-specific CD8(+) T-cell responses exerting strong suppressive pressure on SIV replication. Another set of five D(+) animals that received a prophylactic vaccine using a Gag-expressing Sendai virus vector showed significantly reduced viral loads compared to unvaccinated D(+) animals at 3 months, suggesting rapid SIV control by Gag-specific CD8(+) T-cell responses in addition to Nef-specific ones. These results present a pattern of SIV control with involvement of non-Gag antigen-specific CD8(+) T-cell responses.
    Full-text · Article · Jan 2013 · PLoS ONE
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    • "In a cohort of >200 SIVmac239-infected rhesus macaques, we identified a Mamu-A1*002:01+ (formerly A*02)/Mamu-B*008:01+ (formerly B*08) animal, r00032, that maintained elite control (<1,000 copies vRNA/ml plasma) for over one year. A detailed study of this animal’s acute phase infection has previously been reported [22,23]. At ~96 weeks post-infection, the animal experienced spontaneous viral breakthrough, defined as the time point where viral load irreversibly crossed the elite control threshold of 1,000 copies vRNA/ml plasma (Figure 1A). "
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    ABSTRACT: Background Virus-specific T cells are critical components in the containment of immunodeficiency virus infections. While the protective role of CD8+ T cells is well established by studies of CD8+ T cell-mediated viral escape, it remains unknown if CD4+ T cells can also impose sufficient selective pressure on replicating virus to drive the emergence of high-frequency escape variants. Identifying a high frequency CD4+ T cell driven escape mutation would provide compelling evidence of direct immunological pressure mediated by these cells. Results Here, we studied a SIVmac239-infected elite controller rhesus macaque with a 1,000-fold spontaneous increase in plasma viral load that preceded disease progression and death from AIDS-related complications. We sequenced the viral genome pre- and post-breakthrough and demonstrate that CD8+ T cells drove the majority of the amino acid substitutions outside of Env. However, within a region of Gag p27CA targeted only by CD4+ T cells, we identified a unique post-breakthrough mutation, Gag D205E, which abrogated CD4+ T cell recognition. Further, we demonstrate that the Gag p27CA-specific CD4+ T cells exhibited cytolytic activity and that SIV bearing the Gag D205E mutation escapes this CD4+ T cell effector function ex vivo. Conclusions Cumulatively, these results confirm the importance of virus specific CD8+ T cells and demonstrate that CD4+ T cells can also exert significant selective pressure on immunodeficiency viruses in vivo during low-level viral replication. These results also suggest that further studies of CD4+ T cell escape should focus on cases of elite control with spontaneous viral breakthrough.
    Full-text · Article · Nov 2012 · Retrovirology
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