Targeting of a CD8 T Cell Env Epitope Presented by HLA-B*5802 Is Associated with Markers of HIV Disease Progression and Lack of Selection Pressure

Abstract

In HIV-infected persons, certain HLA class I alleles are associated with effective control of viremia, while others are associated with rapid disease progression. Among the most divergent clinical outcomes are the relatively good prognosis in HLA-B*5801 expressing persons and poor prognosis with HLA-B*5802. These two alleles differ by only three amino acids in regions involved in HLA-peptide recognition. This study evaluated a cohort of over 1000 persons with chronic HIV clade C virus infection to determine whether clinical outcome differences associated with B*5801 (n = 93) and B*5802 ( n = 259) expression are associated with differences in HIV-1-specific CD8 (+) T cell responses. The overall breadth and magnitude of HIV-1-specific CD8(+) T cell responses were lower in persons expressing B*5802, and epitope presentation by B*5802 contributed significantly less to the overall response as compared to B*5801-restricted CD8 (+) T cells. Moreover, viral load in B*5802-positive persons was higher and CD4 cell counts lower when this allele contributed to the overall CD8 (+) T cell response, which was detected exclusively through a single epitope in Env. In addition, persons heterozygous for B*5802 compared to persons homozygous for other HLA-B alleles had significantly higher viral loads. Viral sequencing revealed strong selection pressure mediated through B*5801-restricted responses but not through B*5802. These data indicate that minor differences in HLA sequence can have a major impact on epitope recognition, and that selective targeting of Env through HLA-B*5802 is at least ineffectual if not actively adverse in the containment of viremia. These results provide experimental evidence that not all epitope-specific responses contribute to immune containment, a better understanding of which is essential to shed light on mechanisms involved in HIV disease progression.

Human Leukocyte Antigen Class I Supertypes and HIV-1 Control in African Americans

“…B58s (POR, 0.33; 95% CI, 0.21 to 0.52) was associated with control that was heavily determined by B*57 alleles (POR, 0.11; 95% CI, 0.05 to 0.22). However, neither the strong protective effect observed elsewhere for B*5801 (22,27) nor the strong deleterious effect observed elsewhere for B*5802 (22,23,27) was observed in our study.…”

Correlates of Protective Cellular Immunity Revealed by Analysis of Population-Level Immune Escape Pathways in HIV-1

“…Widespread differential escape is consistent with reported differences in HIV-1 disease progression between HLA alleles differing by as little as 1 amino acid (43,68,86) and also supports the notion that analysis of HLA-associated polymorphisms provides a novel perspective from which to discriminate both quantitative and qualitative differences in HLA-restricted immune responses. Of interest, HLA allele subtype pairs that exhibit the highest level of differential escape were those with the greatest intratype sequence divergence, raising the intriguing hypothesis that differential escape may be a consequence of active positive selection at these loci.…”

“…Immune escape mutations occur within and outside CTL epitopes (13,20,60,99,104) and can compromise peptide-HLA binding (8,65), disrupt intracellular antigen processing (35,122), affect T-cell recognition of the peptide-HLA complex (23,58,59,96,117), and/or potentially affect killer immunoglobulin-like receptor (KIR) binding (16,113). While some escape pathways are likely to be universal across HLA alleles and/or HIV-1 subtypes, widespread examples of differential escape between infected populations (9, 60) and between closely related HLA class I alleles (26,69,86) have also been demonstrated. Population-level studies have also allowed us to estimate rates (18) and clinical implications (21, 81) of immune escape, infer fitness costs of specific mutations (81), discover novel epitopes in conventional (5, 13) and cryptic (10, 12) reading…”

Virological, Immune and Host genetics Markers in the Control of HIV Infection

“…Particularly alleles included in the HLA-B7 (B*5101, B81), HLA-B27 (HLA-B27, B*1503) and HLA-B58 supertypes (HLA-B57, B*5801, B*1516, B*1517) have been associated with improved or impaired levels of HIV control. Of note, almost all the alleles in the HLA-B58 supertype appear to mediate superior control of HIV infection [34]; with the exception being the HLA-B*5802 allele, which is highly prevalent in South Africa and which is associated with elevated median viral loads [35]. The reasons how subtle changes in the HLA sequence (HLA-B*5802 only differs in three amino acids from the "good" HLA-B*5801 allele) can so profoundly affect HIV disease outcome are still unclear and are not in all cases simply attributable to different CTL epitope repertoires presented on these alleles [35,36].…”

“…Of note, almost all the alleles in the HLA-B58 supertype appear to mediate superior control of HIV infection [34]; with the exception being the HLA-B*5802 allele, which is highly prevalent in South Africa and which is associated with elevated median viral loads [35]. The reasons how subtle changes in the HLA sequence (HLA-B*5802 only differs in three amino acids from the "good" HLA-B*5801 allele) can so profoundly affect HIV disease outcome are still unclear and are not in all cases simply attributable to different CTL epitope repertoires presented on these alleles [35,36]. The fact that this allele, as well as the HLA-B*1503 allele are present at high frequency and are both associated with higher viral loads in HIV infected individuals (HLA-B*1503 is a "good" allele in the North American population where it is rare; ref [27]) is in line with earlier reports that found an advantage of expressing rare HLA supertype alleles in controlling HIV [37].…”