Citation Information

Ngumbela KC, Day CL, Mncube Z, Nair K, Ramduth D, Thobakgale C, Moodley E, Reddy S, de Pierres C, Mkhwanazi N, Bishop K, van der Stok M, Ismail N, Honeyborne I, Crawford H, Kavanagh DG, Rousseau C, Nickle D, Mullins J, Heckerman D, Korber B, Coovadia H, Kiepiela P, Goulder PJ, Walker BD (2008). 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. AIDS research and human retroviruses, 24(1), 72-82. (pubmed) (doi)

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-B5801 expressing persons and poor prognosis with HLA-B5802. 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 B5801 (n = 93) and B5802 ( 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 B5802, and epitope presentation by B5802 contributed significantly less to the overall response as compared to B5801-restricted CD8 (+) T cells. Moreover, viral load in B5802-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 B5802 compared to persons homozygous for other HLA-B alleles had significantly higher viral loads. Viral sequencing revealed strong selection pressure mediated through B5801-restricted responses but not through B5802. 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-B5802 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.