The role of HLA-C restricted CD8+T cell responses in the control of HIV replication.

Abstract

Certain HLA-B-restricted CD8+ T cell responses are associated with control of viremia

whereas HLA-Cw* restricted responses, including Gag epitopes are associated with high

viremia. To better understand the role of HLA-Cw* restricted epitopes in viral control,

HLA-Cw* restricted epitopes were optimally defined. Seventy eight study subjects from

a cohort of 451 chronically infected participants had HLA-Cw* restricted CD8+ T cells

responses as quantified by intracellular cytokine staining assessing IFN-γ secretion. Fine

mapping and HLA restriction of the optimally defined HLA-Cw* restricted epitopes were

performed using ELISPOT assay. Functional avidity of responses was assessed by

peptide dilution in an ELISPOT assay. Two novel HLA-Cw* restricted epitopes Cw*04-

TF10 (in reverse transcriptase) and Cw*08-RM9 (in gp120) were optimally defined. A

previously described epitope, Cw*07- KY11 (Nef) was the most frequently targeted

epitope in this cohort (30/78) and has high functional avidity compared to other HLA-Cw

restricted CD8+ T cell responses.

The polyfunctionality of HLA-B*57/5801-restricted Gag-specific HIV-1 CD8+ T cell

responses and HLA-Cw*07-KY11 restricted CD8+ T cell responses within the same

study subject was determined. Polyfunctionality of CD8+ T cell responses to HLAB*

57/5801 and HLA-Cw*07 restricted epitopes were determined in nine study subjects

assessing IFN-γ, TNF-α, IL-2, MIP-1β, and CD107a by multicolour flow cytometry.

Additionally gag and nef genes were sequenced from plasma. HLA-B*57/5801-restricted

IFN-γ-producing CD8+ T cell responses were of lower magnitude than HLA-Cw*07

responses (p=0.0012) for the nine subjects. The majority of responses were

monofunctional (75%), irrespective of HLA restriction. HLA-B*57/5801 and HLACw*

07 restricted CD8+ T cells did not differ significantly in polyfunctionality (p=0.84).

Possession of ≥3 functions correlated positively with CD4+ T cell counts (r=0.85;

p=0.006). The percentages of monofunctional CD8+ T cells inversely correlated with

CD4+ T cell counts (r=-0.79; p=0.05). There was no correlation between

polyfunctionality and viral load and sequence variation within targeted epitopes did not

impact polyfunctionality. These results suggest that polyfunctionality of HIV-1-specific

CD8+ T cells is associated with disease progression independent of restricting HLA

alleles, and that loss of these polyfunctional cells correlates with increased in the

frequency of monofunctional virus-specific CD8+ T cells. In addition, sequence variation

does not appear to significantly impact CD8+ T cell polyfunctionality in chronic HIV

infection.