Abstract
BackgroundSubtype A is a major strain in the HIV-1 pandemic in eastern Europe, central Asia and in certain regions of east Africa, notably in rural Kenya. While considerable effort has been focused upon mapping and defining immunodominant CTL epitopes in HIV-1 subtype B and subtype C infections, few epitope mapping studies have focused upon subtype A.ResultsWe have used the IFN-γ ELIspot assay and overlapping peptide pools to show that the pattern of CTL recognition of the Gag and Nef proteins in subtype A infection is similar to that seen in subtypes B and C. The p17 and p24 proteins of Gag and the central conserved region of Nef were targeted by CTL from HIV-1-infected Kenyans. Several epitope/HLA associations commonly seen in subtype B and C infection were also observed in subtype A infections. Notably, an immunodominant HLA-C restricted epitope (Gag 296–304; YL9) was observed, with 8/9 HLA-CW0304 subjects responding to this epitope. Screening the cohort with peptide sets representing subtypes A, C and D (the three most prevalent HIV-1 subtypes in east Africa), revealed that peptide sets based upon an homologous subtype (either isolate or consensus) only marginally improved the capacity to detect CTL responses. While the different peptide sets detected a similar number of responses (particularly in the Gag protein), each set was capable of detecting unique responses not identified with the other peptide sets.ConclusionHence, screening with multiple peptide sets representing different sequences, and by extension different epitope variants, can increase the detectable breadth of the HIV-1-specific CTL response. Interpreting the true extent of cross-reactivity may be hampered by the use of 15-mer peptides at a single concentration and a lack of knowledge of the sequence that primed any given CTL response. Therefore, reagent choice and knowledge of the exact sequences that prime CTL responses will be important factors in experimentally defining cross-reactive CTL responses and their role in HIV-1 disease pathogenesis and validating vaccines aimed at generating broadly cross-reactive CTL responses.
Highlights
Subtype A is a major strain in the human immunodeficiency virus type 1 (HIV-1) pandemic in eastern Europe, central Asia and in certain regions of east Africa, notably in rural Kenya
The frequency of responses detected in this cohort against individual peptides was not as great as that detected in studies of subtype B infection [10,11], the pattern of cytotoxic T lymphocytes (CTL) responses across the Gag and Nef proteins was remarkably similar to studies from other subtypes [10,11,26,31]
We have shown that in subtype A infections the pattern of immunodominance and epitope clustering observed within the Gag and Nef proteins of HIV-1 is similar to that seen in subtype B and C infections
Summary
Subtype A is a major strain in the HIV-1 pandemic in eastern Europe, central Asia and in certain regions of east Africa, notably in rural Kenya. The development of an efficacious prophylactic vaccine for human immunodeficiency virus type 1 (HIV-1) is the goal of a concerted worldwide research effort [1,2]. The precise correlates of protective immunity against HIV-1 infection are not clearly defined, a large body of accumulated data suggests that an ideal HIV-1 vaccine will need to stimulate both humoral and cellular immune responses against the virus [3]. CD8 cytotoxic T lymphocytes (CTL) constitute a major component of the cellular arm of the immune response, and have a central role in the control of initial viremia immediately following HIV-1 infection and in the establishment of long-term AIDS free survival [6,7]. The fine mapping of T cell epitopes and the identification of immunodominant regions of HIV-1 gene products is integral to vaccine design, to the development of immunotherapeutic strategies, and to the optimization of assays for assessing vaccine efficacy
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