The roles of HIV-1 specific interferon gamma (IFN-gamma) producing CD8+T lymphocyte responses and HLA class I alleles on viral escape and viral control in HIV-1 infected Thai individuals

Abstract

The role of CD8+ T cells and HLA class I in viral escape and viral control has not been well characterized in clade CRF01_AE and Asian ethnics. 240 naïve HIV-1 infected Thai individuals were screened by IFN-γ ELISpot assay for HIV-1 specific CD8+ T cell responses with a set of 413 overlapping peptides (OLPs) of HIV-1 proteome. Novel epitopes were identified by bioinformatics analysis and were further characterized by HLA restriction and fine epitope mapping. The association of epitopes and/or HLA alleles with low plasma HIV-RNA levels and/or viral escape was analyzed using non parametric statistical analysis. We found that HLA-B*1302 and HLA-A*2410 after exclude other known protective alleles were associated with low plasma HIV-RNA level (p = 0.0024 and p = 0.0062, respectively). The four most common CD8+ T cell responded HIV-1 targets included Pol (91%), Gag (87%), Env (83%) and Nef (78%). As reported in other ethnic and subtypes, Gag-specific CD8+ T cell response was found associated with low plasma HIV-RNA level whereas Env-specific CD8+ T cell response was associated with high plasma HIV-RNA level. From 195 HIV-1 CRF01_AE infected Thais, 33 OLPs as potential novel epitopes were identified. A novel immunodominant (29% response rate) restricted by HLA-Cw*0102: YI9 (in Gag-p24) which was associated with viral escape. Mutations at P2 (S278X), P4 (V280X) and P5 (S281G) impaired the ELISpot responses, however the P2 anchor S278K mutation had the highest negative impact (p = 0.0002). We also found two viral control epitopes, the first one is RI10 (HIV-protease, previously described in HIV-1 B clade as -B*13 restricted) was found restricted by HLA-A*0203 in Thais. Interestingly, HLA-A*0203+ve patients with RI10 responders had a significantly lower plasma HIV-RNA level than non-responders (p = 0.0167). Moreover, mutation in this RI10 had resulted to immune escape, but it was remained associated with low plasma HIV-RNA level, this may be due to compromising on their viral fitness. The other one is the known HLA-A*1101 epitope, AK11 (in Gag-p24), there was no significant mutation of viruses found in patients expressing A*1101. In conclusions: HLA-B*1302 and HLA*A2410 were associated with low plasma HIV-RNA level. Pol, Gag, Env and Nef are four most common HIV targets of CD8 T cells, however; only HIV-1 Gag was found associated with low plasma HIV-RNA level. Three CD8 epitopes: YI9, RI10 and AK11 restricted by HLA-Cw*0102, -A*0203 and -A*1101, respectively; were characterized. RI10 and AK11, but not YI9, were associated with lower plasma HIV-RNA level that possibly to HIV viral control. Further characterization of the rest of possible novel epitopes is warranted.