HIV-1-specific T Cell Responses And Its Functional Profile In HIV-1 Clade B' Infected FPDs From Anhui And Henan Provinces

In this study,143 anti-retroviral therapy naive former plasma donors (FPDs) recruited from Anhui and Henan provinces were assessed for HIV-1-specific CTL responses with an IFN-y Elispot assay by using overlapping peptides (OLPs) covering the whole consensus clade B proteome, and 2-digit HLA typing was performed by PCR-SSP. We also evaluated the level of PD-1 expression and cytokine-producing T cell responses against HIV-1 proteins in a subset of 19 progressors and 11 controllers in this cohort to define which responses may lead to better control of viral replication.The structural HIV-1 proteins Gag, Pol, Env and the accessory protein Nef were targeted by 93.01%,86.71%,72.73% and 78.32% of studied individuals, respectively. There was a positive correlation between the cumulative magnitude of total HIV-specific CTL responses and viral loads. The magnitude and breadth of Pol-and Env-specific CTL responses were found positively correlated with viral loads significantly, as well as the magnitude but not breadth of Nef-specific CTL responses. In addition, an inverse correlation between Vpr-specific responses and viral loads was observed whether magnitude or breadth was concerned. When correlation between EFN-γresponse and CD4 counts were analyzed, a weak negative association between the Vpu-specific responses and CD4 counts was observed. Furthermore, we found that an increased breadth of CTL responses targeting Vpr resulted in elevated CD4 counts.To further investigate the role of HIV-1 specific CTL in the viral control, we looked for whether the distribution of HIV-1 protein-specific responses among total responses could have effect on the control of HIV replication. A statistically significant inverse correlation between viral loads and the contribution of Gag-specific response to total response as well as a statistically significant positive correlation between CD4 counts and the contribution of Gag-specific response to total response were observed.The contribution of Pol-and Env-specific responses to total response were found positively correlating with viral loads, while for the contribution of Vpr-specific response to total response, an inverse correlation with viral loads and a positive correlation with CD4 counts were found.In addition, we observed that subjects homozygous at HLA classⅠlocus had higher plasma viral loads. The HLA-A*30/B*13/Cw*06 haplotype was associated with low viral loads in the studied individuals. In HLA-A*30/B*13/Cw*06-positive individuals, an inverse correlation between viral loads and the breadth of Gag-, Vpr-and total HIV-1-specific CTL response was found.PD-1 expression on CD8+T cells in HIV infected progressors was significantly higher than those in elite controllers. PD-1 expression on CD8+T cells as well as CD4+T cells were found positively correlating to plasma viral load in HIV infected progressors. Compared to progressors, more "Only effector" Gag-specific CD4+T cells defined by IFN-γand IL-2 secretion were observed in the controllers. The Gag-specific dual IL-2/IFN-γsecreting CD8+and CD4+ populations and Nef-specific dual IL-2/IFN-γsecreting CD8+ subpopulations in the controllers were significantly higher than progressors. Furthermore, the proportion of Gag-and Pol-specific TNF-α+ IL-2+ IFN-γ+ CD4+ T cells in the controllers were significantly higher than progressors. Response were then grouped by number of functions, and the contribution of each pattern toward the total response was assessed and compared for each peptide pool. Upregulation of PD-1 expression on cytokine-secreting HIV-specific T cells was found. These data are consistent with others that associated decreased viral loads and increased CD4 counts with the relative dominance of Gag-specific CTL responses. Pol-and Env-specific CTL responses seemed less effective than Gag-specific responses in controlling viral replication. The advantage of HLA-A*30/B*13/Cw*06 haplotype with viral control is associated with the contribution of Gag-specific CTL responses. PD-1 which often correlates with T-cell exhaustion is associated with high viral load, and the T-cell exhaustion may be caused by T cell activation. Poly-functional Gag-specific T cell responses in controllers may correlate with better viral control in this population.These findings may provide useful information for HIV-1 vaccine development and evaluation.