Prevalence of coronary heart disease in Scotland: Scottish Heart Health Study.

The biological mechanism(s) underlying the elevated risk of HIV-1 acquisition among vaccine recipients in Merck STEP study remain unclear. HIV-1 frequently adapts to CD8 T cell responses, leading to the accumulation of adapted epitopes (AE). Recently, we demonstrated that in chronic HIV infection, CD8 T responses skewed by HLA-I associated adaptation enhanced HIV trans-infection of CD4 T cells by dendritic cells (DCs). However, whether adaptation in HIV vaccines induces a pro-inflammatory status and aids in potentiating infection is unknown. Using in-vitro studies, we evaluated whether an enhanced CD4 T cell trans-infection mediated by AE-specific CD8 T cells could be a potential biological mechanism for the observed increased risk of HIV acquisition in the Step Study. We found that CD8 T cells responding to AE demonstrated a higher capacity in promoting DCs maturation than non-adapted epitope (NAE) (p=0.007). Additionally, DCs matured by AE-specific CD8 T cells, showed a higher trend in inducing HIV trans-infection of CD4 T cells in each of the four vaccinee samples tested. We also analyzed the potential in-vivo impact of adaptation on the rate of infection among vaccine recipients in the STEP study. Our data showed that vaccine recipients with high adaptation to the vaccine immunogen were at an increased risk of HIV acquisition compared to recipients with medium/low adaptation or placebos (HR=2.98, p=0.02, high (n=21), medium (n=639), low (n=192) and placebo (n=865)). Taken together, our results show that in STEP study, AE-specific CD8 T cells may have contributed to an enhanced risk of HIV-1 acquisition by promoting viral trans-infection of CD4 T cells by DC. These findings have important implications for future HIV vaccine design.