Identification of human endogenous retrovirus (HERV-K (HML-2))-specific mucosal CD4+T cell responses in HIV-1-exposed, seronegative individuals

Abstract

The transcriptional silence of human endogenous retroviruses (HERV) can be disrupted in HIV-1 infection. We have reported that the strength of the HERV-specific CD8+ T cell response predicts lower HIV-1 viral load in untreated adults. To determine whether HERV-K immunity plays a role in inhibiting HIV-1 replication at a major site of transmission and CD4+ T cell depletion, we assessed these responses in gut-associated lymphoid tissue (GALT) from rectosigmoid biopsies and blood of HIV-1 exposed, seronegative (HESN) individuals (n=6) by flow cytometry. CMV pp65- and HIV-1 Gag-specific T cells were also measured, and all responses were compared with peripheral antigen-specific responses in uninfected, low-risk controls (n=11). With the exception of stronger CMV-specific CD8+ T cell responses in the HESN group (p=0.024), there were no significant differences between the magnitudes of peripheral antigen-specific T cell responses in the HESN vs. controls. However, HESN subjects had remarkably robust mucosal HIV-1- (median %CD4+cytokine+cells=2.67) and HERV-specific (median %CD4+cytokine+cells=3.41) CD4+ responses, which were much stronger than the corresponding PBMC responses (p=0.0079 and p<0.0001, respectively). These findings suggest that the GALT is an important site of HERV-K expression and immunity in individuals exposed to HIV-1, and should be further investigated in the context of novel vaccine strategies that target conserved antigens such as HERV.