The loss of CCR6 + and CD161 + CD4 + T-cell homeostasis contributes to disease progression in SIV-infected rhesus macaques

Although previous studies have shown that CD4 + T cells expressing CCR6 and CD161 are depleted from blood during HIV infection, the mechanisms underlying their loss remain unclear. In this study, we investigated how the homeostasis of CCR6 + and CD161 + CD4 + T cells contributes to SIV disease progression and the mechanisms responsible for their loss from circulation. By comparing SIV infection in rhesus macaques (RMs) and natural host sooty mangabeys (SMs), we found that the loss of CCR6 + and CD161 + CD4 + T cells from circulation is a distinguishing feature of progressive SIV infection in RMs. Furthermore, while viral infection critically contributes to the loss of CD161 + CCR6 − CD4 + T cells, a redistribution of CCR6 + CD161 − and CCR6 + CD161 + CD4 + T cells from the blood to the rectal mucosa is a chief mechanism for their loss during SIV infection. Finally, we provide evidence that the accumulation of CCR6 + CD4 + T cells in the mucosa is damaging to the host by demonstrating their reduction from this site following initiation of antiretroviral therapy in SIV-infected RMs and their lack of accumulation in SIV-infected SMs. These data emphasize the importance of maintaining CCR6 + and CD161 + CD4 + T-cell homeostasis, particularly in the mucosa, to prevent disease progression during pathogenic HIV/SIV infection.