Low SAMHD1 expression following T-cell activation and proliferation renders CD4(+) T cells susceptible to HIV-1

OBJECTIVES: HIV-1 replication depends on the state of cell activation and division. It is established that SAMHD1 restricts HIV-1 infection of resting CD4(+) T cells. The modulation of SAMHD1 expression during T-cell activation and proliferation, however, remains unclear, as well as a role for SAMHD1 during HIV-1 pathogenesis. METHODS: SAMHD1 expression was assessed in CD4(+) T cells after their activation and in-vitro HIV-1 infection. We performed phenotype analyzes using flow cytometry on CD4(+) T cells from peripheral blood and lymph nodes from cohorts of HIV-1-infected individuals under antiretroviral treatment or not, and controls. RESULTS: We show that SAMHD1 expression decreased during CD4(+) T-cell proliferation in association with an increased susceptibility to in-vitro HIV-1 infection. Additionally, circulating memory CD4(+) T cells are enriched in cells with low levels of SAMHD1. These SAMHD1(low) cells are highly differentiated, exhibit a large proportion of Ki67(+) cycling cells and are enriched in T-helper 17 cells. Importantly, memory SAMHD1(low) cells were depleted from peripheral blood of HIV-infected individuals. We also found that follicular helper T cells present in secondary lymphoid organs lacked the expression of SAMHD1, which was accompanied by a higher susceptibility to HIV-1 infection in vitro. CONCLUSION: We demonstrate that SAMHD1 expression is decreased during CD4(+) T-cell activation and proliferation. Also, CD4(+) T-cell subsets known to be more susceptible to HIV-1 infection, for example, T-helper 17 and follicular helper T cells, display lower levels of SAMHD1. These results pin point a role for SAMHD1 expression in HIV-1 infection and the concomitant depletion of CD4(+) T cells.