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

Abstract

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 SAMHD1low cells are highly differentiated, exhibit a large proportion of Ki67+ cycling cells and are enriched in T-helper 17 cells. Importantly, memory SAMHD1low 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.

Immune Activation Influences SAMHD1 Expression and Vpx-mediated SAMHD1 Degradation during Chronic HIV-1 Infection

“…Long-term cART will not restore this cell subset. This result is consistent with the result of another study, which revealed that SAMHD1 - activated CD4 + T cells are more permissive to HIV-1 infection and thus might lead to the loss of this cell subset in HIV-1 infected patients26. SAMHD1 is a host enzyme that participates in the metabolism of DNA via regulation of intracellular dNTP levels2.…”

HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms

“…Furthermore, CCR6 + versus CCR6 -T cells stimulated via the TCR in the presence/absence of ATRA expressed decreased levels of IFN-stimulated genes, such as IFITM1, IFITM2, IFITM3, and IRF8 (Supplemental Tables 1-4), consistent with the low Th17 ability to respond to IFN (23). Finally, although differences in the expression of SAMHD1, a key IFN-induced HIV restriction factor (22,56,57), were not observed in the microarrays, in the presence/absence of ATRA, levels of SAMHD1 mRNA measured by RT-PCR were significantly lower in CCR6 + versus CCR6 -T cells (Supplemental Figure 5). This stresses the existence of false negatives in high-throughput transcriptional screenings.…”

“…( [21][22][23]. Most recently, CD4 + T cells expressing the Th17 markers CCR6 and RORγt were identified as the first targets of SIV during vaginal transmission (24); in addition, the detrimental role of viral permissive CCR6 + T cell infiltration into the gut was documented (25).…”

SAMHD1: At the Crossroads of Cell Proliferation, Immune Responses, and Virus Restriction

“…Rhesus macaques infected with a wild-type or a truncated form of Vpx that abrogates its capacity to induce SAMHD1 degradation exhibited a differential virus replication capacity and plasma viremia [56]. CD4 + T cell subsets that are more prone to HIV-1 infection showed reduced SAMHD1 levels [57]. Additionally, a subset of HIV elite controllers (EC) [58], specifically those individuals that suppress virus replication in the absence of antiretroviral therapy for a prolonged period of time, had lower SAMHD1 mRNA expression than did viremic HIV patients or seronegative healthy donors [59].…”