A new mechanism of SAMHD1 inhibition of HIV-1 infection by induction of autophagy

Abstract

Sterile alpha motif and histidine/aspartic domain-containing protein 1 (SAMHD1) can inhibit human immunodeficiency virus (HIV)-1 replication by reducing the intracellular deoxynucleoside triphosphate (dNTP) pool and enhance the antiviral potency of nucleoside reverse transcriptase inhibitors (NRTIs) in myeloid cells. NRTIs work well in activated CD4+ T cells with high dNTP concentrations but fail in SAMHD1(-/-) myeloid cells with lower dNTP concentrations. The reason for the poor performance of NRTIs in SAMHD1(-/-) myeloid cells is unclear. We hypothesize that the low dNTP pool in myeloid cells caused by SAMHD1 phosphohydrolase activity can induce autophagy to inhibit HIV-1 infection, but activated CD4+ T cells do not have such autophagy because of the high concentration of intracellular dNTPs. Our hypothesis is supported by two findings: dNTP deficiency can induce autophagy and autophagy can inhibit HIV-1 infection. The importance of our hypothesis is not limited to the inhibition of HIV-1 infection; it is also of great importance to other viral infections, the immune response, and cancer biology.