The lysosomal glutamine transporter SLC38A7/SNAT7 modulates SAMHD1 antiviral activity and promotes HIV-1 production in human macrophages

Abstract

HIV-1 (Human Immunodeficiency Virus type 1) infects macrophages, which resist to the cytopathic effects of the virus and are considered as viral reservoirs. However, the cellular factors involved in viral production by human macrophages have not been fully identified. In this study, we focused on the amino acid transporter SNAT7 (small neutral amino-acid transporter 7), member of the SLC38 solute carrier family, which is the main lysosomal transporter of glutamine from the lysosome to the cytoplasm. Its expression was increased by HIV-1 infection. We revealed that the absence of SNAT7 inhibited viral production not only at the level of protein synthesis, but also early at the level of reverse transcription, without affecting global RNA or protein synthesis in the cells. The reduction in HIV expression upon SNAT7 depletion correlated with a reduction in the levels of an inactive form of the SAMHD1 (SAM domain- and HD domain-containing protein) restriction factor and was rescued following SAMHD1 degradation. Lastly, supplementation of the extracellular medium with glutamine in the absence of SNAT7 partially restored viral production. Together, our data reveal that glutamine extracted from lysosomes is involved in the early stages of the HIV-1 cycle and that the SNAT7 glutamine transporter acts as a dependency factor for HIV-1 in human macrophages.