ASCT2 inhibits HIV-1 infectivity by promoting the incorporation of a gp160/ASCT2 complex into virions

Abstract

Restriction factors are type I interferon (IFN)-inducible proteins that provide an early line of defense against HIV-1. Our current findings propose the amino acid transporter ASCT2 as a new host plasma membrane transporter that restricts the infectivity of HIV-1 viral particles. Our results show that ASCT2 is constitutively expressed in CD4+ T cells and macrophages, but its expression can be upregulated by the antiviral cytokine IFNα. We also found that ASCT2 is downmodulated from the cell surface of HIV-1-infected CD4+ T cells and macrophages. Our experiments suggest that ASCT2 interacts with the Env precursor gp160 in the endoplasmic reticulum (ER) and forms a complex of uncleaved gp160 and immature ASCT2. This complex can be incorporated into nascent viral particles and may lead to lower infectivity of progeny HIV-1. However, the restriction activity of ASCT2 against HIV-1 is counteracted by the accessory protein Vpu. We found that Vpu interacts with ASCT2 in the ER and prevents ASCT2 maturation through the N-glycosylation pathway, resulting in the downmodulation of ASCT2 from the plasma membrane. In summary, our results suggest that the amino acid transporter ASCT2 functions as an IFNα-inducible restriction factor against HIV-1 by promoting the incorporation of the complex formed by the inactive precursor of Env gp160 and immature ASCT2 into the viral particles, which is counteracted by the HIV-1 accessory protein Vpu.