Membrane metalloprotease TRABD2A restricts HIV-1 progeny production in resting CD4+ T cells by degrading viral Gag polyprotein

Abstract

Resting CD4⁺ T cells are highly resistant to the production of human immunodeficiency virus type 1 (HIV-1). However, the mechanism by which resting CD4⁺ T cells restrict such production in the late viral replication phase of infection has remained unclear. In this study, we found that the cell membrane metalloprotease TRAB domain-containing protein 2A (TRABD2A) inhibited this production in resting CD4⁺ T cells by degrading the virion structural precursor polyprotein Gag at the plasma membrane. Depletion or inhibition of metalloprotease activity by TRABD2A profoundly enhanced HIV-1 production in resting CD4⁺ T cells. TRABD2A expression was much higher in resting CD4⁺ T cells than in activated CD4⁺ T cells and was considerably reduced by T cell activation. Moreover, reexpressing TRABD2A reinforced the resistance of activated CD4⁺ T cells to the production of HIV-1 progeny. Collectively, these results elucidate the molecular mechanism employed by resting CD4⁺ T cells to potently restrict the assembly and production of HIV-1 progeny.