HIV envelope suppresses CD4⁺ T cell activation independent of T regulatory cells

We previously demonstrated that HIV envelope glycoprotein (Env), delivered in the form of a vaccine and expressed by dendritic cells or 293T cells, could suppress Ag-stimulated CD4⁺ T cell proliferation. The mechanism remains to be identified but is dependent on CD4 and independent of coreceptor binding. Recently, CD4⁺ regulatory T (Treg) cells were found to inhibit protective anti-HIV CD4⁺ and CD8⁺ T cell responses. However, the role of Tregs in HIV remains highly controversial. HIV Env is a potent immune inhibitory molecule that interacts with host CD4 ⁺ cells, including Treg cells. Using an in vitro model, we investigated whether Treg cells are involved in Env-induced suppression of CD4⁺ T cell proliferation, and whether Env directly affects the functional activity of Treg cells. Our data shows that exposure of human CD4⁺ T cells to Env neither induced a higher frequency nor a more activated phenotype of Treg cells. Depletion of CD25⁺ Treg cells from PBMC did not overcome the Env-induced suppression of CD4⁺ T cell proliferation, demonstrating that CD25⁺FoxP3⁺ Treg cells are not involved in Envinduced suppression of CD4⁺ T cell proliferation. In addition, we extend our observation that similar to Env expressed on cells, Env present on virions also suppresses CD4⁺ T cell proliferation.