HIV-1 promotes loss of CD4 ⁺ T cell stemness and enrichment of effector-like states via Vpr-mediated TCF7 degradation

HIV-1 Vpr is abundantly packaged into virions and remodels host cells immediately after entry. Here, using high-efficiency HIV-1 infection protocols and unbiased proteomics in primary CD4+ T cells, we identify the T cell fate regulator TCF7 (TCF-1) as a previously unrecognized Vpr target. Virion-delivered Vpr rapidly depleted TCF7 in both resting and activated CD4+ T cells, which was a conserved activity of diverse Vpr proteins. The activity was independent of canonical Vpr substrate engagement but resulted terminally in proteasomal degradation of TCF7. TCF7 suppressed HIV-1 production and Env incorporation, whereas its depletion promoted loss of stem-like properties and differentiation toward effector phenotypes. Accordingly, effector T cell differentiation states are associated with productive HIV-1 infection and reduced TCF7 abundance. Thus, Vpr-mediated TCF7 depletion couples enhanced viral fitness to reprogramming of CD4+ T cell identity, generating permissive differentiated cells while impairing the maintenance of effective antiviral immunity via reduced T cell stemness.