Leyens, J. | Search bioRxiv

bioRxiv2026

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.

microbiology↗

bioRxiv2024

CD4+ T cells facilitate replication of primary HIV-1 strains in macrophages and formation of macrophage internal virus-containing compartments.

HIV-1 infects CD4+ T cells and macrophages. However, replication of HIV-1 in these cell types is highly variable and may depend on the use of CCR5 as a co-receptor. In addition, there is internal accumulation of infectious HIV-1 in so-called virus-containing compartments of macrophages (VCCs). VCCs are thought to represent a persistent viral reservoir that is shielded from the antiviral immune response. To date, VCC formation has only been studied in lab-adapted HIV-1 and it is unknown whether VCCs play a role in the replication of primary HIV-1 strains. Furthermore, although macrophages transmit HIV-1 from VCCs to CD4+ T cells, it is unknown whether T cells have an impact on VCC formation. We analyzed the ability of primary and lab-adapted HIV-1 to replicate in macrophages, the effect of coculture with non-infected CD4+ T cells and the extent of VCC formation. Although differentially, all HIV-1 strains replicated in CD4+ T cells, whereas only lab-adapted HIV-1 replicated in macrophages. Strikingly, replication of patient-derived HIV-1 in macrophages was enhanced by coculture with non-infected CD4+ T cells and correlated with VCC formation. In conclusion, non-infected CD4+ T cells facilitate the replication of primary HIV-1 strains in macrophages and the formation of VCCs appears to be a proxy for this phenotype. Our study suggests an essential role for VCCs in the replication of patient-derived HIV-1 in macrophages, which is fueled by non-infected CD4+ T cells. Furthermore, our findings call for strategies to specifically disrupt VCC formation in order to eliminate the HIV-1 reservoir in macrophages. IMPORTANCEHere we focus on the intimate interplay between HIV-1 infected macrophages and CD4+ T cells. Specifically, we analyzed whether primary HIV-1 strains induce virus-containing compartments (VCCs) within macrophages, which are thought to serve as viral sanctuaries and macrophage reservoirs. Notably, primary HIV-1 strains were unable to replicate in macrophages and induce VCCs unless they were cocultured with non-infected CD4+ T cells, leading to increased VCC formation and viral replication. This suggests an essential role for non-infected CD4+ T cells in facilitating primary HIV-1 replication in macrophages. Our data highlight the importance of not only targeting the latent HIV-1 T-cell reservoir, but also targeting VCC formation in macrophages to achieve the ultimate goal of functional HIV-1 cure.

microbiology↗