{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Victoria S"],"funding":["Deutsche Forschungsgemeinschaft"],"pagination":["e0018225"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11998544"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["99(4)"],"pubmed_abstract":["HIV-1 replication in macrophages is highly variable with internal virus accumulation in so-called virus-containing compartments (VCCs). VCCs represent a reservoir that is shielded from the antiviral immune response. VCC formation has been studied in lab-adapted HIV-1, but it has not been investigated whether primary HIV-1 strains induce VCCs. Furthermore, although macrophages transmit HIV-1 from VCCs to CD4+ T cells, the effect of T cells on VCCs is unknown. We analyzed the ability of primary and lab-adapted HIV-1 to replicate in macrophages, the effect of non-infected CD4+ T cell coculture, and VCC formation. All HIV-1 strains replicated in CD4+ T cells, whereas only lab-adapted HIV-1 replicated efficiently in macrophage monocultures. Coculture with non-infected CD4+ T cells enhanced the replication of primary HIV-1 in macrophages, a process associated with increased VCC formation and dependent on direct cell-to-cell contact. Broadly neutralizing antibodies differentially affected CD4+ T cell-mediated enhancement of HIV-1 replication in macrophages. CD4 antibody treatment of macrophages phenocopied the infection-promoting effect of CD4+ T cell coculture. In conclusion, non-infected CD4+ T cells facilitate primary HIV-1 replication in macrophages, and the induction of VCCs appears to be a proxy for this phenotype. VCC formation and HIV-1 replication in macrophages are promoted by non-infected CD4+ T cells in a CD4- and GP120-dependent manner. Our findings highlight the critical role of T cell-macrophage interaction in HIV-1 replication dynamics and VCC formation and call for strategies to interfere with VCCs in order to target 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 enhanced 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 addressing the latent HIV-1 T cell reservoir but also targeting VCC formation in macrophages to achieve the ultimate goal of functional HIV-1 cure."],"journal":["Journal of virology"],"pubmed_title":["CD4+ T cells facilitate replication of primary HIV-1 strains in macrophages and formation of macrophage internal virus-containing compartments."],"pmcid":["PMC11998544"],"funding_grant_id":["SCHI1073/11-1 431861552"],"pubmed_authors":["Victoria S","Vavouras Syrigos G","Schindler M","Leyens J","Meckes LM","Turk G"],"additional_accession":[]},"is_claimable":false,"name":"CD4+ T cells facilitate replication of primary HIV-1 strains in macrophages and formation of macrophage internal virus-containing compartments.","description":"HIV-1 replication in macrophages is highly variable with internal virus accumulation in so-called virus-containing compartments (VCCs). VCCs represent a reservoir that is shielded from the antiviral immune response. VCC formation has been studied in lab-adapted HIV-1, but it has not been investigated whether primary HIV-1 strains induce VCCs. Furthermore, although macrophages transmit HIV-1 from VCCs to CD4+ T cells, the effect of T cells on VCCs is unknown. We analyzed the ability of primary and lab-adapted HIV-1 to replicate in macrophages, the effect of non-infected CD4+ T cell coculture, and VCC formation. All HIV-1 strains replicated in CD4+ T cells, whereas only lab-adapted HIV-1 replicated efficiently in macrophage monocultures. Coculture with non-infected CD4+ T cells enhanced the replication of primary HIV-1 in macrophages, a process associated with increased VCC formation and dependent on direct cell-to-cell contact. Broadly neutralizing antibodies differentially affected CD4+ T cell-mediated enhancement of HIV-1 replication in macrophages. CD4 antibody treatment of macrophages phenocopied the infection-promoting effect of CD4+ T cell coculture. In conclusion, non-infected CD4+ T cells facilitate primary HIV-1 replication in macrophages, and the induction of VCCs appears to be a proxy for this phenotype. VCC formation and HIV-1 replication in macrophages are promoted by non-infected CD4+ T cells in a CD4- and GP120-dependent manner. Our findings highlight the critical role of T cell-macrophage interaction in HIV-1 replication dynamics and VCC formation and call for strategies to interfere with VCCs in order to target 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 enhanced 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 addressing the latent HIV-1 T cell reservoir but also targeting VCC formation in macrophages to achieve the ultimate goal of functional HIV-1 cure.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Apr","modification":"2025-07-03T03:06:47.719Z","creation":"2025-07-03T03:06:47.719Z"},"accession":"S-EPMC11998544","cross_references":{"pubmed":["40130873"],"doi":["10.1128/jvi.00182-25"]}}