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

Abstract

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.