Dendritic cell and T cell interactions: their role in HIV-1 spread and latency

Human immunodeficiency virus (HIV-1) infection remains a global health issue with approximately 33 million people living with HIV-1 worldwide. While HIV-1 preferentially infects activated T cells, multiple cells, including dendritic cells (DC), can also be infected. In vitro, thymocytes and resting CD4+ T cells are relatively resistant to CCR5 (R5)-tropic HIV-1 infection. In comparison, thymocytes and resting CD4+ T cells found in lymphoid tissues are clearly infected, suggesting a requirement for interactions with other cells and/or soluble factors. We hypothesised that the interaction between DC and T cells within tissues can facilitate infection of thymocytes and resting T cells, which may lead to altered CD4+ T cell homeostasis and long term persistence of HIV-1. Here we demonstrate a role for DC in the: [1] enhancement of productive infection in the thymus; and [2] establishment of latency in resting CD4+ T cells. We first demonstrated that productive HIV-1 infection can be established in both thymic plasmacytoid DC (pDC) and myeloid DC (mDC) and that thymic pDC were able to efficiently transfer productive R5 HIV-1 infection to both mature CD3hi and immature CD3lo thymocytes, which were otherwise refractory to R5 virus. This efficient transfer may represent a pathway to early infection and impaired production of thymocytes and CD4+ T cells in HIV-1-infected individuals. We then examined interactions between DC and resting CD4+ T cells isolated from blood to determine if this interaction was critical for infection of resting CD4+ T cells and the establishment of latency. We established a unique in vitro model, using enhanced green fluorescent protein (EGFP)-reporter viruses and resting CD4+ T cells labelled with the proliferation dye SNARF, to study the establishment of latency in resting CD4+ T cells. We demonstrated post-integration latency in non-proliferating CD4+ T cells following co-culture with syngeneic DC, which was facilitated by mDC, but not pDC. This effect was enhanced in the presence of an additional microbial stimulus, SEB, and required both DC-T cell contact and soluble factors, secreted by the DC as a result of HIV-1 stimulation. By comparing the gene profiles of these latently infected CD4+ T cells with those of mock-infected CD4+ T cells, we observed the induction of multiple genes associated with cell cycle arrest and the inhibition of HIV-1 transcription, while genes required for active cell cycle and NF-kappaB activation were repressed. Our results suggest a possible pathway for mDC-induced latency in CD4+ T cells in which low levels of cell activation may allow for enhanced HIV-1 integration but subsequent blocks in transcription and cell proliferation prevent progression to productive infection. This novel model can be used to further understand the different mechanisms involved in the establishment of HIV-1 latency. In summary, we have demonstrated that DC are important both in the spread of productive HIV-1 infection and the establishment of HIV-1 latency. An improved understanding of the interactions between DC and T cells, in the presence of HIV-1, may identify novel approaches to overcome the reduced thymic output of CD4+ T cells and eliminate the HIV-1 reservoir.