The role of antigen presenting cells in the induction of HIV-1 latency in resting CD4⁺ T-cells

Background: Combination antiretroviral therapy (cART) is able to control HIV-1 viral replication, however long-lived latent infection in resting memory CD4⁺ T-cells persist. The mechanisms for establishment and maintenance of latent infection in resting memory CD4⁺ T-cells remain unclear. Previously we have shown that HIV-1 infection of resting CD4⁺ T-cells co-cultured with CD11c⁺ myeloid dendritic cells (mDC) produced a population of non-proliferating T-cells with latent infection. Here we asked whether different antigen presenting cells (APC), including subpopulations of DC and monocytes, were able to induce post-integration latent infection in resting CD4⁺ T-cells, and examined potential cell interactions that may be involved using RNA-seq. Results: mDC (CD1c⁺), SLAN⁺ DC and CD14⁺ monocytes were most efficient in stimulating proliferation of CD4⁺ T-cells during syngeneic culture and in generating post-integration latent infection in non-proliferating CD4⁺ T-cells following HIV-1 infection of APC-T cell co-cultures. In comparison, plasmacytoid DC (pDC) and B-cells did not induce latent infection in APC-T-cell co-cultures. We compared the RNA expression profiles of APC subpopulations that could and could not induce latency in non-proliferating CD4⁺ T-cells. Gene expression analysis, comparing the CD1c⁺ mDC, SLAN⁺ DC and CD14⁺ monocyte subpopulations to pDC identified 53 upregulated genes that encode proteins expressed on the plasma membrane that could signal to CD4⁺ T-cells via cell-cell interactions (32 genes), immune checkpoints (IC) (5 genes), T-cell activation (9 genes), regulation of apoptosis (5 genes), antigen presentation (1 gene) and through unknown ligands (1 gene). Conclusions: APC subpopulations from the myeloid lineage, specifically mDC subpopulations and CD14⁺ monocytes, were able to efficiently induce post-integration HIV-1 latency in non-proliferating CD4⁺ T-cells in vitro. Inhibition of key pathways involved in mDC-T-cell interactions and HIV-1 latency may provide novel targets to eliminate HIV-1 latency.