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

Abstract

BackgroundCombination 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.ResultsmDC (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).ConclusionsAPC 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0204-2) contains supplementary material, which is available to authorized users.

The Pathway To Establishing HIV Latency Is Critical to How Latency Is Maintained and Reversed

“…This observation is in agreement with data from our previous work (35). Coculture of myeloid cells with T cells at the time of infection maintained latency in nonproliferating T cells in a model of postactivation latency (35). Our study suggests that there is ongoing expression from latently infected cells in both pre-and postactivation latency albeit with different frequencies.…”

“…Although it is critical to determine the frequency of noninduced latently infected cells among proliferating T cells, the specificity of the effect on monocyte-containing cultures suggests that APC-derived interactions could maintain latency by suppressing EGFP expression in postactivation latency despite activation and proliferation. This observation is in agreement with data from our previous work (35). Coculture of myeloid cells with T cells at the time of infection maintained latency in nonproliferating T cells in a model of postactivation latency (35).…”

“…Low-level transcription from latently infected T cells, as measured by cell-associated unspliced HIV RNA, has been described for HIV-infected individuals on suppressive ART (31)(32)(33). In addition, in vitro, the spontaneous expression of either EGFP or Gag without exogenous stimulation has been demonstrated (34,35). We found a significantly lower frequency of spontaneous EGFP expression in the preactivation latency than in the postactivation latency model with matched donors (Fig.…”

“…In our previous study, using transcriptome sequencing (RNA-seq) analysis of APC-T cell cocultures, we identified 4 surface proteins, including members of the sialic acid binding immunoglobulin-type lectin (SIGLEC) family, the C-type lectin domaincontaining (CLEC) family, the leukocyte-associated immunoglobulin-like receptor (LILRA) family, and the G-protein-coupled receptor (GPCR) family (35). Molecules from the SIGLEC family are able to inhibit T cell activation (53).…”

Coexpression of CD163 and CD141 identifies human circulating IL-10-producing dendritic cells (DC-10)

“…The ex vivo DC-10 transcriptome resembles that of monocyte-derived DC-10 To study similarities between ex vivo and in vitro differentiated DC-10, we performed RNA-sequencing analyses. As a control, we used donor-matched in vitro differentiated mDCs (in vitro mDCs) and published RNA-seq data of FACS-isolated cDCs (ex vivo cDCs, GSE70106 30 ). The large majority of transcriptional variance (55%) was linked to the origin of cell populations, with in vitro DC-10 and mDCs divided from ex vivo DC-10 and cDCs by PC1 (Fig.…”