Myeloid dendritic cells induce HIV-1 latency in non-proliferating CD4+ T cells

PLoS Pathog. 2013;9(12):e1003799. doi: 10.1371/journal.ppat.1003799. Epub 2013 Dec 5.

Abstract

Latently infected resting CD4(+) T cells are a major barrier to HIV cure. Understanding how latency is established, maintained and reversed is critical to identifying novel strategies to eliminate latently infected cells. We demonstrate here that co-culture of resting CD4(+) T cells and syngeneic myeloid dendritic cells (mDC) can dramatically increase the frequency of HIV DNA integration and latent HIV infection in non-proliferating memory, but not naïve, CD4(+) T cells. Latency was eliminated when cell-to-cell contact was prevented in the mDC-T cell co-cultures and reduced when clustering was minimised in the mDC-T cell co-cultures. Supernatants from infected mDC-T cell co-cultures did not facilitate the establishment of latency, consistent with cell-cell contact and not a soluble factor being critical for mediating latent infection of resting CD4(+) T cells. Gene expression in non-proliferating CD4(+) T cells, enriched for latent infection, showed significant changes in the expression of genes involved in cellular activation and interferon regulated pathways, including the down-regulation of genes controlling both NF-κB and cell cycle. We conclude that mDC play a key role in the establishment of HIV latency in resting memory CD4(+) T cells, which is predominantly mediated through signalling during DC-T cell contact.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology*
  • Cell Cycle Checkpoints / genetics
  • Cell Proliferation
  • Cells, Cultured
  • Dendritic Cells / physiology*
  • Gene Regulatory Networks
  • HEK293 Cells
  • HIV-1 / physiology*
  • Humans
  • Microarray Analysis
  • Myeloid Cells / physiology*
  • Transcriptome
  • Virus Latency* / genetics
  • Virus Latency* / immunology