Myeloid Dendritic Cells Induce HIV-1 Latency in Non-proliferating CD4+ T Cells

Vanessa A Evans,Oleg Yegorov,Rafick-Pierre Sekaly,Paul U Cameron,Francesco A Procopio,Elias K Haddad,Sharon R Lewin,Paula C Ellenberg,Nitasha Kumar,Ali Filali,Candida Da Fonseca Pereira,Suha Saleh,Jean-Philippe Goulet,Susan R Ross

doi:10.1371/journal.ppat.1003799

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.

Highlights

Antiretroviral therapy (ART) for the treatment of HIV has led to a substantial reduction in morbidity and mortality; ART cannot cure HIV and life-long treatment is required
Using a novel model of resting CD4+ T cells co-cultured with primary Dendritic cells (DC), we demonstrate that myeloid DC induce post-integration latency in resting memory CD4+ T cells, which required close DC-T cell contact
We have developed a novel model of HIV latency in the laboratory

Summary

Introduction

Antiretroviral therapy (ART) for the treatment of HIV has led to a substantial reduction in morbidity and mortality; ART cannot cure HIV and life-long treatment is required This is directly due to the persistence of long-lived latently infected cellular reservoirs, that include microglia, astrocytes, macrophages and naıve T cells [1,2,3,4], resting memory CD4+ T cells [5,6,7], are considered to be the major contributors. The frequency of latently infected cells is up to ten times higher in tissue than in blood in HIV-infected patients or SIV-infected macaques on suppressive ART [8,10] It is unclear how latency is established in vivo. Using a novel model of resting CD4+ T cells co-cultured with primary DC, we demonstrate that myeloid DC (mDC) induce post-integration latency in resting memory CD4+ T cells, which required close DC-T cell contact

Methods

Results

Discussion

Conclusion