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

TY - JOUR

T1 - Myeloid dendritic cells induce HIV-1 latency in non-proliferating CD4+ T cells

AU - Evans, Vanessa Anne

AU - Kumar, Nitasha

AU - Filali, Ali

AU - Procopio, Francesco A

AU - Yegorov, Oleg

AU - Goulet, Jean-Philippe

AU - Saleh, Suha Mahdi

AU - Haddad, Elias K

AU - Pereira, Candida da Fonseca

AU - Ellenberg, Paula Clarisa

AU - Sekaly, Rafick-Pierre

AU - Cameron, Paul Urquhart

AU - Lewin, Sharon Ruth

PY - 2013

Y1 - 2013

N2 - 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 naive, 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-?B 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.

AB - 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 naive, 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-?B 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.

UR - http://www.plospathogens.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.ppat.1003799&representation=PDF

U2 - 10.1371/journal.ppat.1003799

DO - 10.1371/journal.ppat.1003799

M3 - Article

VL - 9

SP - 1

EP - 14

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 12 (Art. No.: e1003799)

ER -