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

• Published in: PLoS pathogens 2013, Vol.9 (12), p.e1003799-e1003799
• Main Authors: Evans, Vanessa A, Kumar, Nitasha, Filali, Ali, Procopio, Francesco A, Yegorov, Oleg, Goulet, Jean-Philippe, Saleh, Suha, Haddad, Elias K, da Fonseca Pereira, Candida, Ellenberg, Paula C, Sekaly, Rafick-Pierre, Cameron, Paul U, Lewin, Sharon R
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - virology; Cell Cycle Checkpoints - genetics; Cell division; Cell Proliferation; Cells, Cultured; Colleges & universities; Dendritic Cells - physiology; Flow cytometry; Gene expression; Gene Regulatory Networks; HEK293 Cells; HIV; HIV-1 - physiology; Human immunodeficiency virus; Humans; Infections; Lymphocytes; Microarray Analysis; Mortality; Myeloid Cells - physiology; Transcriptome; Virus Latency - genetics; Virus Latency - immunology
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003799

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.