Elite controllers (EC) are a small group of HIV-infected individuals who are able to suppress the virus in the absence of antiretroviral therapy. EC demonstrate that the human immune system, in principle, is capable of rendering HIV harmless. A study published on June 11th in PLOS Pathogens shows that dendritic cells (DC) of EC are supersensitive to early signs of HIV infection, and contribute to a stronger immune response than that seen in individuals who fail to control the virus in the long term.
Previous studies on the anti-HIV response in EC have focused on CD8+ killer T cells, and shown that they play an important role in the long-term suppression of the virus. However, CD8+ killer T cells depend on interactions with and signals from other immune cells, including DC, which Xu Yu, from the Ragon Institute of MGH, MIT and Harvard, Cambridge, USA, and colleagues, show in this study to be more potent in EC than individuals who need antiretroviral therapy to control HIV (also called chronic progressors).
HIV does infect DC, and, like other human cells, they have the ability to respond to viral infection by cell-intrinsic immune responses that lead to secretion of general immune stimulating factors called type I interferons (IFN), which in turn upregulates a wide panel of IFN-stimulated genes with antiviral functions. This cell-intrinsic immune response is effective in defending the host against a panel of different viruses but HIV seems to be able to escape from such cell-intrinsic immunity in most patients.
However, as the researchers found, DC from elite controllers have the ability to effectively mount cell-intrinsic type I IFN secretion in response to HIV-1 infection. Unlike DC from chronic progressors, the DC from EC seem to be able to sense very early products of HIV activity, namely DNA that the virus produces in order to integrate itself into the genome of the host cell, and respond with rapid and sustained secretion of type 1 interferons.
The ability to spot these early products appears to depend on high levels of a sensor protein called GAS that detects unusual pieces of DNA present in the cell. EC seem to have higher levels of GAS in DC than chronic progressors, and the DC support of an effective HIV-specific CD8+ T cell response depends on the DC ability to detect the early viral activity.
Their study suggests, the scientists conclude, "that previously unrecognized innate [non-specific] mechanisms of HIV immune recognition contribute to T cell-mediated immune control of HIV-1", a finding with potential implications for preventative or therapeutic clinical purposes.
Sarah Sullivan (Ragon Institute Communications Manager)
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Authors and Affiliations:
Enrique Martin-Gayo, Ragon Institute of MGH, MIT and Harvard, USA
Maria Jose Buzon, Ragon Institute of MGH, MIT and Harvard, USA; Massachusetts General Hospital, USA
Zhengyu Ouyang, Ragon Institute of MGH, MIT and Harvard, USA
Taylor Hickman, Ragon Institute of MGH, MIT and Harvard, USA
Jacqueline Cronin, Ragon Institute of MGH, MIT and Harvard, USA
Dina Pimenova, Ragon Institute of MGH, MIT and Harvard, USA
Bruce D. Walker, Ragon Institute of MGH, MIT and Harvard, USA; Howard Hughes Medical Institute, USA
Mathias Lichterfeld, Ragon Institute of MGH, MIT and Harvard, USA; Massachusetts General Hospital, USA; Brigham and Women's Hospital, USA
Xu G. Yu, Ragon Institute of MGH, MIT and Harvard, USA
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Funding: This work was supported for the US National Institutes of Health (grants AI078799, AI089339, HL121890, AI098484, HL126554, AI116228 and AI087452 to XGY; AI098487 and AI106468 to ML). EMG is supported by the Harvard University Center of AIDS research (HU CFAR NIH/NIAID fund 5P30AI060354-10). PBMC sample collection was supported by the Bill and Melinda Gates Foundation (OPP 1066973), the Mark and Lisa Swartz Foundation, the Ragon Institute of MGH, MIT and Harvard, and the International HIV Controller Consortium. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Citation: Martin-Gayo E, Buzon MJ, Ouyang Z, Hickman T, Cronin J, Pimenova D, et al. (2015) Potent Cell-Intrinsic Immune Responses in Dendritic Cells Facilitate HIV-1-Specific T Cell Immunity in HIV-1 Elite Controllers. PLoS Pathog 11(6): e1004930. doi:10.1371/journal.ppat.1004930