Type i interferon responses in rhesus macaques prevent SIV infection and slow disease progression
Sandler NG, Bosinger SE, Estes JD, Zhu RT, Tharp GK, Boritz E, Levin D, Wijeyesinghe S, Nganou-Makamdop K, Del Prete GQ, Hill BJ, Timmer JK, Reiss E, Yarden G, Darko S, Contijoch E, Todd JP, Silvestri G, Nason M, Norgren RB, Keele BF, Rao S, Langer JA, Lifson JD, Schreiber G, Douek DC (2014)
Publication Type: Journal article
Publication year: 2014
Journal
Book Volume: 511
Pages Range: 601-605
Journal Issue: 7511
DOI: 10.1038/nature13554
Abstract
Inflammation in HIV infection is predictive of non-AIDS morbidity and death, higher set point plasma virus load2 and virus acquisition; thus, therapeutic agents are in development to reduce its causes and consequences. However, inflammation may simultaneously confer both detrimental and beneficial effects. This dichotomy is particularly applicable to type I interferons (IFN-I) which, while contributing to innate control of infection4-10, also provide target cells for the virus during acute infection, impair CD4 T-cell recovery, and are associated with disease progression6,7,11-19. Here we manipulated IFN-I signalling in rhesus macaques (Macaca mulatta) during simian immunodeficiency virus (SIV) transmission and acute infection with two complementary in vivo interventions. We show that blockade of the IFN-I receptor caused reduced antiviral gene expression, increased SIV reservoir size and accelerated CD4 T-cell depletion with progression to AIDS despite decreased T-cell activation. In contrast, IFN-α2a administration initially upregulated expression of antiviral genes and prevented systemic infection. However, continued IFN-α2a treatment induced IFN-I desensitization and decreased antiviral gene expression, enabling infection with increased SIV reservoir size and accelerated CD4 T-cell loss. Thus, the timing of IFN-induced innate responses in acute SIV infection profoundly affects overall disease course and outweighs the detrimental consequences of increased immune activation. Yet, the clinical consequences of manipulation of IFN signalling are difficult to predict in vivo and therapeutic interventions in human studies should be approached with caution. © 2014 Macmillan Publishers Limited. All rights reserved.
Authors with CRIS profile
Involved external institutions
US National Institutes of Health (NIH)
United States (USA) (US)
Emory University
United States (USA) (US)
Leidos Biomedical Research Inc.
United States (USA) (US)
Weizmann Institute of Science
Israel (IL)
University of Nebraska Medical Center (UNMC)
United States (USA) (US)
Rutgers, The State University of New Jersey
United States (USA) (US)
United States (USA) (US)
Emory University
United States (USA) (US)
Leidos Biomedical Research Inc.
United States (USA) (US)
Weizmann Institute of Science
Israel (IL)
University of Nebraska Medical Center (UNMC)
United States (USA) (US)
Rutgers, The State University of New Jersey
United States (USA) (US)
How to cite
APA:
Sandler, N.G., Bosinger, S.E., Estes, J.D., Zhu, R.T., Tharp, G.K., Boritz, E.,... Douek, D.C. (2014). Type i interferon responses in rhesus macaques prevent SIV infection and slow disease progression. Nature, 511(7511), 601-605. https://doi.org/10.1038/nature13554
MLA:
Sandler, Netanya G., et al. "Type i interferon responses in rhesus macaques prevent SIV infection and slow disease progression." Nature 511.7511 (2014): 601-605.
BibTeX: Download