Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression

Authors

Netanya G. Sandler, National Institutes of Health
Steven E. Bosinger, Yerkes National Primate Research CenterFollow
Jacob D. Estes, Frederick National LaboratoryFollow
Richard T. R. Zhu, National Institutes of Health
Gregory K. Tharp, Yerkes National Primate Research Center
Eli Boritz, National Institutes of Health
Doron Levin, Weizmann Institute of Science
Sathi Wijeyesinghe, National Institutes of Health
Krystelle Nganou Makamdop, National Institutes of Health
Gregory D. del Prete, Frederick National Laboratory
Brenna J. Hill, National Institutes of Health
J. Katherina Timmer, National Institutes of Health
Emma Reiss, National Institutes of Health
Ganit Yarden, Weizmann Institute of Science
Samuel Darko, National Institutes of Health
Eduardo Contijoch, National Institutes of Health
John Paul Todd, National Institutes of Health
Guido Silvestri, Yerkes National Primate Research Center
Martha Nason, National Institutes of Health
Robert B. Norgren Jr., University of Nebraska Medical CenterFollow
Brandon F. Keele, Frederick National Laboratory
Srinivas Rao, National Institutes of Health
Jerome A. Langer, Rutgers - Robert Wood Johnson Medical School
Jeffrey D. Lifson, Frederick National Laboratory
Gideon Schreiber, Weizmann Institute of Science
Daniel C. Douek, National Institutes of Health

Date of this Version

2014

Citation

Research Letter: Nature 511; doi:10.1038/nature13554

Comments

U.S. Government Work

Abstract

Inflammation in HIV infection is predictive of non-AIDSmorbidity and death¹, higher set point plasma virus load² and virus acquisition³; 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 infection^4–10, also provide target cells for the virus during acute infection, impairCD4T-cell recovery, and are associated with disease progression^6,7,11–19.Herewe manipulated IFN-I signalling in rhesus macaques (Macaca mulatta) during simian immunodeficiency virus (SIV) transmission and acute infection with two complementary in vivointerventions. 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.