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

Nature. 2014 Jul 31;511(7511):601-5. doi: 10.1038/nature13554. Epub 2014 Jul 9.

Abstract

Inflammation in HIV infection is predictive of non-AIDS morbidity and death, higher set point plasma virus load 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 infection, also provide target cells for the virus during acute infection, impair CD4 T-cell recovery, and are associated with disease progression. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • Disease Progression*
  • Gene Expression Regulation / drug effects
  • Immunity, Innate / drug effects
  • Interferon-alpha / pharmacology
  • Interferon-alpha / therapeutic use*
  • Kaplan-Meier Estimate
  • Macaca mulatta / immunology*
  • Signal Transduction / drug effects
  • Simian Acquired Immunodeficiency Syndrome* / drug therapy
  • Simian Acquired Immunodeficiency Syndrome* / immunology
  • Simian Acquired Immunodeficiency Syndrome* / prevention & control
  • Simian Immunodeficiency Virus / immunology*

Substances

  • Antiviral Agents
  • Interferon-alpha

Associated data

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