Inflammation in HIV infection is predictive of non-AIDS morbidity 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 infection4,5,6,7,8,9,10, also provide target cells for the virus during acute infection, impair CD4 T-cell recovery, and are associated with disease progression6,7,11,12,13,14,15,16,17,18,19. 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.

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Gene Expression Omnibus

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Gene expression data are available at the Gene Expression Omnibus under accession codes GSM1298835 through GSM1299037.


  1. 1.

    et al. Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection. J. Infect. Dis. (21 April 2014)

  2. 2.

    et al. Genital tract inflammation during early HIV-1 infection predicts higher plasma viral load set point in women. J. Infect. Dis. 205, 194–203 (2012)

  3. 3.

    et al. Innate immune activation enhances HIV acquisition in women, diminishing the effectiveness of tenofovir microbicide gel. J. Infect. Dis. 206, 993–1001 (2012)

  4. 4.

    et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472, 481–485 (2011)

  5. 5.

    et al. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 505, 691–695 (2013)

  6. 6.

    , , & Immunomodulatory functions of type I interferons. Nature Rev. Immunol. 12, 125–135 (2012)

  7. 7.

    et al. Anti-retroviral effects of interferon-α in AIDS-associated Kaposi’s sarcoma. Lancet 332, 1218–1222 (1988)

  8. 8.

    et al. Interferon-alpha administration enhances CD8+ T cell activation in HIV infection. PLoS ONE 7, e30306 (2012)

  9. 9.

    et al. Pegylated Interferon alfa-2a monotherapy results in suppression of HIV type 1 replication and decreased cell-associated HIV DNA integration. J. Infect. Dis. 207, 213–222 (2013)

  10. 10.

    & Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 436, 967–972 (2005)

  11. 11.

    et al. Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. J. Virol. 83, 3719–3733 (2009)

  12. 12.

    et al. Type I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection. PLoS Pathog. 9, e1003658 (2013)

  13. 13.

    et al. The relationship between simian immunodeficiency virus RNA levels and the mRNA levels of α/β interferons (IFN-alpha/beta) and IFN-α/β-inducible Mx in lymphoid tissues of rhesus macaques during acute and chronic infection. J. Virol. 76, 8433–8445 (2002)

  14. 14.

    et al. Persistent LCMV infection is controlled by blockade of type I interferon signaling. Science 340, 207–211 (2013)

  15. 15.

    et al. Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science 340, 202–207 (2013)

  16. 16.

    et al. Glycerol monolaurate prevents mucosal SIV transmission. Nature 458, 1034–1038 (2009)

  17. 17.

    et al. A randomized trial of interferon alpha therapy for HIV type 1 infection. AIDS Res. Hum. Retroviruses 16, 183–190 (2000)

  18. 18.

    et al. CD4+ T-cell deficiency in HIV patients responding to antiretroviral therapy is associated with increased expression of interferon-stimulated genes in CD4+ T cells. J. Infect. Dis. 204, 1927–1935 (2011)

  19. 19.

    et al. Multifaceted activities of type I interferon are revealed by a receptor antagonist. Sci. Signal. 7, ra50 (2014)

  20. 20.

    et al. Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection. Nature 502, 559–562 (2013)

  21. 21.

    et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772–777 (2005)

  22. 22.

    et al. Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys. Nature 482, 89–93 (2012)

  23. 23.

    & Innate immune control of HIV. Cold Spring Harb. Perspect. Med. 2, a007070 (2012)

  24. 24.

    et al. Pegylated interferon-α 2a treatment of chronic SIV-infected macaques. J. Med. Primatol. 37, 26–30 (2008)

  25. 25.

    et al. A FOXO3–IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses. Nature 490, 421–425 (2012)

  26. 26.

    et al. The effect of recombinant human interferon αB/D compared to interferon α2b on SIV infection in rhesus macaques. Antiviral Res. 32, 1–8 (1996)

  27. 27.

    , & Therapeutic depletion of natural killer cells controls persistent infection. J. Virol. 88, 1953–1960 (2014)

  28. 28.

    et al. Phenotypic properties of transmitted founder HIV-1. Proc. Natl Acad. Sci. USA 110, 6626–6633 (2013)

  29. 29.

    et al. Relative resistance of HIV-1 founder viruses to control by interferon-alpha. Retrovirology 10, 146 (2013)

  30. 30.

    et al. Comprehensive assessment of HIV target cells in the distal human gut suggests increasing HIV susceptibility toward the anus. J. Acquir. Immune Defic. Syndr. 63, 263–271 (2013)

  31. 31.

    et al. Treatment of SIV-infected sooty mangabeys with a type-I IFN agonist results in decreased virus replication without inducing hyperimmune activation. Blood 119, 5750–5757 (2012)

  32. 32.

    et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013)

  33. 33.

    et al. Differential analysis of gene regulation at transcript resolution with RNA-seq. Nature Biotechnol. 31, 46–53 (2013)

  34. 34.

    et al. Differential infection patterns of CD4+ T cells and lymphoid tissue viral burden distinguish progressive and nonprogressive lentiviral infections. Blood 120, 4172–4181 (2012)

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We would like to acknowledge A. Zimin for his work in creating the MuSuRCA rhesus assembly, C. Miller for the gift of 6 rhesus macaques and Y. Peleg and S. Albeck at the Israel Structure Proteomic Center and G. Jona from Weizmann Institute Biological services for helping with protein production and purification; A. Roque and N. Haining for initial work on the pilot study; N. Modi, D. Ambrozak, R. Koup, M. Ghosh, I. Srivastava, R. Schwartz, F. Villinger, K. Zoon, J. Bekisz, K. Ghneim, A. Filali, R. Sekaly, L. Mach and L. Shen for their assistance on the current project; and A. Somasunderam for additional support. This project was supported by NIH Intramural Funding, federal funds from NCI/NIH Contract HHSN261200800001E, NIH R24 RR017444, NIH AI-076174, I-CORE Program of the Planning and Budgeting Committee and the Israel Science Foundation grant No. 1775/12.

Author information

Author notes

    • Netanya G. Sandler

    Present address: Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas 77555, USA.


  1. Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Netanya G. Sandler
    • , Richard T. R. Zhu
    • , Eli Boritz
    • , Sathi Wijeyesinghe
    • , Krystelle Nganou Makamdop
    • , Brenna J. Hill
    • , J. Katherina Timmer
    • , Emma Reiss
    • , Samuel Darko
    • , Eduardo Contijoch
    •  & Daniel C. Douek
  2. Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia 30322, USA

    • Steven E. Bosinger
    • , Gregory K. Tharp
    •  & Guido Silvestri
  3. Non-Human Primate Genomics Core, Yerkes National Primate Research Center, Robert W. Woodruff Health Sciences Center, Emory University, Atlanta, Georgia 30322, USA

    • Steven E. Bosinger
    •  & Gregory K. Tharp
  4. AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland 21702, USA

    • Jacob D. Estes
    • , Gregory Q. del Prete
    • , Brandon F. Keele
    •  & Jeffrey D. Lifson
  5. Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel

    • Doron Levin
    • , Ganit Yarden
    •  & Gideon Schreiber
  6. Laboratory of Animal Medicine, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA

    • John Paul Todd
    •  & Srinivas Rao
  7. Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Martha Nason
  8. Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA

    • Robert B. Norgren Jr
  9. Department of Pharmacology, Rutgers - Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA

    • Jerome A. Langer


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N.G.S. designed and coordinated the study, developed and performed experiments, interpreted the data and prepared the manuscript. S.E.B. analysed and interpreted the sequencing data, generated figures and contributed to manuscript preparation. J.D.E. contributed to study design and developed and performed in situ hybridization and immunohistochemistry assays. R.T.R.Z. processed samples, performed flow cytometry and analysis, performed qRT–PCR and generated the sequencing libraries. G.K.T. analysed and interpreted the sequencing data and generated figures. E.B. developed the library generation protocol and supervised library generation. D.L. and G.Y. synthesized the IFN-1ant. S.W. generated sequencing libraries and assisted in analysis of the sequencing data. K.N.M. assisted with sample processing, performed flow cytometry assays, and assessed plasma for neutralizing activity. G.Q.d.P. evaluated circulating SIV for IFN resistance. B.J.H. designed, performed and analysed qRT–PCR assays. J.K.T. processed samples and performed ELISAs. E.R. assisted with sample processing and performed flow cytometry assays. S.D. assisted with sequencing analysis. E.C. assisted with sample processing and performed flow cytometry assays. J.P.T. performed SIV inoculations and coordinated the study at Bioqual. G.Si. established the Non-Human Primate Sequencing Core and facilitated sequencing analysis and contributed to data interpretation. M.N. assisted with statistical analyses. R.B.N. generated the MuSuRCA Macaca mulatta assembly. B.F.K. sequenced the transmitted/founder variants. S.R. contributed to study design and followed the rhesus macaques clinically. J.A.L. contributed to IFN-1ant design and assisted with analysis. J.D.L. contributed to study design, assessment for IFN-resistant viruses and manuscript preparation. G.Sc. contributed to study design, IFN-1ant design and production and assisted with analysis. D.C.D. designed and supervised the study, interpreted the data and prepared the manuscript.

Competing interests

The type I interferon receptor antagonist used in this study and related type I interferon antagonists are covered in the Patent Application PCT/US2009/056366 held by J.A.L. and G.Sc.

Corresponding author

Correspondence to Daniel C. Douek.

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