Abstract

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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Primary accessions

Gene Expression Omnibus

Data deposits

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

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Acknowledgements

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.

Affiliations

  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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Contributions

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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https://doi.org/10.1038/nature13554

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