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Abstract

The viral reservoir represents a critical challenge for human immunodeficiency virus type 1 (HIV-1) eradication strategies1,2,3,4,5. However, it remains unclear when and where the viral reservoir is seeded during acute infection and the extent to which it is susceptible to early antiretroviral therapy (ART). Here we show that the viral reservoir is seeded rapidly after mucosal simian immunodeficiency virus (SIV) infection of rhesus monkeys and before systemic viraemia. We initiated suppressive ART in groups of monkeys on days 3, 7, 10 and 14 after intrarectal SIVMAC251 infection. Treatment with ART on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later time points. In addition, treatment on day 3 abrogated the induction of SIV-specific humoral and cellular immune responses. Nevertheless, after discontinuation of ART following 24 weeks of fully suppressive therapy, virus rebounded in all animals, although the monkeys that were treated on day 3 exhibited a delayed viral rebound as compared with those treated on days 7, 10 and 14. The time to viral rebound correlated with total viraemia during acute infection and with proviral DNA at the time of ART discontinuation. These data demonstrate that the viral reservoir is seeded rapidly after intrarectal SIV infection of rhesus monkeys, during the ‘eclipse’ phase, and before detectable viraemia. This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.

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Acknowledgements

We thank M. Pensiero, M. Marovich, C. Dieffenbach, W. Wagner, C. Gittens, J. Yalley-Ogunro, M. Nowak, R. Siliciano, D. Persaud, S. Deeks, N. Chomont, J. Ananworanich, L. Picker, F. Stephens, R. Hamel, K. Kelly and L. Dunne for advice, assistance and reagents. The SIVMAC239 peptides were obtained from the National Institutes of Health (NIH) AIDS Research and Reference Reagent Program. We acknowledge support from the US Army Medical Research and Material Command and the US Military HIV Research Program through its cooperative agreement with the Henry M. Jackson Foundation for the Advancement of Military Medicine (W81XWH-07-2-0067, W81XWH-11-2-0174); the NIH (AI060354, AI078526, AI084794, AI095985, AI096040, AI100645); and the Ragon Institute of MGH, MIT and Harvard. The views expressed in this manuscript are those of the authors and do not represent the official views of the Department of the Army or the Department of Defense.

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Affiliations

  1. Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA

    • James B. Whitney
    • , Srisowmya Sanisetty
    • , Pablo Penaloza-MacMaster
    • , Jinyan Liu
    • , Mayuri Shetty
    • , Lily Parenteau
    • , Crystal Cabral
    • , Jennifer Shields
    • , Stephen Blackmore
    • , Jeffrey Y. Smith
    • , Amanda L. Brinkman
    • , Lauren E. Peter
    • , Sheeba I. Mathew
    • , Kaitlin M. Smith
    • , Erica N. Borducchi
    •  & Dan H. Barouch
  2. Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA

    • James B. Whitney
    •  & Dan H. Barouch
  3. Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138 USA

    • Alison L. Hill
    •  & Daniel I. S. Rosenbloom
  4. Bioqual, Rockville, Maryland 20852, USA

    • Mark G. Lewis
  5. Gilead Sciences, Foster City, California 94404, USA

    • Jillian Hattersley
    • , Bei Li
    • , Joseph Hesselgesser
    •  & Romas Geleziunas
  6. US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA

    • Merlin L. Robb
    • , Jerome H. Kim
    •  & Nelson L. Michael

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Contributions

J.B.W., R.G., M.L.R., J.H.K., N.L.M. and D.H.B. designed the studies and interpreted the data. J.B.W. and S.S. led the virological assays. P.P.-M., J.L., M.S., L.P., C.C., J.S., S.B., J.Y.S., A.L.B., L.E.P., E.N.B. and K.M.S. led the study operations and the immunological assays. A.L.H. and D.I.S.R. led the mathematical modelling and statistical analysis. M.G.L. led the clinical care of the rhesus monkeys. B.L., J.Ha., J.Hi. and R.G. developed the antiretroviral drug cocktail. J.B.W. and D.H.B. wrote the paper with all co-authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dan H. Barouch.

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https://doi.org/10.1038/nature13594

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