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Early antiretroviral therapy limits SIV reservoir establishment to delay or prevent post-treatment viral rebound

Nature Medicine volume 24, pages 1430–1440 (2018)Cite this article

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Abstract

Prophylactic vaccination of rhesus macaques with rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) elicits immune responses that stringently control highly pathogenic SIV infection, with subsequent apparent clearance of the infection, in ~50% of vaccinees. In contrast, here, we show that therapeutic RhCMV/SIV vaccination of rhesus macaques previously infected with SIV and given continuous combination antiretroviral therapy (cART) beginning 4–9 d post-SIV infection does not mediate measurable SIV reservoir clearance during over 600 d of follow-up on cART relative to RhCMV/control vaccination. However, none of the six animals started on cART on day four or five, across both RhCMV/SIV- and RhCMV/control-vaccinated groups, those rhesus macaques with SIV reservoirs most closely resembling those of prophylactically RhCMV/SIV-vaccinated and protected animals early in their course, showed post-cART viral rebound with up to nine months of follow-up. Moreover, at necropsy, these rhesus macaques showed little to no evidence of replication-competent SIV. These results suggest that the early SIV reservoir is limited in durability and that effective blockade of viral replication and spread in this critical time window by either pharmacologic or immunologic suppression may result in reduction, and potentially loss, of rebound-competent virus over a period of ~two years.

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Fig. 1: Early cART limits virus dissemination.
Fig. 2: RhCMV/SIV vector immunogenicity in cART-suppressed rhesus macaques.
Fig. 3: Time of cART initiation affects virus rebound kinetics.
Fig. 4: Analysis of residual replication-competent virus in post-cART non-rebounders.
Fig. 5: Virological analysis of post-cART non-rebounders at necropsy.

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Acknowledgements

This work was supported by the US National Institutes of Health (grants U19AI096109, U19AI095985, UM1AI126611, UM1AI124377, R37AI054292, and P51OD011092, L.J.P.), by the Bill and Melinda Gates Foundation (grant OPP1094567, L.J.P.), and supported in part with federal funds from the National Cancer Institute, National Institutes of Health (Contract No. HHSN261200800001E, J.D.L.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The authors thank B. Keele (Leidos Biomedical Research, Inc.) for providing SIVmac239X and Janssen Pharmaceuticals for providing Darunavir. The CD8+ lymphocyte-depleting monoclonal antibody, M-T807R1, was provided by the National Institutes of Health’s Nonhuman Primate Reagent Resource Program. We thank A. Sylwester, S. Hagen, T. Swanson, M. Fischer, S. Planer, C. Kahl, D. Siess, M. Reyes, J. Clock, A. Konfe, C. Abana, C. Pexton, E. McDonald, K. Jeffries, M. Grey, C. Xu, W. Brantley, A. Maxwell, M. Lidell, D. Malouli, M. Marenco, A. Townsend, and L. Boshears for technical or administrative assistance.

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Authors and Affiliations

  1. Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA

    Afam A. Okoye, Scott G. Hansen, Mukta Vaidya, Yoshinori Fukazawa, Haesun Park, Derick M. Duell, Richard Lum, Colette M. Hughes, Abigail B. Ventura, Emily Ainslie, Julia C. Ford, David Morrow, Roxanne M. Gilbride, Alfred W. Legasse, Michael K. Axthelm & Louis J. Picker

  2. Gilead Sciences, Inc., Foster City, CA, USA

    Joseph Hesselgesser & Romas Geleziunas

  3. AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    Yuan Li, Kelli Oswald, Rebecca Shoemaker, Randy Fast, William J. Bosche & Jeffrey D. Lifson

  4. Statistical Center for HIV/AIDS Research and Prevention, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Bhavesh R. Borate & Paul T. Edlefsen

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Contributions

L.J.P. and J.D.L. conceived of the study and wrote the paper with assistance from A.A.O. A.A.O. and S.G.H. managed the project, performed all animal experiments, and analyzed immunological and virological data, assisted by M.V., Y.F., H.P., D.M.D., R.L., C.M.H., A.B.V., E.A., J.C.F., D.M., and R.M.G. J.D.L. planned and performed SIV quantification assisted by K.O., R.S., R.F., and W.J.B. A.W.L. and M.K.A. managed the animal protocols and J.D.L., J.H., and R.G. developed the injectable cART formulation. P.T.E. and B.R.B. conducted all statistical analyses and contributed to the writing of the paper.

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Correspondence to Louis J. Picker or Jeffrey D. Lifson.

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Oregon Health & Science University, L.J.P., and S.G.H. have a financial interest in Vir Biotechnology, Inc., a company that may have a commercial interest in the results of this research and technology. The potential individual and institutional conflicts of interest have been reviewed and managed by Oregon Health & Science University.

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Okoye, A.A., Hansen, S.G., Vaidya, M. et al. Early antiretroviral therapy limits SIV reservoir establishment to delay or prevent post-treatment viral rebound. Nat Med 24, 1430–1440 (2018). https://doi.org/10.1038/s41591-018-0130-7

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