Abstract

The development of immunologic interventions that can target the viral reservoir in HIV-1-infected individuals is a major goal of HIV-1 research1,2. However, little evidence exists that the viral reservoir can be sufficiently targeted to improve virologic control following discontinuation of antiretroviral therapy. Here we show that therapeutic vaccination with Ad26/MVA (recombinant adenovirus serotype 26 (Ad26) prime, modified vaccinia Ankara (MVA) boost)3,4 and stimulation of TLR7 (Toll-like receptor 7) improves virologic control and delays viral rebound following discontinuation of antiretroviral therapy in SIV-infected rhesus monkeys that began antiretroviral therapy during acute infection. Therapeutic vaccination with Ad26/MVA resulted in a marked increase in the magnitude and breadth of SIV-specific cellular immune responses in virologically suppressed, SIV-infected monkeys. TLR7 agonist administration led to innate immune stimulation and cellular immune activation. The combination of Ad26/MVA vaccination and TLR7 stimulation resulted in decreased levels of viral DNA in lymph nodes and peripheral blood, and improved virologic control and delayed viral rebound following discontinuation of antiretroviral therapy. The breadth of cellular immune responses correlated inversely with set point viral loads and correlated directly with time to viral rebound. These data demonstrate the potential of therapeutic vaccination combined with innate immune stimulation as a strategy aimed at a functional cure for HIV-1 infection.

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Acknowledgements

We thank C. Linde, T. Broge, T. Barnes, D. van Manen, F. Wegmann, C. Shaver, W. Wagner, M. Boyd, R. Nityanandam, K. Smith, S. Blackmore, L. Parenteau, P. Giglio, M. Shetty, S. Levin, J. Shields, G. Neubauer, and F. Stephens for generous advice, assistance, and reagents. We acknowledge support from the US Army Medical Research and Materiel Command and the Military HIV Research Program, Walter Reed Army Institute of Research through its cooperative agreement with the Henry M. Jackson Foundation (W81XWH-11-2-0174); the National Institutes of Health (AI096040, AI124377, AI126603, OD019851); the Ragon Institute of MGH, MIT, and Harvard. Mathematical model fitting was performed on the Orchestra High Performance Compute Cluster at Harvard Medical School. 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.

Author information

Author notes

    • Jerome H. Kim

    Present address: International Vaccine Institute, Seoul, South Korea.

Affiliations

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

    • Erica N. Borducchi
    • , Crystal Cabral
    • , Kathryn E. Stephenson
    • , Jinyan Liu
    • , Peter Abbink
    • , David Ng’ang’a
    • , Joseph P. Nkolola
    • , Amanda L. Brinkman
    • , Lauren Peter
    • , Benjamin C. Lee
    • , Jessica Jimenez
    • , David Jetton
    • , Jade Mondesir
    • , Shanell Mojta
    • , Abishek Chandrashekar
    • , Katherine Molloy
    •  & Dan H. Barouch
  2. Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, USA

    • Galit Alter
    •  & Dan H. Barouch
  3. Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138 USA

    • Jeffrey M. Gerold
    •  & Alison L. Hill
  4. Bioqual, Rockville, Maryland 20852, USA

    • Mark G. Lewis
  5. Janssen Infectious Diseases and Vaccines, 2301 Leiden, The Netherlands

    • Maria G. Pau
    •  & Hanneke Schuitemaker
  6. Gilead Sciences, Foster City, California 94404, USA

    • Joseph Hesselgesser
    •  & Romas Geleziunas
  7. US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA

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

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Contributions

D.H.B, N.L.M., J.H.K., M.L.R., M.G.P., H.S., and R.G. designed the studies. J.H. and R.G. developed the ART formulation and TLR7 agonist. E.N.B., C.C., K.E.S., J.L., J.P.N., A.L.B., L.P., B.C.L., J.J., D.J., J.M., S.M., A.C., K.M., and G.A. performed the immunologic assays. P.A. and D.N. conducted the virologic assays. J.M.G. and A.L.H. performed the viral dynamics modelling. M.G.L. led the clinical care of the rhesus monkeys. D.H.B. wrote the paper with all co-authors.

Competing interests

M.G.P. and H.S. are employees of Janssen Infectious Diseases and Vaccines. J.H. and R.G. are employees of Gilead Sciences.

Corresponding author

Correspondence to Dan H. Barouch.

Reviewer Information

Nature thanks S. Lewin and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature20583

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