Ad26/MVA therapeutic vaccination with TLR7 stimulation in SIV-infected rhesus monkeys

  • Nature volume 540, pages 284287 (08 December 2016)
  • doi:10.1038/nature20583
  • Download Citation


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.

  • Subscribe to Nature for full access:



Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.


  1. 1.

    & Immunologic strategies for HIV-1 remission and eradication. Science 345, 169–174 (2014)

  2. 2.

    et al. International AIDS Society global scientific strategy: towards an HIV cure 2016. Nat. Med. 22, 839–850 (2016)

  3. 3.

    et al. Protective efficacy of a global HIV-1 mosaic vaccine against heterologous SHIV challenges in rhesus monkeys. Cell 155, 531–539 (2013)

  4. 4.

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

  5. 5.

    et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295–1300 (1997)

  6. 6.

    , , & Latency in human immunodeficiency virus type 1 infection: no easy answers. J. Virol. 77, 1659–1665 (2003)

  7. 7.

    et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl Acad. Sci. USA 94, 13193–13197 (1997)

  8. 8.

    et al. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155, 540–551 (2013)

  9. 9.

    et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat. Med. 5, 512–517 (1999)

  10. 10.

    , , , & Re-emergence of HIV after stopping therapy. Nature 401, 874–875 (1999)

  11. 11.

    et al. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity 36, 491–501 (2012)

  12. 12.

    et al. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature 517, 381–385 (2015)

  13. 13.

    et al. Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys. Nature 457, 87–91 (2009)

  14. 14.

    et al. Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. Nature 512, 74–77 (2014)

  15. 15.

    et al. Comparative seroprevalence and immunogenicity of six rare serotype recombinant adenovirus vaccine vectors from subgroups B and D. J. Virol. 81, 4654–4663 (2007)

  16. 16.

    et al. Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat. Immunol. 5, 1061–1068 (2004)

  17. 17.

    et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3, 196–200 (2002)

  18. 18.

    et al. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann. Intern. Med. 161, 319–327 (2014)

  19. 19.

    et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N. Engl. J. Med. 369, 1828–1835 (2013)

  20. 20.

    et al. PD-1+ and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals. Nat. Med. 22, 754–761 (2016)

  21. 21.

    et al. Viremia control following antiretroviral treatment and therapeutic immunization during primary SIV251 infection of macaques. Nat. Med. 6, 1140–1146 (2000)

  22. 22.

    et al. Safety and immunogenicity of therapeutic DNA vaccination in individuals treated with antiretroviral therapy during acute/early HIV-1 infection. PLoS One 5, e10555 (2010)

  23. 23.

    et al. Factors associated with viral rebound in HIV-1-infected individuals enrolled in a therapeutic HIV-1 gag vaccine trial. J. Infect. Dis. 203, 976–983 (2011)

  24. 24.

    et al. Low-dose mucosal simian immunodeficiency virus infection restricts early replication kinetics and transmitted virus variants in rhesus monkeys. J. Virol. 84, 10406–10412 (2010)

  25. 25.

    , , & Mathematical modeling of viral kinetics under immune control during primary HIV-1 infection. J. Theor. Biol. 259, 751–759 (2009)

  26. 26.

    et al. A new theory of cytotoxic T-lymphocyte memory: implications for HIV treatment. Philos. Trans. R. Soc. B Biol. Sci. 355, 329–343 (2000)

  27. 27.

    , , , & Low level viral persistence after infection with LCMV: a quantitative insight through numerical bifurcation analysis. Math. Biosci. 173, 1–23 (2001)

  28. 28.

    & Dynamics of immune escape during HIV/SIV infection. PLOS Comput. Biol. 4, e1000103 (2008)

  29. 29.

    et al. Why don’t CD8+ T cells reduce the lifespan of SIV-infected cells in vivo? PLOS Comput. Biol. 7, e1002200 (2011)

  30. 30.

    , & Notwithstanding circumstantial alibis, cytotoxic T cells can be major killers of HIV-1 infected cells. J. Virol. 306–316 (2016)

  31. 31.

    , , , & Determination of virus burst size in vivo using a single-cycle SIV in rhesus macaques. Proc. Natl Acad. Sci. USA 104, 19079–19084 (2007)

  32. 32.

    , & Current estimates for HIV-1 production imply rapid viral clearance in lymphoid tissues. PLOS Comput. Biol. 6, e1000906 (2010)

  33. 33.

    et al. Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis. Lancet 354, 1782–1785 (1999)

  34. 34.

    MHadaptive: General Markov Chain Monte Carlo for Bayesian Inference using adaptive Metropolis-Hastings sampling. (2012)

  35. 35.

    , & deSolve: Solvers for Initial Value Problems of Differential Equations (ODE, DAE, DDE). (2016)

Download references


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.


  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


  1. Search for Erica N. Borducchi in:

  2. Search for Crystal Cabral in:

  3. Search for Kathryn E. Stephenson in:

  4. Search for Jinyan Liu in:

  5. Search for Peter Abbink in:

  6. Search for David Ng’ang’a in:

  7. Search for Joseph P. Nkolola in:

  8. Search for Amanda L. Brinkman in:

  9. Search for Lauren Peter in:

  10. Search for Benjamin C. Lee in:

  11. Search for Jessica Jimenez in:

  12. Search for David Jetton in:

  13. Search for Jade Mondesir in:

  14. Search for Shanell Mojta in:

  15. Search for Abishek Chandrashekar in:

  16. Search for Katherine Molloy in:

  17. Search for Galit Alter in:

  18. Search for Jeffrey M. Gerold in:

  19. Search for Alison L. Hill in:

  20. Search for Mark G. Lewis in:

  21. Search for Maria G. Pau in:

  22. Search for Hanneke Schuitemaker in:

  23. Search for Joseph Hesselgesser in:

  24. Search for Romas Geleziunas in:

  25. Search for Jerome H. Kim in:

  26. Search for Merlin L. Robb in:

  27. Search for Nelson L. Michael in:

  28. Search for Dan H. Barouch in:


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.

Extended data


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.