Ad26/MVA Therapeutic Vaccination with TLR7 Stimulation in SIV-infected Rhesus Monkeys

Overview

Journal Nature

Specialty Science

Date 2016 Nov 15

PMID 27841870

Citations 175

Authors

Erica N Borducchi

Crystal Cabral

Kathryn E Stephenson

Jinyan Liu

Peter Abbink

David Nganga

Joseph P Nkolola

Amanda L Brinkman

Lauren Peter

Benjamin C Lee

Jessica Jimenez

David Jetton

Jade Mondesir

Shanell Mojta

Abishek Chandrashekar

Katherine Molloy

Galit Alter

Jeffrey M Gerold

Alison L Hill

Mark G Lewis

Maria G Pau

Hanneke Schuitemaker

Joseph Hesselgesser

Romas Geleziunas

Jerome H Kim

Merlin L Robb

Nelson L Michael

Dan H Barouch

Affiliations

Soon will be listed here.

Abstract

The development of immunologic interventions that can target the viral reservoir in HIV-1-infected individuals is a major goal of HIV-1 research. 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) 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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References

Chun T, Stuyver L, Mizell S, Ehler L, Mican J, Baseler M . Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 1997; 94(24):13193-7. PMC: 24285. DOI: 10.1073/pnas.94.24.13193. View

Althaus C, De Boer R . Dynamics of immune escape during HIV/SIV infection. PLoS Comput Biol. 2008; 4(7):e1000103. PMC: 2423483. DOI: 10.1371/journal.pcbi.1000103. View

Luzyanina T, Engelborghs K, Ehl S, Klenerman P, Bocharov G . Low level viral persistence after infection with LCMV: a quantitative insight through numerical bifurcation analysis. Math Biosci. 2001; 173(1):1-23. DOI: 10.1016/s0025-5564(01)00072-4. View

Deng K, Pertea M, Rongvaux A, Wang L, Durand C, Ghiaur G . Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature. 2015; 517(7534):381-5. PMC: 4406054. DOI: 10.1038/nature14053. View

Ramratnam B, Bonhoeffer S, Binley J, Hurley A, Zhang L, Mittler J . Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis. Lancet. 1999; 354(9192):1782-5. DOI: 10.1016/S0140-6736(99)02035-8. View

Chen H, Di Mascio M, Perelson A, Ho D, Zhang L . Determination of virus burst size in vivo using a single-cycle SIV in rhesus macaques. Proc Natl Acad Sci U S A. 2007; 104(48):19079-84. PMC: 2141911. DOI: 10.1073/pnas.0707449104. View

Liu J, Keele B, Li H, Keating S, Norris P, Carville A . Low-dose mucosal simian immunodeficiency virus infection restricts early replication kinetics and transmitted virus variants in rhesus monkeys. J Virol. 2010; 84(19):10406-12. PMC: 2937794. DOI: 10.1128/JVI.01155-10. View

Finzi D, Blankson J, Siliciano J, Margolick J, Chadwick K, Pierson T . Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999; 5(5):512-7. DOI: 10.1038/8394. View

De Boer R, Ribeiro R, Perelson A . Current estimates for HIV-1 production imply rapid viral clearance in lymphoid tissues. PLoS Comput Biol. 2010; 6(9):e1000906. PMC: 2932679. DOI: 10.1371/journal.pcbi.1000906. View

10.

Persaud D, Gay H, Ziemniak C, Chen Y, Piatak Jr M, Chun T . Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med. 2013; 369(19):1828-35. PMC: 3954754. DOI: 10.1056/NEJMoa1302976. View

11.

Persaud D, Zhou Y, Siliciano J, Siliciano R . Latency in human immunodeficiency virus type 1 infection: no easy answers. J Virol. 2003; 77(3):1659-65. PMC: 140995. DOI: 10.1128/jvi.77.3.1659-1665.2003. View

12.

Wodarz D, Page K, Arnaout R, Thomsen A, Lifson J, Nowak M . A new theory of cytotoxic T-lymphocyte memory: implications for HIV treatment. Philos Trans R Soc Lond B Biol Sci. 2000; 355(1395):329-43. PMC: 1692738. DOI: 10.1098/rstb.2000.0570. View

13.

Liu J, OBrien K, Lynch D, Simmons N, La Porte A, Riggs A . Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys. Nature. 2008; 457(7225):87-91. PMC: 2614452. DOI: 10.1038/nature07469. View

14.

Ho Y, Shan L, Hosmane N, Wang J, Laskey S, Rosenbloom D . Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell. 2013; 155(3):540-51. PMC: 3896327. DOI: 10.1016/j.cell.2013.09.020. View

15.

Whitney J, Hill A, Sanisetty S, Penaloza-MacMaster P, Liu J, Shetty M . Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. Nature. 2014; 512(7512):74-7. PMC: 4126858. DOI: 10.1038/nature13594. View

16.

Abbink P, Lemckert A, Ewald B, Lynch D, Denholtz M, Smits S . Comparative seroprevalence and immunogenicity of six rare serotype recombinant adenovirus vaccine vectors from subgroups B and D. J Virol. 2007; 81(9):4654-63. PMC: 1900173. DOI: 10.1128/JVI.02696-06. View

17.

Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K . Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol. 2002; 3(2):196-200. DOI: 10.1038/ni758. View

18.

Banga R, Procopio F, Noto A, Pollakis G, Cavassini M, Ohmiti K . PD-1(+) and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals. Nat Med. 2016; 22(7):754-61. DOI: 10.1038/nm.4113. View

19.

Henrich T, Hanhauser E, Marty F, Sirignano M, Keating S, Lee T . Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann Intern Med. 2014; 161(5):319-27. PMC: 4236912. DOI: 10.7326/M14-1027. View

20.

Kawai T, Sato S, Ishii K, Coban C, Hemmi H, Yamamoto M . Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol. 2004; 5(10):1061-8. DOI: 10.1038/ni1118. View