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Viral rebound kinetics following single and combination immunotherapy for HIV/SIV

View ORCID ProfileMélanie Prague, Jeffrey M Gerold, Irene Balelli, Chloé Pasin, Jonathan Z Li, Dan H Barouch, James B Whitney, View ORCID ProfileAlison L Hill
doi: https://doi.org/10.1101/700401
Mélanie Prague
1University of Bordeaux, Inria Bordeaux Sud-Ouest, Inserm, Bordeaux Population Health Research Center, SISTM Team, UMR 1219, F-33000 Bordeaux, France
2Vaccine Research Institute, Créteil, France
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  • ORCID record for Mélanie Prague
Jeffrey M Gerold
3Program for Evolutionary Dynamics, Harvard University, Cambridge, MA 02138
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Irene Balelli
1University of Bordeaux, Inria Bordeaux Sud-Ouest, Inserm, Bordeaux Population Health Research Center, SISTM Team, UMR 1219, F-33000 Bordeaux, France
2Vaccine Research Institute, Créteil, France
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Chloé Pasin
1University of Bordeaux, Inria Bordeaux Sud-Ouest, Inserm, Bordeaux Population Health Research Center, SISTM Team, UMR 1219, F-33000 Bordeaux, France
2Vaccine Research Institute, Créteil, France
4Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032
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Jonathan Z Li
5Brigham and Women’s Hospital, Harvard Medical School, Boston MA 02215, USA
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Dan H Barouch
6Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
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James B Whitney
6Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
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Alison L Hill
3Program for Evolutionary Dynamics, Harvard University, Cambridge, MA 02138
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  • ORCID record for Alison L Hill
  • For correspondence: alhill@fas.harvard.edu
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Abstract

HIV infection can be treated but not cured with antiretroviral therapy, motivating the development of new therapies that instead target host immune responses. Three such immunotherapies were recently tested in non-human primates – a TLR7-agonist, therapeutic vaccine, and broadly-neutralizing antibody – and cured a subset of animals by preventing or controlling viral rebound after antiretrovirals were stopped. However, their mechanism of action remains unknown; for example, whether they reduced the pool of latently-infected cells versus boosted antiviral immunity, and whether they acted independently or synergistically. Here we conduct a detailed analysis of the kinetics of viral rebound after immunotherapy, and use mathematical models combined with rigorous statistical fitting to quantify the impact of these interventions on viral dynamics. We find that the vaccine reduced reactivation of latent virus by 4-fold, and boosted the avidity of antiviral immune responses by 17-fold when alone and 210-fold when combined with the TLR7-agonist. In the context of later initiation of antiretroviral therapy only, the TLR7-agonist reduced latent reservoir reactivation by 8-fold, but also slightly increased target cell availability (1.5-fold). The antibody boosted immune response avidity (8-fold) and displayed no detectable synergy with the TLR7-agonist. To predict the impact of these immunotherapies in clinical trials, we calibrated a model of HIV rebound to human treatment interruption trials and simulated the effect of adding each therapy. Overall, our results provide a framework for understanding the relative contributions of different mechanisms of preventing viral rebound and highlight the multifaceted roles of TLR7-agonists for HIV/SIV cure.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted August 01, 2019.
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Viral rebound kinetics following single and combination immunotherapy for HIV/SIV
Mélanie Prague, Jeffrey M Gerold, Irene Balelli, Chloé Pasin, Jonathan Z Li, Dan H Barouch, James B Whitney, Alison L Hill
bioRxiv 700401; doi: https://doi.org/10.1101/700401
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Viral rebound kinetics following single and combination immunotherapy for HIV/SIV
Mélanie Prague, Jeffrey M Gerold, Irene Balelli, Chloé Pasin, Jonathan Z Li, Dan H Barouch, James B Whitney, Alison L Hill
bioRxiv 700401; doi: https://doi.org/10.1101/700401

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