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4<title>Viral rebound kinetics following single and combination immunotherapy for HIV/SIV | Madeleine S. Gastonguay</title></head><body id=top data-spy=scroll data-offset=70 data-target=#TableOfContents class=page-wrapper data-wc-page-id=3a8d058b21445ad2a3aad91a29557218>
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4<aside class=search-modal id=search><div class=container><section class=search-header><div class="row no-gutters justify-content-between mb-3"><div class=col-6><h1>Search</h1></div><div class="col-6 col-search-close"><a class=js-search href=# aria-label=Close><i class="fas fa-times-circle text-muted" aria-hidden=true></i></a></div></div><div id=search-box><input name=q id=search-query placeholder=Search... autocapitalize=off autocomplete=off autocorrect=off spellcheck=false type=search class=form-control aria-label=Search...></div></section><section class=section-search-results><div id=search-hits></div></section></div></aside><div class=page-header><nav class="navbar navbar-expand-lg navbar-light compensate-for-scrollbar" id=navbar-main><div class=container-xl><div class="d-none d-lg-inline-flex"><a class=navbar-brand href=/>Madeleine S. Gastonguay</a></div><button type=button class=navbar-toggler data-toggle=collapse data-target=#navbar-content aria-controls=navbar aria-expanded=false aria-label="Toggle navigation"> 5<span><i class="fas fa-bars"></i></span></button><div class="navbar-brand-mobile-wrapper d-inline-flex d-lg-none"><a class=navbar-brand href=/>Madeleine S. Gastonguay</a></div><div class="navbar-collapse main-menu-item collapse justify-content-start" id=navbar-content><ul class="navbar-nav d-md-inline-flex"><li class=nav-item><a class="nav-link active" href=/project/><span>Projects</span></a></li><li class=nav-item><a class=nav-link href=/publication/><span>Publications</span></a></li><li class=nav-item><a class=nav-link href=/media/Gastonguay_Madeleine_CV.pdf><span>CV</span></a></li><li class=nav-item><a class=nav-link href=/#contact><span>Contact Me</span></a></li></ul></div><ul class="nav-icons navbar-nav flex-row ml-auto d-flex pl-md-2"><li class="nav-item d-none d-lg-inline-flex"><a class=nav-link href=https://twitter.com/MS_Gastonguay data-toggle=tooltip data-placement=bottom title="Follow me on Twitter" target=_blank rel=noopener aria-label="Follow me on Twitter"><i class="fab fa-twitter" aria-hidden=true></i></a></li><li class=nav-item><a class="nav-link js-search" href=# aria-label=Search><i class="fas fa-search" aria-hidden=true></i></a></li><li class="nav-item dropdown theme-dropdown"><a href=# class=nav-link data-toggle=dropdown aria-haspopup=true aria-label="Display preferences"><i class="fas fa-moon" aria-hidden=true></i></a><div class=dropdown-menu><a href=# class="dropdown-item js-set-theme-light"><span>Light</span></a> 6<a href=# class="dropdown-item js-set-theme-dark"><span>Dark</span></a> 7<a href=# class="dropdown-item js-set-theme-auto"><span>Automatic</span></a></div></li></ul></div></nav></div><div class=page-body><article class="article article-project"><div class="article-container pt-3"><h1>Viral rebound kinetics following single and combination immunotherapy for HIV/SIV</h1><div class=article-metadata><span class=article-date>Last updated on 8Feb 28, 2025</span></div></div><div class="article-header article-container featured-image-wrapper mt-4 mb-4" style=max-width:702px;max-height:546px><div style=position:relative><img src=/project/viral_rebound/featured.png alt class=featured-image></div></div><div class=article-container><div class=article-style><p>Combination antiretroviral therapy (ART) can treat but not cure HIV, motivating the 9development of therapies that stimulate the immune system to control or eliminate infection. 10Two such immunotherapies- a TLR7 agonist and a therapeutic vaccine - 11were previously tested in SIV-infected rhesus macaques. Animals received ART alone 12or with concurrent single or combination immunotherapy, and viral rebound was monitored 13after treatment interruption. Many treated animals exhibited altered rebound kinetics, 14and a subset achieved either complete viral suppression or immune control after an initial rebound. 15However, the mechanisms driving these effects are unknown: do these therapies deplete the 16latent reservoir or enhance antiviral immunity, and do they act synergistically?</p><p>To investigate the effects of immunotherapy, we built a mathematical model of viral 17dynamics incorporating latent cell reactivation and a generalized immune response. 18We confirmed the model could reproduce the range of rebound trajectories seen in the data, 19and examined whether parameters could be reliably estimated from the available data 20by assessing structural and practical identifiability. Using nonlinear mixed-effects modeling, 21we quantified inter-individual variability and identified significant differences in model parameters between treatment groups. 22We fond that commonly used deterministc stepwise model selection methods using 23arbitrarily small difference in goodness of fit criteria were sensitive to changes 24in initial parameter guesses, and the biological meaning of the selected model was 25often difficult to interpret. Thus, we implemented a threshold of model fit improvement 26that must be met to include a treatment effect, and developed an approach to
26systematically 27evaluate alternatives to the best fit model at each step of the selection process. 28These adjustments provided more robust results to the model fitting procedure.</p><p>Our results indicate that the vaccine alone reduces latent virus reactivation and 29enhances immune response avidity. The TLR7 agonist, when administered after late ART initiation, 30increases target cell availability and reduces the latent reservoir. We found that regardless of ART initiation, 31the two therapies act synergistically to further enhance immune response avidity. 32Immune avidity appeared to increase with later ART initiation, although whether 33this effect is specific to TLR7 treatment is unclear. Our model provides mechanistic 34insight into immunotherapeutic control of viral rebound and can be adapted to predict 35their impact in controlling HIV, guiding future therapeutic design and clinical trials.</p><p>Co-authors: MeÌlanie Prague, Jeffrey M Gerold, Irene Balelli, ChloeÌ Pasin, Jonathan Z Li, Dan H Barouch, James B Whitney, and Alison L Hill</p></div><div class=article-tags><a class="badge badge-light" href=/tag/viral-dynamics/>Viral Dynamics</a> 36<a class="badge badge-light" href=/tag/nonlinear-mixed-effect-modeling/>Nonlinear mixed-effect modeling</a> 37<a class="badge badge-light" href=/tag/mathematical-modeling/>Mathematical modeling</a></div><div class=share-box aria-hidden=true><ul class=share><li><a href="https://twitter.com/intent/tweet?url=https://madeleine-gastonguay.netlify.app/project/viral_rebound/&text=Viral%20rebound%20kinetics%20following%20single%20and%20combination%20immunotherapy%20for%20HIV/SIV" target=_blank rel=noopener class=share-btn-twitter><i class="fab fa-twitter"></i></a></li><li><a href="https://www.facebook.com/sharer.php?u=https://madeleine-gastonguay.netlify.app/project/viral_rebound/&t=Viral%20rebound%20kinetics%20following%20single%20and%20combination%20immunotherapy%20for%20HIV/SIV" target=_blank rel=noopener class=share-btn-facebook><i class="fab fa-facebook"></i></a></li><li><a href="mailto:?subject=Viral%20rebound%20kinetics%20following%20single%20and%20combination%20immunotherapy%20for%20HIV/SIV&body=https://madeleine-gastonguay.netlify.app/project/viral_rebound/" target=_blank rel=noopener class=share-btn-email><i class="fas fa-envelope"></i></a></li><li><a href="https://www.linkedin.com/shareArticle?url=https://madeleine-gastonguay.netlify.app/project/viral_rebound/&title=Viral%20rebound%20kinetics%20following%20single%20and%20combination%20immunotherapy%20for%20HIV/SIV" target=_blank rel=noopener class=share-btn-l
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