Ellie Mainou , Stella J. Berendam , Veronica Obregon-Perko , Emilie A. Uffman , Caroline T. Phan , George M. Shaw , Katharine J. Bar , Mithra R. Kumar , Emily J. Fray , Janet M. Siliciano , Robert F. Siliciano , Guido Silvestri , Sallie R. Permar , Genevieve G. Fouda , Janice McCarthy , Ann Chahroudi , Jessica M. Conway , Cliburn Chan
{"title":"Assessing the impact of autologous virus neutralizing antibodies on viral rebound time in postnatally SHIV-infected ART-treated infant rhesus macaques","authors":"Ellie Mainou , Stella J. Berendam , Veronica Obregon-Perko , Emilie A. Uffman , Caroline T. Phan , George M. Shaw , Katharine J. Bar , Mithra R. Kumar , Emily J. Fray , Janet M. Siliciano , Robert F. Siliciano , Guido Silvestri , Sallie R. Permar , Genevieve G. Fouda , Janice McCarthy , Ann Chahroudi , Jessica M. Conway , Cliburn Chan","doi":"10.1016/j.epidem.2024.100780","DOIUrl":null,"url":null,"abstract":"<div><p>While the benefits of early antiretroviral therapy (ART) initiation in perinatally infected infants are well documented, early initiation is not always possible in postnatal pediatric HIV infections. The timing of ART initiation is likely to affect the size of the latent viral reservoir established, as well as the development of adaptive immune responses, such as the generation of neutralizing antibody responses against the virus. How these parameters impact the ability of infants to control viremia and the time to viral rebound after ART interruption is unclear and has never been modeled in infants. To investigate this question we used an infant nonhuman primate Simian/Human Immunodeficiency Virus (SHIV) infection model. Infant Rhesus macaques (RMs) were orally challenged with SHIV.C.CH505 375H dCT and either given ART at 4-7 days post-infection (early ART condition), at 2 weeks post-infection (intermediate ART condition), or at 8 weeks post-infection (late ART condition). These infants were then monitored for up to 60 months post-infection with serial viral load and immune measurements. To gain insight into early after analytic treatment interruption (ATI), we constructed mathematical models to investigate the effect of time of ART initiation in delaying viral rebound when treatment is interrupted, focusing on the relative contributions of latent reservoir size and autologous virus neutralizing antibody responses. We developed a stochastic mathematical model to investigate the joint effect of latent reservoir size, the autologous neutralizing antibody potency, and CD4+ T cell levels on the time to viral rebound for RMs rebounding up to 60 days post-ATI. We find that the latent reservoir size is an important determinant in explaining time to viral rebound in infant macaques by affecting the growth rate of the virus. The presence of neutralizing antibodies can also delay rebound, but we find this effect for high potency antibody responses only. Finally, we discuss the therapeutic implications of our findings.</p></div>","PeriodicalId":49206,"journal":{"name":"Epidemics","volume":null,"pages":null},"PeriodicalIF":3.0000,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1755436524000410/pdfft?md5=8d613cadb218eb75cd648d89f8bd3941&pid=1-s2.0-S1755436524000410-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Epidemics","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1755436524000410","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"INFECTIOUS DISEASES","Score":null,"Total":0}
引用次数: 0
Abstract
While the benefits of early antiretroviral therapy (ART) initiation in perinatally infected infants are well documented, early initiation is not always possible in postnatal pediatric HIV infections. The timing of ART initiation is likely to affect the size of the latent viral reservoir established, as well as the development of adaptive immune responses, such as the generation of neutralizing antibody responses against the virus. How these parameters impact the ability of infants to control viremia and the time to viral rebound after ART interruption is unclear and has never been modeled in infants. To investigate this question we used an infant nonhuman primate Simian/Human Immunodeficiency Virus (SHIV) infection model. Infant Rhesus macaques (RMs) were orally challenged with SHIV.C.CH505 375H dCT and either given ART at 4-7 days post-infection (early ART condition), at 2 weeks post-infection (intermediate ART condition), or at 8 weeks post-infection (late ART condition). These infants were then monitored for up to 60 months post-infection with serial viral load and immune measurements. To gain insight into early after analytic treatment interruption (ATI), we constructed mathematical models to investigate the effect of time of ART initiation in delaying viral rebound when treatment is interrupted, focusing on the relative contributions of latent reservoir size and autologous virus neutralizing antibody responses. We developed a stochastic mathematical model to investigate the joint effect of latent reservoir size, the autologous neutralizing antibody potency, and CD4+ T cell levels on the time to viral rebound for RMs rebounding up to 60 days post-ATI. We find that the latent reservoir size is an important determinant in explaining time to viral rebound in infant macaques by affecting the growth rate of the virus. The presence of neutralizing antibodies can also delay rebound, but we find this effect for high potency antibody responses only. Finally, we discuss the therapeutic implications of our findings.
期刊介绍:
Epidemics publishes papers on infectious disease dynamics in the broadest sense. Its scope covers both within-host dynamics of infectious agents and dynamics at the population level, particularly the interaction between the two. Areas of emphasis include: spread, transmission, persistence, implications and population dynamics of infectious diseases; population and public health as well as policy aspects of control and prevention; dynamics at the individual level; interaction with the environment, ecology and evolution of infectious diseases, as well as population genetics of infectious agents.