Assessing the impact of autologous virus neutralizing antibodies on viral rebound time in postnatally SHIV-infected ART-treated infant rhesus macaques

IF 3 3区 医学 Q2 INFECTIOUS DISEASES
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
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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.

评估自体病毒中和抗体对产后感染 SHIV 并接受抗逆转录病毒疗法治疗的猕猴幼鼠病毒反弹时间的影响。
尽管早期开始抗逆转录病毒疗法(ART)对围产期感染婴儿的益处已得到充分证实,但对于产后感染艾滋病病毒的儿科患者来说,早期开始抗逆转录病毒疗法并不总是可行的。开始抗逆转录病毒疗法的时机可能会影响潜伏病毒库的规模,以及适应性免疫反应的发展,如产生针对病毒的中和抗体反应。这些参数如何影响婴儿控制病毒血症的能力以及抗逆转录病毒疗法中断后病毒反弹的时间尚不清楚,也从未在婴儿中模拟过。为了研究这个问题,我们使用了非人灵长类猿猴/人类免疫缺陷病毒(SHIV)婴儿感染模型。婴儿猕猴(RMs)口服 SHIV.C.CH505 375H dCT,并在感染后 4-7 天(早期抗逆转录病毒疗法条件)、感染后 2 周(中期抗逆转录病毒疗法条件)或感染后 8 周(晚期抗逆转录病毒疗法条件)接受抗逆转录病毒疗法。然后对这些婴儿进行长达 60 个月的病毒载量和免疫测定监测。为了深入了解分析性治疗中断 (ATI) 后的早期情况,我们构建了数学模型来研究开始抗逆转录病毒疗法的时间对治疗中断后延缓病毒反弹的影响,重点是潜伏库规模和自体病毒中和抗体反应的相对贡献。我们建立了一个随机数学模型,以研究潜伏库规模、自体中和抗体效价和 CD4+ T 细胞水平对急性抗逆转录病毒治疗后 60 天内反弹的 RM 病毒反弹时间的共同影响。我们发现,潜伏库的大小会影响病毒的生长速度,是解释婴儿猕猴病毒反弹时间的重要决定因素。中和抗体的存在也会延缓反弹,但我们发现只有高效力抗体反应才会产生这种效应。最后,我们讨论了研究结果的治疗意义。
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来源期刊
Epidemics
Epidemics INFECTIOUS DISEASES-
CiteScore
6.00
自引率
7.90%
发文量
92
审稿时长
140 days
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.
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