HIV Post-Treatment: Stochastic Modeling Insights on Rebound and Control

HIV 治疗后：反弹和控制的随机建模见解

• 批准号: 1714654
• 负责人: Jessica Conway
• 金额: $ 27万
• 依托单位: Pennsylvania State Univ University Park
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1714654&HistoricalAwards=false
• 关键词: HIV; Post; Treatment; Stochastic; Modeling

Antiretroviral drug therapy (ART) can effectively control HIV infection and reduce plasma virus load from very high, to undetectably low, levels. Cessation of ART is typically followed by rapid viral rebound (VR) to the high, pre-ART viral loads. However, recent observations give nuance to this pattern. In 2013, reports of the "Mississippi baby" emerged, a child born with HIV and treated with ART shortly after birth. Taken off ART at 18 months of age, she appeared to be cured, only for HIV to reappear and rebound after 27 months. The following year, a study revealed 14 HIV+ individuals - "the VISCONTI cohort" - who continued to control their HIV infection in spite of having stopped ART 4-10 years before study publication. These and other examples show that in some HIV-infected individuals, there can be significant delays between the suspension of ART and VR. Delayed VR and the potential for post-treatment control (PTC) are poorly understood but suggest exciting possibilities for treatment of HIV without ART, thereby avoiding side effects and high drug costs. Further, people who control HIV to undetectable levels are unlikely to infect others, thus reducing the possibility of HIV transmission in the population as a whole. The goal of this project is to better understand delayed VR and PTC by analyzing the following three questions: Under what circumstances will ART suspension lead to delayed VR or PTC? If ART suspension leads to VR, when will it occur? Can one predict when a patient can control infection off ART, permanently?Central to this project is the development of mathematical viral dynamics models to investigate VR in HIV+ individuals following cessation of ART. The models will make use of stochastic multi-type branching processes, since viral populations in treated patients are small. While stochastic methods have been used to model viral dynamics, the standard approach is extensive simulation; in this project, the Principal Investigator will emphasize the derivation of analytic results instead, thereby introducing novel tools from applied probability to viral dynamics problems. The objectives will be addressed by stochastic models that will increase in complexity and realism through projects focusing on different biological aspects of HIV control such as immune responses. These models will be validated using data on HIV dynamics and VR from experimental collaborators and published data. The aim of this modeling is to better characterize VR dynamics, make testable predictions on times to VR, and gain insights into post-treatment control of HIV. In medical settings, the models developed may inform clinical guidelines with regards to ART suspension, lead to optimizing testing frequency during the ART interruption to detect VR and predicting PTC or "HIV remission" where VR will be unlikely.

抗逆转录病毒药物治疗（ART）可以有效地控制HIV感染，并将血浆病毒载量从非常高的水平降低到无法检测的低水平。ART停止后通常会出现病毒快速反弹（VR），达到ART前的高病毒载量。然而，最近的观察对这一模式作出了细微的解释。2013年，出现了“密西西比婴儿”的报告，这是一个出生时感染艾滋病毒并在出生后不久接受抗逆转录病毒治疗的孩子。她在18个月大时停止了抗逆转录病毒疗法，似乎治愈了，只是艾滋病毒在27个月后再次出现并反弹。第二年，一项研究揭示了14名艾滋病毒阳性个体--“VISCONTI队列”--尽管在研究发表前4-10年停止了抗逆转录病毒治疗，但他们继续控制着艾滋病毒感染。这些和其他例子表明，在一些艾滋病毒感染者中，在暂停ART和VR之间可能存在显着延迟。延迟VR和治疗后控制（PTC）的潜力知之甚少，但表明令人兴奋的可能性，治疗艾滋病毒没有ART，从而避免副作用和高昂的药物成本。此外，将艾滋病毒控制在无法检测的水平的人不太可能感染其他人，从而降低了艾滋病毒在整个人口中传播的可能性。 本项目的目标是通过分析以下三个问题来更好地理解延迟VR和PTC：在什么情况下ART暂停会导致延迟VR或PTC？如果ART暂停导致VR，什么时候会发生？我们能否预测患者何时可以永久地控制ART的感染？该项目的核心是开发数学病毒动力学模型，以研究ART停止后HIV+个体的VR。该模型将利用随机多类型分支过程，因为接受治疗的患者中的病毒群体很小。虽然随机方法已被用来模拟病毒动力学，标准的方法是广泛的模拟;在这个项目中，主要研究者将强调分析结果的推导，而不是，从而引入新的工具，从应用概率病毒动力学问题。这些目标将通过随机模型来实现，这些模型将通过侧重于艾滋病毒控制的不同生物方面（如免疫反应）的项目来增加复杂性和现实性。这些模型将使用来自实验合作者和已发表数据的HIV动力学和VR数据进行验证。这种建模的目的是更好地表征VR动态，对VR时间进行可测试的预测，并深入了解艾滋病毒的治疗后控制。在医疗环境中，开发的模型可以告知关于ART暂停的临床指南，导致在ART中断期间优化测试频率以检测VR并预测PTC或“HIV缓解”，其中VR不太可能。

项目成果

Mathematical Modeling of Remdesivir to Treat COVID-19: Can Dosing Be Optimized?

• DOI: 10.3390/pharmaceutics13081181
• 发表时间: 2021-07-31
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Conway JM;Abel Zur Wiesch P
• 通讯作者: Abel Zur Wiesch P

Determinants of the efficacy of HIV latency-reversing agents and implications for drug and treatment design

• DOI: 10.1172/jci.insight.123052
• 发表时间: 2018-10-18
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Ke, Ruian;Conway, Jessica M.;Perelson, Alan S.
• 通讯作者: Perelson, Alan S.

Viral Load Kinetics of Severe Acute Respiratory Syndrome Coronavirus 2 in Hospitalized Individuals With Coronavirus Disease 2019.

• DOI: 10.1093/ofid/ofab153
• 发表时间: 2021-08
• 期刊: Open forum infectious diseases
• 影响因子: 4.2
• 作者: Regan J;Flynn JP;Rosenthal A;Jordan H;Li Y;Chishti R;Giguel F;Corry H;Coxen K;Fajnzylber J;Gillespie E;Kuritzkes DR;Hacohen N;Goldberg MB;Filbin MR;Yu XG;Baden L;Ribeiro RM;Perelson AS;Conway JM;Li JZ;MGH COVID-19 Collection & Processing Teams
• 通讯作者: MGH COVID-19 Collection & Processing Teams

Predictions of time to HIV viral rebound following ART suspension that incorporate personal biomarkers

• DOI: 10.1371/journal.pcbi.1007229
• 发表时间: 2019-07-01
• 期刊: PLOS COMPUTATIONAL BIOLOGY
• 影响因子: 4.3
• 作者: Conway, Jessica M.;Perelson, Alan S.;Li, Jonathan Z.
• 通讯作者: Li, Jonathan Z.

Defining early SIV replication and dissemination dynamics following vaginal transmission

• DOI: 10.1126/sciadv.aav7116
• 发表时间: 2019-05-01
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Deleage, Claire;Immonen, Taina T.;Keele, Brandon F.
• 通讯作者: Keele, Brandon F.