HIV Reservoir Ecology of Viral Remission

摘要 艾滋病毒领域的最优先事项之一是寻找能够导致持续 抗逆转录病毒疗法(ART)-艾滋病毒缓解。尽管大多数艾滋病毒感染者会经历快速的病毒感染 在ART中断后反弹，有罕见的个体，称为治疗后控制者(PTCs)，他们 在停止治疗后的几个月或几年内表现出持续的病毒学抑制。这些人 被认为是艾滋病毒持久控制的理想范例，对艾滋病毒治愈研究有直接影响。 然而，我们对艾滋病毒缓解的决定因素的了解仍然不完整。这部分归因于 通过任何一个研究中心或临床试验确定的PTC的稀缺性。为了绕过这一障碍，斯图尔特博士。 Jonathan Li和他的同事在抗逆转录病毒药物暂停后建立了对艾滋病毒的控制 (CHAMP)研究，世界上最大的PTCS研究。到目前为止，大多数努力都集中在对 病毒库、潜伏期和T细胞免疫反应，但仍然存在许多障碍。新战略以实现 因此，有必要促进艾滋病毒的缓解。众所周知，艾滋病毒复制会导致广泛的B细胞 失灵了。也有证据表明，抗逆转录病毒治疗可促进PWH患者B细胞功能的恢复。 这项建议的主要目的是揭示自体抗体反应在体内的决定因素。 治疗后对艾滋病毒复制的控制。抗体反应与降低感染艾滋病毒的风险有关 8感染和自发的艾滋病毒控制。此应用程序建立在李博士最近的Anab发现和 结合了几种独特的成分：1)来自罕见的PTC队列的可用样本和治疗后的非 控制器(NCS)，2)李博士的HIV储存库和序列特征，以及3)Fofana博士的演示 体液免疫和长篇测序方面的专业知识。我们之前已经开发了一种 噬菌体展示和长阅读测序(LRS)方法用于大规模表征病毒特异性 抗体。最近，LRS方案已经被更新，以表征免疫球蛋白重链 基因座(高)多样性。此外，使用艾滋病毒/艾滋病的SIV/猕猴模型，我们观察到非 中和抗体在减缓疾病进展以及病毒抑制近... 检测不到的水平。在这里，我们假设Anab反应在抑制HIV中发挥关键作用 跟随ATI。在这里，我们建议对PTC和PTC的同期抗体反应进行深入分析。 NCS通过以下具体目标：具体目标1：评估艾滋病毒特异性抗体的多样性 特定目标2：捕获PTCS中免疫球蛋白重链的遗传多样性。我们相信 识别PTC和NCS中艾滋病毒特异性抗体的基因构成不仅有助于 预测治疗中断结果，但也促进治疗性抗体策略的设计 伴随治疗中断，促进艾滋病毒持续缓解。

ABSTRACT Among the top priorities of the HIV field is the search for therapeutic interventions that can lead to sustained antiretroviral therapy (ART)-free HIV remission. Although most HIV-infected persons will experience rapid viral rebound after ART interruption, there are rare individuals, termed post-treatment controllers (PTCs), who demonstrate sustained virologic suppression for months or years after treatment cessation. These individuals are considered an ideal example of durable HIV control, with direct implications for HIV cure research. However, our understanding of the determinants of HIV remission remains incomplete. This is in part due to the scarcity of PTCs identified through any one research center or clinical trial. To circumvent this obstacle, Dr. Jonathan Li and Colleagues have established the Control of HIV after Antiretroviral Medication Pause (CHAMP) study, the largest study of PTCs world-wide. So far, most efforts have focused on characterization of viral reservoir, latency and T-cell immune responses but numerous hurdles remain. Novel strategies to promote HIV remission are therefore warranted. It is known that HIV replication causes extensive B-cell disfunction. There is also evidence that ART improves restoration of B-cell function in PWH. The main goal of this proposal is to reveal the determinants of autologous antibody responses at play during post-treatment control of HIV replication. Antibody responses have been associated with reduced risk of HIV infection8 and spontaneous HIV control. This application builds upon Dr. Li’s recent aNAb findings and combines several unique ingredients: 1) available samples from a rare cohort of PTCs and post-treatment non- controllers (NCs), 2) HIV reservoir and sequence characterization by Dr. Li, and 3) Dr. Fofana’s demonstrated expertise in characterizing the humoral immunity and long-read sequencing. We have previously developed a phage display and long read sequencing (LRS) approach for large-scale characterization of viral-specific antibodies. More recently, the LRS protocol has been updated to characterize immunoglobulin heavy chain locus (IGH) diversity. Furthermore, using the SIV/macaque model of HIV/AIDS, we observed that non- neutralizing antibodies play a key role in slow disease progression along with viral suppression to near- undetectable levels. Here, we hypothesize that aNAb responses play a critical role in HIV suppression following ATI. Here, we propose an in-depth analysis of contemporaneous antibody responses in PTCs and NCs by way of the following specific aims: Specific Aim 1: Assess the diversity of HIV-specific antibodies in PTCs; Specific Aim 2: Capture the genetic diversity of the Immunoglobulin heavy chain in PTCs. We believe that identification of the genetic makeup of HIV-specific antibodies in PTCs and NCs will not only facilitate prediction of treatment interruption outcome but also boost the design of therapeutic antibody strategies to accompany treatment interruption and promote sustained HIV remission.