HIV Reservoir Ecology of Viral Remission

病毒缓解的 HIV 储存生态学

• 批准号: 10754800
• 负责人: Jonathan Li
• 金额: $ 8.24万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-21 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10754800
• 关键词: Aftercare; Anti-Retroviral Agents; Antibodies; Antibody Response; Antibody-mediated protection; Autologous; B-Lymphocytes; CD8-Positive T-Lymphocytes; Cardiovascular Diseases; Cell physiology; Clinical Trials; Collaborations; Complementary DNA; Data; Development; Disease Progression; Disease remission; Ecology; Evolution; Frequencies; Functional disorder; Genetic Polymorphism; Genetic Variation; Genomic DNA; Genotype; Goals; HIV; HIV Infections; HIV/AIDS; HLA-B Antigens; Heavy-Chain Immunoglobulins; Humoral Immunities; IGH@ gene cluster; Immune; Immune response; Immunologics; Income; Individual; Inflammation; Interferon Type II; Interruption; Low income; Macaca; Maintenance; Malignant Neoplasms; Modeling; Morbidity - disease rate; Nature; Outcome; Patients; Persons; Phage Display; Pharmaceutical Preparations; Play; Population; Prediction of Response to Therapy; Prevalence; Prevention; Protocols documentation; Reporting; Research; Risk; Role; SIV; Sampling; T-Lymphocyte; Therapeutic Intervention; Therapeutic antibodies; Update; Variant; Viral; Viral reservoir; Virus; Withholding Treatment; antiretroviral therapy; bioinformatics tool; cohort; design; experience; genetic makeup; glycosylation; improved; interest; mortality; neutralizing antibody; novel strategies; prevent; response; restoration; social stigma; viral rebound

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.

摘要 艾滋病毒领域的最高优先事项之一是寻求治疗干预措施， 抗逆转录病毒治疗（ART）-免费艾滋病毒缓解。虽然大多数艾滋病毒感染者会经历快速的病毒感染， 在抗逆转录病毒治疗中断后的反弹中，有罕见的个体，称为治疗后控制者（PTC）， 在治疗停止后持续数月或数年的病毒学抑制。这些人 被认为是持久艾滋病毒控制的理想例子，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理解仍然不完整。这部分是由于 通过任何一个研究中心或临床试验确定的PTC的稀缺性。为了克服这个障碍，博士。 Jonathan Li和同事建立了抗逆转录病毒药物治疗后的艾滋病毒控制研究小组 （CHAMP）研究，全球最大的PTC研究。到目前为止，大多数努力都集中在表征 病毒库、潜伏期和T细胞免疫应答，但仍存在许多障碍。的新策略 因此，促进艾滋病毒缓解是必要的。众所周知，艾滋病毒的复制会导致广泛的B细胞 功能障碍也有证据表明，ART可以改善PWH中B细胞功能的恢复。 这项建议的主要目标是揭示在免疫过程中起作用的自体抗体反应的决定因素。 治疗后控制艾滋病毒复制。抗体反应与降低艾滋病毒风险有关 感染8和自发的艾滋病毒控制。该应用基于Li博士最近的aNAb发现， 结合了几种独特的成分：1）来自罕见的PTC队列和治疗后非 控制器（NC），2）Li博士的HIV储库和序列表征，以及3）Fofana博士证明了 在表征体液免疫和长读序方面的专业知识。我们以前开发了一个 噬菌体展示和长读段测序（LRS）方法用于大规模表征病毒特异性 抗体的最近，LRS方案已更新，以表征免疫球蛋白重链 基因座（IGH）多样性。此外，使用HIV/AIDS的SIV/猕猴模型，我们观察到， 中和抗体在减缓疾病进展中起关键作用，沿着病毒抑制， 无法检测的水平。在这里，我们假设aNAb反应在HIV抑制中起关键作用， 在ATI之后在这里，我们提出了一个深入的分析同期抗体反应的PTC和 具体目标1：评估艾滋病毒特异性抗体的多样性， PTC;特定目标2：捕获PTC中免疫球蛋白重链的遗传多样性。我们认为 在PTC和NC中识别HIV特异性抗体的基因组成不仅有助于 预测治疗中断的结果，而且还促进了治疗性抗体策略的设计， 伴随治疗中断，促进持续的艾滋病毒缓解。