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.

抽象的 HIV 领域的首要任务之一是寻找能够导致持续性治疗的治疗干预措施。 尽管大多数艾滋病毒感染者会经历快速病毒感染，但无需抗逆转录病毒治疗（ART）即可缓解艾滋病毒。 ART 中断后反弹，有极少数人，称为治疗后控制者 (PTC)， 在治疗停止后数月或数年表现出持续的病毒学抑制。 被认为是持久艾滋病毒控制的理想范例，对艾滋病毒治疗研究具有直接影响。 然而，我们对艾滋病毒缓解的决定因素的理解仍然不完整，部分原因是。 通过任何一个研究中心或临床试验发现的 PTC 都很稀缺，为了规避这一障碍，Dr. 乔纳森·李（Jonathan Li）和他的同事们在抗逆转录病毒药物治疗暂停后建立了对艾滋病毒的控制 (CHAMP) 研究是迄今为止全球最大的 PTC 研究，大部分工作都集中在 PTC 的表征上。 病毒库、潜伏期和 T 细胞免疫反应，但仍存在许多新策略。 因此，促进 HIV 缓解是有必要的。众所周知，HIV 复制会导致 B 细胞大量复制。 还有证据表明，ART 可以改善 PWH 中 B 细胞功能的恢复。 该提案的主要目标是揭示自体抗体反应的决定因素 治疗后控制艾滋病毒复制与降低艾滋病毒风险有关。 该应用建立在李博士最近的 aNAb 研究结果和 结合了几种独特的成分：1）来自一组罕见的 PTC 和治疗后非 控制器 (NC)，2) 李博士的 HIV 储存库和序列表征，以及 3) Fofana 博士证明 我们之前开发了一种表征体液免疫和长读测序的专业知识。 噬菌体展示和长读长测序 (LRS) 方法用于大规模表征病毒特异性 最近，LRS 方案已更新以表征免疫球蛋白重链。 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方面发挥着关键作用 在这里，我们发现 aNAb 反应在 HIV 抑制中发挥着关键作用。 在此，我们建议对 PTC 中的同期抗体反应进行深入分析。 NC 通过以下具体目标： 具体目标 1：评估 HIV 特异性抗体的多样性 PTC；具体目标 2：捕获 PTC 中免疫球蛋白重链的遗传多样性。 PTC 和 NC 中 HIV 特异性抗体的基因组成的鉴定不仅将有助于 预测治疗中断结果，同时也促进治疗抗体策略的设计 伴随治疗中断并促进艾滋病毒持续缓解。