Effects of Mu-opiate receptor engagement on the persistence of HIV-associated activation and viral reservoirs in individuals receiving medication assisted treatment for opioid use disorder

Mu-阿片受体参与对接受阿片类药物使用障碍药物辅助治疗的个体中 HIV 相关激活和病毒库持续性的影响

• 批准号: 10381326
• 负责人: Luis J Montaner
• 金额: $ 15.69万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381326
• 关键词: 2019-nCoV; Address; Affect; Agonist; Antibodies; Antibody Response; Antibody titer measurement; Antiviral Agents; Award; Bacterial Translocation; Binding; Blood specimen; Buprenorphine; CD14 gene; COVID-19; COVID-19 patient; COVID-19 vaccination; COVID-19 vaccine; Cells; Chronic; Complement; DNA; Data; Deposition; Development; Genetic Transcription; HIV; HIV Infections; HIV antiretroviral; HIV-1; Humoral Immunities; Immune; Immune response; Immunotherapy; Individual; Infection; Inflammation; Literature; Measures; Methadone; Mucous Membrane; Myelogenous; Opioid Receptor; Opioid agonist; Parents; Patients; Persons; Phagocytosis; Pharmaceutical Preparations; Philadelphia; Pilot Projects; Plasma; Population; Proteins; RNA; RNA vaccine; Recovery; SARS-CoV-2 B.1.1.7; SARS-CoV-2 B.1.351; SARS-CoV-2 antibody; South Africa; Structure; Suboxone; Testing; Time; Transcript; Vaccination; Vaccines; Vero Cells; Viral reservoir; antibody-dependent cell cytotoxicity; antiretroviral therapy; base; cohort; cytotoxicity; disorder control; immune activation; innate immune function; insight; intestinal fatty acid binding protein; medication-assisted treatment; microbial; mu opioid receptors; neutralizing antibody; non-opioid analgesic; novel; opioid use; opioid use disorder; patient population; prescription opioid; recruit; response; vaccine response; variants of concern; zonulin

SUMMARY The administration of effective anti- SARS-CoV-2 vaccines capable of eliciting a protective immune response in a large proportion of the population is a major public heath priority in combating Coronavirus disease 2019 (COVID-19). Our studies indicates that the functionality of soluble antibodies (i.e.: humoral immunity) is affected by chronic inflammation, such as chronic HIV infection and/or opioid use. Our short-term objective is to evaluate the quality and persistence of anti-SARS-CoV-2 antibody response in people living with HIV (PLWH) a) receiving a SARS-CoV-2 vaccination, b) on treatment with suppressive antiretroviral therapy (ART) and c) on treatment with mu opioid receptor (MOR) agonists methadone or buprenorphine for opioid use disorder (OUD). Based on the literature and our pilot studies, our primary hypothesis is that in ART-treated PLWH receiving MOR agonists-based treatment and SARS-CoV-2 vaccination will result in shorter retention of neutralizing titers and with different qualitative antibody responses [including lower antibody-dependent cell cytotoxicity (ADCC)/antibody-dependent cell phagocytosis (ADCP)] when compared to vaccine responses in ART suppressed PLWH who do not use opioids. To address this hypothesis, we will study a cohort of 90 PLWH receiving suppressive ART (VL < 50 c/ml) at approximately 4, 8 and 12 months from SARS-CoV-2 vaccination, in the following groups: (1) OUD on methadone, (2) OUD on buprenorphine/naloxone (Suboxone), and (3) ART- only non-OUD control. We will test our hypothesis by completion of the following aims: Specific Aim 1. To quantify functional anti-SARS-CoV-2 antibody responses by measuring: (a) SARS-CoV-2 antibody response by total binding antibody to Spike protein, and titers of neutralizing antibody against of Vero cells infected with wildtype SarsCoV2 (WA1/2020-Wuhan) or variants of concern (B.1.1.7-UK, or B.1.351-South Africa); (b) Anti-SARS-CoV-2 antibody activity in recruiting innate immune functions by complement deposition (ADCD), phagocytosis (ADCP), and cytotoxicity (ADCC). Specific Aim 2. To evaluate the relationships between SARS-CoV-2 antibody responses, immune activation and HIV latency by measuring: (a) Microbial translocation and mucosal integrity by assessing plasma markers of bacterial translocation (e.g.: sCD14, sCD163, LPS, EndoCAB), and mucosal structural integrity (e.g.: Intestinal fatty acid-binding protein (I-FABP) and Zonulin-1); (b) Levels of cell-associated HIV DNA (intact and total), HIV RNA (different transcript), and HIV transcriptional activity (ratio of HIVDNA/HIV RNA. The successful completion of this study will provide novel insights on the ability of ART-suppressed PLWH receiving treatment with MOR agonists to fully benefit from SARS-CoV-2 vaccinations.

概括 施用有效的抗 SARS-CoV-2 疫苗能够在体内引发保护性免疫反应 很大一部分人口是抗击 2019 年冠状病毒病的主要公共卫生优先事项 （新冠肺炎）。我们的研究表明可溶性抗体的功能（即体液免疫）受到影响 慢性炎症，例如慢性 HIV 感染和/或阿片类药物的使用。我们的短期目标是评估 HIV 感染者 (PLWH) 的抗 SARS-CoV-2 抗体反应的质量和持久性 a) 接受治疗 a SARS-CoV-2 疫苗接种，b) 抑制性抗逆转录病毒疗法 (ART) 治疗，以及 c) 治疗 与μ阿片受体（MOR）激动剂美沙酮或丁丙诺啡一起治疗阿片类药物使用障碍（OUD）。基于 根据文献和我们的试点研究，我们的主要假设是，在接受 ART 治疗的 PLWH 中接受 MOR 基于激动剂的治疗和 SARS-CoV-2 疫苗接种将导致中和滴度保留时间缩短， 具有不同定性的抗体反应[包括较低的抗体依赖性细胞毒性 (ADCC)/抗体依赖性细胞吞噬作用(ADCP)]与ART中的疫苗反应相比 不使用阿片类药物的艾滋病毒感染者受到抑制。为了验证这一假设，我们将研究 90 名 PLWH 患者的队列 在 SARS-CoV-2 疫苗接种后约 4、8 和 12 个月时接受抑制性 ART（VL < 50 c/ml）， 分为以下几组：(1) 美沙酮 OUD，(2) 丁丙诺啡/纳洛酮（Suboxone）OUD，以及 (3) ART- 仅非 OUD 控制。我们将通过完成以下目标来检验我们的假设： 具体目标 1. 通过测量以下指标来量化功能性抗 SARS-CoV-2 抗体反应： (a) SARS-CoV-2 刺突蛋白总结合抗体的抗体反应，以及针对 Vero 的中和抗体滴度 感染野生型 SarsCoV2 (WA1/2020-Wuhan) 或相关变体（B.1.1.7-UK 或 B.1.351-South）的细胞 非洲）; (b) 抗 SARS-CoV-2 抗体通过补体沉积募集先天免疫功能的活性 （ADCD）、吞噬作用（ADCP）和细胞毒性（ADCC）。 具体目标 2. 评估 SARS-CoV-2 抗体反应与免疫激活之间的关系 和 HIV 潜伏期，通过测量： (a) 通过评估血浆标记物来评估微生物易位和粘膜完整性 细菌易位（例如：sCD14、sCD163、LPS、EndoCAB）和粘膜结构完整性（例如：肠 脂肪酸结合蛋白 (I-FABP) 和 Zonulin-1)； (b) 细胞相关 HIV DNA 水平（完整和全部）、HIV RNA（不同转录本）和HIV转录活性（HIVDNA/HIV RNA的比率。成功完成 这项研究将为 ART 抑制的 PLWH 接受 MOR 治疗的能力提供新的见解 激动剂以充分受益于 SARS-CoV-2 疫苗接种。