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

总结 有效的抗SARS-CoV-2疫苗的接种能够引起保护性免疫应答， 大部分人口是抗击冠状病毒疾病的主要公共卫生优先事项2019 （COVID-19）.我们的研究表明，可溶性抗体的功能性（即：体液免疫）受到影响 慢性炎症，如慢性HIV感染和/或阿片类药物使用。我们的短期目标是评估 艾滋病毒感染者（PLWH）抗SARS-CoV-2抗体反应的质量和持久性a）接受 a）SARS-CoV-2疫苗接种，B）接受抑制性抗逆转录病毒疗法（ART）治疗和c）接受治疗 与μ阿片受体（莫尔）激动剂美沙酮或丁丙诺啡联合治疗阿片类药物使用障碍（OUD）。基于 根据文献和我们的初步研究，我们的主要假设是，在接受莫尔的ART治疗的PLWH中， 基于激动剂的治疗和SARS-CoV-2疫苗接种将导致更短的中和滴度保留， 具有不同的定性抗体应答[包括较低的抗体依赖性细胞毒性 （ADCC）/抗体依赖性细胞吞噬（ADCP）]与ART中的疫苗应答相比 不使用阿片类药物的受抑制的PLWH。为了解决这一假设，我们将研究一个队列的90 PLWH 在SARS-CoV-2疫苗接种后约4、8和12个月接受抑制性ART（VL < 50 c/ml）， 在以下组中：（1）美沙酮OUD，（2）丁丙诺啡/纳洛酮（Suboxone）OUD，和（3）ART- 只有非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。通过测量以下指标定量功能性抗SARS-CoV-2抗体应答：（a）SARS-CoV-2 通过与刺突蛋白的总结合抗体的抗体应答，以及针对Vero的中和抗体的滴度 感染野生型SarsCoV 2（WA 1/2020-武汉）或相关变体（B.1.1.7-UK或B.1.351-South 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。为了评价SARS-CoV-2抗体应答、免疫激活和免疫应答之间的关系， （a）通过评估血浆标志物， 细菌易位（例如：sCD 14、sCD 163、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（完整和总）、HIV RNA（不同的转录物）和HIV转录活性（HIV DNA/HIV RNA的比率。圆满完成 本研究的结论将为ART抑制的PLWH接受莫尔治疗的能力提供新的见解 从SARS-CoV-2疫苗接种中充分受益。

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.