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

摘要 接种有效的抗SARS-CoV-2疫苗可诱导保护性免疫反应 很大比例的人口是2019年抗击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，如慢性艾滋病毒感染和/或阿片类药物的使用。我们的短期目标是评估 HIV感染者接受抗SARS-CoV-2抗体应答的质量和持久性 A)接种SARS-CoV-2疫苗，b)接受抑制性抗逆转录病毒治疗(ART)，c)接受治疗 使用MU阿片受体(MOR)激动剂美沙酮或丁丙诺啡治疗阿片使用障碍(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ART治疗的PLWH中，接受更多治疗 以激动剂为基础的治疗和SARS-CoV-2疫苗接种将缩短中和滴度的保留时间，并 具有不同性质的抗体反应[包括较低的抗体依赖细胞细胞毒性 (ADCC)/抗体依赖细胞吞噬(ADCP)]与ART中疫苗反应的比较 抑制不使用阿片类药物的PLWH。为了解决这一假设，我们将研究90名PLWH的队列 在接种SARS-CoV-2疫苗后大约4个月、8个月和12个月接受抑制性ART(VL和Lt；50c/ml)， (1)服用美沙酮，(2)服用丁丙诺啡/纳洛酮(亚博酮)，以及(3)服用ART- 只有非OUD控件。我们将通过完成以下目标来验证我们的假设： 具体目的1.通过测量：(A)SARS-CoV-2，量化功能性抗SARS-CoV-2抗体反应 刺突蛋白总结合抗体的抗体应答及Vero中和抗体效价 感染野生型SarsCoV2(WA1/2020-武汉)或相关变异(B.1.1.7-UK或B.1.351-South)的细胞 非洲)；(B)通过补体沉积招募先天免疫功能的抗SARS-CoV-2抗体活性 (ADCD)、吞噬作用(ADCP)和细胞毒性(ADCC)。 特异性目的2.评价SARS-CoV-2抗体应答、免疫激活之间的关系 和艾滋病毒潜伏期：(A)通过评估血浆标志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：肠道 (B)细胞相关的艾滋病毒DNA水平(完整和全部)、艾滋病毒 RNA(不同转录物)和HIV转录活性(HIVDNA/HIV RNA的比率。圆满完成 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 激动剂充分受益于SARS-CoV-2疫苗接种。

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.