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

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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.