Abstract The novel SARS-CoV2 Coronavirus has, within a short time, caused a worldwide pandemic of epic proportions and unprecedented dimensions in modern times. As previously observed in the HIV-1 epidemic, understanding the complex pathogenesis and host response of CoV2 infection will represent the cornerstone for developing effective treatment strategies. One particularly important aspect will be to identify subpopulations of patients with increased vulnerability to CoV2, and to understand possible connections between CoV2 and other viral infections. Moreover, the CoV2 pandemic occurs in the midst of the ongoing opioid epidemic in the US, and people who use opioids are likely to have specific behavioral and immunological characteristics that may increase susceptibility to severe CoV2 infection. In the proposed work, we will perform what we consider the first dedicated analysis of virological and immunological characteristics of CoV2- patients with HIV-1 co-infection, and with opioid abuse. Our work will focus on identifying CoV2/HIV-1 co-infected patients with or without opioid abuse, using large cohorts of CoV2 patients that are currently actively enrolling in the Boston area (Specific aim 1). Using well pedigreed samples from such patient cohorts available through a centralized biorepository, we will conduct virological and immunological studies to define the replicative behavior of CoV2 in such patients and characterize host immune cell perturbations and inflammatory markers, relative to CoV2-monoinefcetd patients (Specific aim 2). Finally, we will determine how CoV2 infection affects viral reservoir cells in HIV-1 infected patients, a question of important significance as modeling predicts that a large proportion of all US citizens, and of all US-based HIV-1-patients, may ultimately be exposed and infected with CoV2 (Specific aim 3). Together, these proposed studies will address fundamental question of CoV2 pathogenesis and critically define the understanding of CoV2 pathogenesis in HIV-1 patients.