Risk factors for developing severe illness/acute respiratory distress syndrome from coronavirus disease 2019 (COVID-19) include older age, male gender, and underlying conditions, currently identified as smoking, chronic lung disease or moderate to severe asthma, heart disease with complications, severe obesity, diabetes, renal failure or liver disease. Immune factors are likely to contribute to disease progression. While immune activation is required for anti-viral response, severely ill patients show an excessive and aberrant host immune response as evidenced by high inflammatory markers and proinflammatory cytokines. On the other hand, factors associated with less robust immune response against the virus, such as advanced age are associated with severe disease. Opioid use disorder (OUD) is an important public heath condition associated with dysregulated immunity. This may be related to higher prevalence of systemic comorbid conditions and concomitant conditions like chronic HIV, hepatitis C or incident infections related to injection drug use, which may further influence immune response to infections. An especially vulnerable group is people living with HIV (PLWH) with OUD, which are expected to have further immune dysregulations due to twin effect of HIV and opioids on immunity. Additionally, people with OUD are at increased risk of COVID-19 due to social factors such as homelessness, poor access to healthcare, housing insecurity, greater likelihood of incarceration, which can make it more difficult to maintain social distancing and these individuals may not seek medical care promptly due to lack of access to outpatient care. We are asking whether OUD constitutes a risk factor for progressive (COVID-19), especially in PLWH. We are investigating immune responses in individuals with OUD and HIV infection under our NIDA funded R01; leveraging the clinical cohorts and IRB approved blood collection protocols from COVID-19 patients, here we will investigate incidence and progression of COVID-19 in these patient populations. First, we will document clinical course and outcomes of COVID-19 in patients with or without OUD/HIV. To identify immune correlates of COVID-19 severity, we will perform analysis of B and T cell responses and study impact of OUD and HIV on this response. Our investigation of clinical and immunological features of the disease in PLWH and OUD will expand on known correlates of progressive COVID-19 and will inform treatment and prophylactic approaches for COVID-19 in vulnerable groups.