Since emerging into the human population in late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has reached across the globe to infect >80 million people. The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 can range in severity from mild and asymptomatic to severe and fatal. Identifying risk factors for adverse outcomes in COVID-19 is a major challenge. In the context of the existing HIV-1 pandemic, whether COVID-19 disproportionately burdens people living with HIV-1 infection (PLWH) is unclear. The following discussion highlights pressing questions and challenges in the HIV-1 and SARS-CoV-2 syndemic, including (i) age, sex, and race as drivers of COVID-19 severity; (ii) whether chronic inflammation common in PLWH influences immune response; (iii) whether disease severity and trajectory models for COVID-19 ought to be calibrated for PLWH; (iv) vaccine considerations, and finally, (v) long-term health outcomes in PLWH that are further burdened by coinfection with SARS-CoV-2.