Pressing Questions and Challenges in the HIV-1 and SARS-CoV-2 Syndemic

Abstract

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.

Keywords: COVID-19; HIV/AIDS; aging; inflammation.

FIG. 1.

(1) SARS-CoV-2 infection of susceptible cells mediated by ACE2 and TMPRSS2. The infection of susceptible host cells by SARS-CoV-2. Potential dysregulation in sex hormone regulation and levels of inflammatory factors commonly observed in PLWH may impact SARS-CoV-2 receptor/coreceptor levels on susceptible cells, leukocyte trafficking at mucosal surfaces, and viral replication amplitude and duration once cells are infected. (2) Innate viral RNA sensing. Acute and innate viral RNA sensing in key cell subsets (e.g., macrophages) may be attenuated in PLWH, with aggravated activation of inflammatory factors and insufficient interferon type 1 responses, that phenocopy age-related response to other respiratory pathogens (e.g., flu). (3) Viral replication and expansion. The replication of SARS-CoV-2 depends, in part, on access to replication competent cells and host mechanisms limiting viral expansion. Leukocyte trafficking to mucosal sites, immune activation, and clearance of infected cells may be altered or impaired in PLWH. (4) Adaptive response. A coordinated response of innate and adaptive mechanisms necessary to control SARS-CoV-2 infection may be altered or attenuated in PLWH for whom immunocompetence is incomplete, despite effective ART. (5) Multisystem inflammatory syndrome. The chronic dysregulation of inflammatory pathways and multimorbidity that are common in PLWH may influence the composition and magnitude of inflammatory response, as well as time-to-resolution and recovery. (6) Postacute COVID-19 syndrome. Persistence of SARS-CoV-2 in mucosal sites (e.g., gut) may differ in PLWH because dysregulated mucosal immunity in the gut is common. In addition, chronic fatigue and cognitive deficits common in PLWH may be aggravated in postacute COVID-19 syndrome. ACE2, angiotensin-converting enzyme 2; ART, antiretroviral therapy; COVID-19, coronavirus disease 2019; PLWH, people living with HIV-1 infection; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; TMPRSS2, transmembrane protease serine 2.