Grant: Op. Gr.:Emerging COVID-19 Res. Gaps & Priorities - HIV and SARS-CoV-2

Recent large cohort studies have identified HIV infection as strong risk factor for severe COVID- 19. Importantly, even PLWH with low or undetectable HIV load and reconstituted CD4+ T-cell immunity still display a two-fold increased COVID-19 associated mortality over the HIV-free population. As in COVID-19, HIV infection is a strong risk factor for tuberculosis disease and mortality. Previous or current tuberculosis increased mortality of COVID-19 patients two-fold in South Africa suggesting an overlap in host vulnerability between tuberculosis and COVID-19. Recent data suggest that the cross talk of alveolar macrophages with T cells, mediated through secretion of chemokines by alveolar macrophages, is a key event in the prevention of death in COVID-19. We have shown that alveolar macrophage from PLWH mount a significantly weaker transcriptional response to infection with Mycobacterium tuberculosis leading to a significantly lower chemokine and cytokine secretion by alveolar macrophages. Unexpectedly, we showed that this reduced host responsiveness of pulmonary macrophages was primarily linked to ART and not HIV. Here we propose to test if HIV and/or ART result in reduced host responses of alveolar macrophages against SARS-CoV-2 which would likely result in increased risk of mortality. If our working hypothesis is correct, this would identify both PLWH and PrEP persons as high risk groups for adverse outcomes from COVID-19. Inclusion in the high risk COVID-19 category for PrEP users would be an important step of social justice for this historically disenfranchised population. A substantial proportion of PLWH and PrEP persons belong to groups with low socioeconomic status that are often under-represented and under-studied in advanced biomedical research, which is a shortcoming that is addressed by our experiments