Longitudinal profiling of plasma cytokines and soluble proteases in relation to clinical outcomes of COVID-19 patients with and without HIV

The coronavirus disease-2019 (COVID-19) pandemic has highlighted many vulnerabilities, both biological and social, that can predispose Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infected individuals to a greater risk of poor clinical outcomes. Risk factors for severe disease include higher age (>60 years), male sex, obesity and co-morbidities such as diabetes, hypertension, cardiovascular disease, cerebrovascular disease and chronic respiratory disease. There is an urgent need to evaluate HIV coinfection as a risk factor in our setting. The course of COVID-19 varies substantially among different individuals. Effective viral clearance and resolution of immune response characterizes asymptomatic and mild forms, while the development of an uncontrolled hyperinflammatory immune response, called "cytokine storm" is associated with more severe and critical illness. This study will develop a cohort of black South African patients with COVID-19 at Chris Hani Baragwanath Hospital in order to longitudinally investigate the SARS-CoV-2 immune response with clinical outcomes of patients with moderate to severe COVID19, and with and without HIV-1 infection. We will focus on the cytokine storm response (65 cytokines) as well as soluble versions of proteases important in coronavirus-host cell infection and in comorbidities known to be risk factors for severe clinical outcomes - angiotensin converting enzyme 2 (ACE2) and dipeptidyl peptidase 4 (DPP4). We will determine associations of these plasma biomarkers with clinical characteristics and COVID-19 outcomes. Findings from this study will provide important insights into immune mechanisms that underlie host differences (age, sex, race, comorbidities) in COVID-19 disease progression, and will inform treatment strategies for at risk populations. Expected Outputs Expected outputs: Capacity development: We will gain expertise and experience in working with a new pandemic pathogen within a local African context. Master and PhD student training and development: A huge amount of data will be generated through this study, thereby providing a data resource for addressing many specific COVID-19 related research questions, that many students could use in pursuing further degrees at the University of the Witwatersrand. Publications: We anticipate that several high impact publications will result from this work; at least two within the project period directly pertaining to this proposal and many more through the use of the developed data resource. Expected outcomes: We will have developed a cohort of SARS-CoV-2 infected hospitalized patients with and without HIV-1 infection, have stored samples and generated large datasets for this study and for future studies. This is a very important resource, and represents samples and data from black African individuals (both genders) - currently understudied in the COVID-19 pandemic. Importantly, this provides the basis for the establishment of many further collaborations. We anticipate deriving a clinical risk score for severity in the context of SARS-CoV-2 infection with or without HIV-1 infection, and contributing to new knowledge on sex-specific COVID-19 immune responses, and immune responses in comorbid conditions in black Africans.