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Steven Grinspoon, MD, and Marton Kolossváry, MD, PhD, are co-authors of a new study in eBbiomedicine, Identification of pre-infection markers and differential plasma protein expression following SARS-CoV-2 infection in people living with HIV

What was the question you set out to answer with this study?

COVID-19 may be more severe in PWH. However, underlying biological mechanisms associated with the development of COVID-19 and its clinical severity among antiretroviral therapy (ART) treated PWH are largely unknown.

Among people living with HIV at risk for worse COVID-19 outcomes, is there a proteomic signature associated with more severe COVID-19 infection?

What Methods or Approach Did You Use?

We evaluated temporal changes in plasma proteins following SARS-CoV-2 infection and identified pre-infection proteomic markers associated with future COVID-19.

We leveraged data from the global Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE). Antiretroviral therapy (ART)-treated PWH with clinical, antibody confirmed COVID-19 as of September 2021 were matched on geographic region, age, and sample timing to antibody negative controls.

For cases and controls, pre COVID-19 pandemic specimens were obtained prior to January 2020 to assess change over time and relationship to COVID-19 severity, using false-discovery adjusted mixed-effects modeling.

What Did You Find?

We compared 257 unique plasma proteins in 94 COVID-19 antibody-confirmed clinical cases and 113 matched antibody-negative controls, excluding COVID-19 vaccinated participants (age 50 years, 73% male). 40% of cases were characterized as mild; 60% moderate to severe. Median time from COVID-19 infection to follow-up sampling was 4 months.

Temporal patterns of protein changes differed based on COVID-19 disease severity. Among those experiencing moderate to severe disease vs. controls, NOS3 increased whereas ANG, CASP-8, CD5, GZMH, GZMB, ITGB2, and KLRD1 decreased.

Higher pre-pandemic levels of granzymes A, B and H (GZMA, GZMB and GZMH) were associated with the future development of moderate-severe COVID-19 and were related to immune function.

What are the Implications?

We identified temporal changes in proteins closely linked to inflammatory, immune, and fibrotic pathways which may relate to COVID-19-related morbidity among ART-treated PWH.

Further we found increased pre-pandemic circulating concentrations of granzymes A, B, and H to be an independent risk factor for the development of subsequent moderate-to-severe COVID-19 among well treated PWH receiving ART. These results shed light on critical biological responses to COVID-19 which may contribute to disease severity

Paper cited:

Kolossváry, M., deFilippi, C., McCallum, S., Fitch, K. V., Diggs, M. R., Fulda, E. S., Ribaudo, H. J., Fichtenbaum, C. J., Aberg, J. A., Malvestutto, C. D., Currier, J. S., Casado, J. L., Gutiérrez, F., Sereti, I., Douglas, P. S., Zanni, M. V., & Grinspoon, S. K. (2023). Identification of pre-infection markers and differential plasma protein expression following SARS-CoV-2 infection in people living with HIV. EBioMedicine90, 104538. Advance online publication. https://doi.org/10.1016/j.ebiom.2023.104538

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham healthcare system.