Identification of pre-infection markers and differential plasma protein expression following SARS-CoV-2 infection in people living with HIV

BACKGROUND: Mechanisms contributing to COVID-19 severity in people with HIV (PWH) are poorly understood. We evaluated temporal changes in plasma proteins following SARS-CoV-2 infection and identified pre-infection proteomic markers associated with future COVID-19. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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 identified key granzyme proteins associated with future COVID-19 in PWH. FUNDING: This study is supported through 10.13039/100000002NIH grants U01HL123336, U01HL123336-06 and 3U01HL12336-06S3, to the clinical coordinating center, and U01HL123339, to the data coordinating center as well as funding from 10.13039/100011027Kowa Pharmaceuticals, 10.13039/100005564Gilead Sciences, and a grant award through 10.13039/100010877ViiV Healthcare. The 10.13039/100000060NIAID supported this study through grants UM1 AI068636, which supports the 10.13039/100006392AIDS Clinical Trials Group (ACTG) Leadership and Operations Center, and UM1 AI106701, which supports the ACTG Laboratory Center. This work was also supported by 10.13039/100000060NIAID through grant K24AI157882 to MZ. The work of IS was supported by the intramural research program of NIAID/10.13039/100000002NIH.