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SARS-CoV-2 and HIV-1 are RNA viruses that have killed millions of people worldwide. Understanding the similarities and differences between these two infections is critical for understanding disease progression and for developing effective vaccines and therapies, particularly for 38 million HIV-1+ individuals who are vulnerable to SARS-CoV-2 co-infection. Here, we utilized single-cell transcriptomics to perform a systematic comparison of 94,442 PBMCs from 7 COVID-19 and 9 HIV-1+ patients in an integrated immune atlas, in which 27 different cell types were identified using an accurate consensus single-cell annotation method. While immune cells in both cohorts show shared inflammation and disrupted mitochondrial function, COVID-19 patients exhibit stronger humoral immunity, broader IFN-I signaling, elevated Rho GTPase and mTOR pathway activities, and downregulated mitophagy. Our results elucidate transcriptional signatures associated with COVID-19 and HIV-1 that may reveal insights into fundamental disease biology and potential therapeutic targets to treat these viral infections.

Introduction: Within the inflammatory immune response to viral infection, the distribution and cell type-specific profiles of immune cell populations and the immune-mediated viral clearance pathways vary according to the specific virus. Uncovering the immunological similarities and differences between viral infections is critical to understanding disease progression and developing effective vaccines and therapies. Insight into COVID-19 disease progression has been bolstered by the integration of single-cell (sc)RNA-seq data from COVID-19 patients with data from related viruses to compare immune responses. Expanding this concept, we propose that a high-resolution, systematic comparison between immune cells from SARS-CoV-2 infection and an inflammatory infectious disease with a different pathophysiology will provide a more comprehensive picture of the viral clearance pathways that underscore immunological and clinical differences between infections.Methods: Using a novel consensus single-cell annotation method, we integrate previously published scRNA-seq data from 111,566 single PBMCs from 7 COVID-19, 10 HIV-1+, and 3 healthy patients into a unified cellular atlas. We compare in detail the phenotypic features and regulatory pathways in the major immune cell clusters.Results: While immune cells in both COVID-19 and HIV-1+ cohorts show shared inflammation and disrupted mitochondrial function, COVID-19 patients exhibit stronger humoral immunity, broader IFN-I signaling, elevated Rho GTPase and mTOR pathway activity, and downregulated mitophagy.Discussion: Our results indicate that differential IFN-I signaling regulates the distinct immune responses in the two diseases, revealing insight into fundamental disease biology and potential therapeutic candidates.