ABSTRACT
Translation of open reading frame 1b (ORF1b) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires a programmed -1 ribosomal frameshift (-1 PRF) promoted by an RNA pseudoknot. The extent to which SARS-CoV-2 replication may be sensitive to changes in -1 PRF efficiency is currently unknown. Through an unbiased, reporter-based high-throughput compound screen, we identified merafloxacin, a fluoroquinolone antibacterial, as a -1 PRF inhibitor for SARS-CoV-2. Frameshift inhibition by merafloxacin is robust to mutations within the pseudoknot region and is similarly effective on -1 PRF of other betacoronaviruses. Consistent with the essential role of -1 PRF in viral gene expression, merafloxacin impedes SARS-CoV-2 replication in Vero E6 cells, thereby providing proof-of-principle for targeting -1 PRF as a plausible and effective antiviral strategy for SARS-CoV-2 and other coronaviruses.
Subject(s)
Antiviral Agents/pharmacology , Frameshifting, Ribosomal/drug effects , SARS-CoV-2/drug effects , Virus Replication/drug effects , Animals , Betacoronavirus , Chlorocebus aethiops , Fluoroquinolones/pharmacology , Frameshifting, Ribosomal/genetics , Mutation , Nucleic Acid Conformation , RNA, Viral/chemistry , RNA, Viral/genetics , SARS-CoV-2/physiology , Vero CellsABSTRACT
PURPOSE OF REVIEW: CD4 T cell loss is the hallmark of uncontrolled HIV-1 infection. Strikingly, CD4 T cell depletion is a strong indicator for disease severity in the recently emerged coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We reviewed recent single-cell immune profiling studies in HIV-1 infection and COVID-19 to provide critical insight in virus-induced immunopathogenesis. RECENT FINDINGS: Cytokine dysregulation in HIV-1 leads to chronic inflammation, while severe SARS-CoV-2 infection induces cytokine release syndrome and increased mortality. HIV-1-specific CD4 T cells are dysfunctional, while SARS-CoV-2-specific CD4 T cells exhibit robust Th1 function and correlate with protective antibody responses. In HIV-1 infection, follicular helper T cells (TFH) are susceptible to HIV-1 infection and persist in immune-sanctuary sites in lymphoid tissues as an HIV-1 reservoir. In severe SARS-CoV-2 infection, TFH are absent in lymphoid tissues and are associated with diminished protective immunity. Advancement in HIV-1 DNA, RNA, and protein-based single-cell capture methods can overcome the rarity and heterogeneity of HIV-1-infected cells and identify mechanisms of HIV-1 persistence and clonal expansion dynamics. SUMMARY: Single-cell immune profiling identifies a high-resolution picture of immune dysregulation in HIV-1 and SARS-CoV-2 infection and informs outcome prediction and therapeutic interventions.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , HIV Infections/immunology , SARS-CoV-2/immunology , Animals , COVID-19/genetics , COVID-19/virology , Cytokines/genetics , Cytokines/immunology , HIV Infections/genetics , HIV Infections/virology , Humans , Pandemics , SARS-CoV-2/geneticsABSTRACT
The pandemic coronavirus infectious disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is rapidly spreading across the globe. In this issue of the JCI, Chen and colleagues compared the clinical and immunological characteristics between moderate and severe COVID-19. The authors found that respiratory distress on admission is associated with unfavorable outcomes. Increased cytokine levels (IL-6, IL-10, and TNF-α), lymphopenia (in CD4+ and CD8+ T cells), and decreased IFN-γ expression in CD4+ T cells are associated with severe COVID-19. Overall, this study characterized the cytokine storm in severe COVID-19 and provides insights into immune therapeutics and vaccine design.