28Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of 29 coronavirus disease 2019 , is now pandemic with nearly three million cases 30 reported to date 1 . Although the majority of COVID-19 patients experience only mild or 31 moderate symptoms, a subset will progress to severe disease with pneumonia and acute 32 respiratory distress syndrome (ARDS) requiring mechanical ventilation 2 . Emerging results 33 indicate a dysregulated immune response characterized by runaway inflammation, 34including cytokine release syndrome (CRS), as the major driver of pathology in severe 35 -19 3,4 . With no treatments currently approved for COVID-19, therapeutics to 36 prevent or treat the excessive inflammation in severe disease caused by SARS-CoV-2 37 infection are urgently needed. Here, in 10 terminally-ill, critical COVID-19 patients we 38 report profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell 39 levels, and SARS-CoV-2 plasma viremia. Following compassionate care treatment with 40 the CCR5 blocking antibody leronlimab, we observed complete CCR5 receptor 41 occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the 42 CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. Consistent 43 with reduction of plasma IL-6, single-cell RNA-sequencing revealed declines in 44 transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes. These 45 results demonstrate a novel approach to resolving unchecked inflammation, restoring 46 immunologic deficiencies, and reducing SARS-CoV-2 plasma viral load via disruption of 47 COVID MAIN TEXT 51 52Since the initial cases of COVID-19 were reported from Wuhan, China in December 53 2019 2 , SARS-CoV-2 has emerged as a global pandemic with an ever-increasing number 54 of severe cases requiring invasive external ventilation that threatens to overwhelm health 55

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is now pandemic with nearly three million cases reported to date1. Although the majority of COVID-19 patients experience only mild or moderate symptoms, a subset will progress to severe disease with pneumonia and acute respiratory distress syndrome (ARDS) requiring mechanical ventilation2. Emerging results indicate a dysregulated immune response characterized by runaway inflammation, including cytokine release syndrome (CRS), as the major driver of pathology in severe COVID-193,4. With no treatments currently approved for COVID-19, therapeutics to prevent or treat the excessive inflammation in severe disease caused by SARS-CoV-2 infection are urgently needed. Here, in 10 terminally-ill, critical COVID-19 patients we report profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell levels, and SARS-CoV-2 plasma viremia. Following compassionate care treatment with the CCR5 blocking antibody leronlimab, we observed complete CCR5 receptor occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. Consistent with reduction of plasma IL-6, single-cell RNA-sequencing revealed declines in transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes. These results demonstrate a novel approach to resolving unchecked inflammation, restoring immunologic deficiencies, and reducing SARS-CoV-2 plasma viral load via disruption of the CCL5-CCR5 axis, and support randomized clinical trials to assess clinical efficacy of leronlimab-mediated inhibition of CCR5 for COVID-19.