Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19
Year: 2020
Type: preprint
Abstract: 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.
Authors: Bruce Pattterson, Harish Seetthamraju, Kush Dhody, Michael Corley, Kazem Kazempour, Jay Lalezari, Alina Pang, Christopher Sugai, Edgar Francisco, Amruta Pise, Hallison Rodrigues, Matthew Ryou, Helen Wu, Gabriela Webb, Byung Park, Scott Kelly, Nader Pourhassan, Alena Lelic, Lama Kdouh, Monica Herrera, Eric Hall, Enver Aklin, Lishomwa Ndhlovu, Jonah Sacha
Institutions: IncellDx (United States), Montefiore Medical Center, Amarex Clinical Research, LLC (United States), Weill Cornell Medicine, Quest Clinical Research (United States), University of Hawaiʻi at Mānoa, University of Hawaii System, Oregon Health & Science University, CytoDyn Inc. (United States), Beckman Coulter (United States), Bio-Rad (United States)
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4233505395