Better antiviral and lung-protective effects of Carrimycin in combination with Azvudine in rhesus macaques infected with SARS-CoV-2

With the ongoing evolution and mutation of SARS-CoV-2, current antiviral therapies face notable limitations, including emerging resistance mutations, inadequate immunomodulation, and suboptimal organ protection. This situation highlights the urgent need for novel therapeutic strategies. In this study, we evaluated the combined effects of Carrimycin (CAM) and Azvudine (FNC) in SARS-CoV-2-infected rhesus macaques (RMs), focusing on their antiviral activity, lung protection, and immunoinflammatory modulation roles. RMs were intratracheally challenged with SARS-CoV-2 and treated orally for 7 days with CAM (9 mg/kg), FNC (0.07 mg/kg), or their combination. Viral load, lung pathology, immune responses, and gut microbiota were analyzed. Both CAM and FNC monotherapies significantly inhibited SARS-CoV-2 replication, while their combination produced additive antiviral effects, reducing viral loads in throat swabs and lung tissue without significant side effects. Chest imaging and histopathological examination of lung tissues showed reduced ground-glass opacities and a mitigation of focal interstitial pneumonia with monotherapy, while the combination treatment demonstrated superior efficacy. Transcriptomic and immunofluorescence analyses of the lung indicated enhanced immunomodulation with combination therapy, including suppressed neutrophil degranulation, increased CD19⁺ B and CD3⁺ T cells, decreased CD68⁺ macrophages, and downregulation of pro-inflammatory and apoptotic markers, suggesting improved adaptive immunity and lung protection. Furthermore, CAM, but not FNC, increased beneficial short-chain fatty acid-producing gut bacteria and decreased harmful pathogens associated with COVID-19 progression. The combination of CAM and FNC showed superior efficacy in suppressing viral replication, alleviating lung injury, and correcting immune and inflammatory dysregulation, with CAM alone providing additional gut microbiota benefits. This combination represents a promising therapeutic strategy against COVID-19 and its complications.