Resistance Evolution against Host-directed Antiviral Agents: Buffalopox Virus Switches to Use p38-ϒ under Long-term Selective Pressure of an Inhibitor Targeting p38-α. (17th August 2022)

• Record Type: Journal Article
• Authors: Chander, Yogesh; Kumar, Ram; Verma, Assim; Khandelwal, Nitin; Nagori, Himanshu; Singh, Namita; Sharma, Shalini; Pal, Yash; Puvar, Apurvasinh; Pandit, Rameshchandra; Shukla, Nitin; Chavada, Priyank; Tripathi, Bhupendra N; Barua, Sanjay; Kumar, Naveen
• Editors: Xia, Xuhua
• Is Part Of: Molecular biology and evolution. Volume 39:Number 9(2022)
• Publication Date: 2022-08-17
• Subjects: p38 -- SB239063 -- virus -- switch to use alternate cellular factor -- drug resistance -- host-directed antiviral agents; Molecular biology -- Periodicals; Molecular evolution -- Periodicals; Evolution, Molecular -- Periodicals; Molecular Biology -- Periodicals; 572.8
• DOI: 10.1093/molbev/msac177
• Languages: English
• ISSNs: 0737-4038

Abstract

Abstract: Host-dependency factors have increasingly been targeted to minimize antiviral drug resistance. In this study, we have demonstrated that inhibition of p38 mitogen-activated protein kinase (a cellular protein) suppresses buffalopox virus (BPXV) protein synthesis by targeting p38-MNK1-eIF4E signaling pathway. In order to provide insights into the evolution of drug resistance, we selected resistant mutants by long-term sequential passages (P; n = 60) in the presence of p38 inhibitor (SB239063). The P60-SB239063 virus exhibited significant resistance to SB239063 as compared to the P60-Control virus. To provide mechanistic insights on the acquisition of resistance by BPXV-P60-SB239063, we generated p38-α and p38-ϒ (isoforms of p38) knockout Vero cells by CRISPR/Cas9-mediated genome editing. It was demonstrated that unlike the wild type (WT) virus which is dependent on p38-α isoform, the resistant virus (BPXV-P60-SB239063) switches over to use p38-ϒ so as to efficiently replicate in the target cells. This is a rare evidence wherein a virus was shown to bypass the dependency on a critical cellular factor under selective pressure of a drug.