Resistance Evolution against Host-directed Antiviral Agents: Buffalopox Virus Switches to Use p38-[gamma] under Long-term Selective Pressure of an Inhibitor Targeting p38-[alpha]

• Published in: Molecular biology and evolution 2022-09, Vol.39 (9)
• Main 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
• Format: Article
• Language: English
• Subjects: Antiviral agents; Cellular proteins; Drug resistance; Genomics; Mitogens; Protein biosynthesis; Protein kinases
• ISSN: 0737-4038
• DOI: 10.1093/molbev/msac177

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-[alpha] and p38-[gamma] (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- [alpha] isoform, the resistant virus (BPXV-P60-SB239063) switches over to use p38-[gamma] 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. Key words: p38, SB239063, virus, switch to use alternate cellular factor, drug resistance, host-directed antiviral agents.