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 |
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Authors: | Yogesh Chander Ram Kumar Assim Verma Nitin Khandelwal Himanshu Nagori Namita Singh Shalini Sharma Yash Pal Apurvasinh Puvar Rameshchandra Pandit Nitin Shukla Priyank Chavada Bhupendra N Tripathi Sanjay Barua Naveen Kumar |
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Affiliation: | National Centre for Veterinary Type Cultures, ICAR-National Research Centre on Equines, Hisar, India;Department of Bio and Nano Technology, Guru Jambeshwar University of Science and Technology, Hisar, Haryana, India;Department of Veterinary Physiology and Biochemistry, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hiar, Haryana, India;Gujarat Biotechnology Research Centre, Department of Science & Technology, Government of Gujarat, Gandhinagar, India |
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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. |
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Keywords: | p38 SB239063 virus switch to use alternate cellular factor drug resistance host-directed antiviral agents |
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