Host DNA repair factors empower a mechanism of antiviral nucleoside analog resistance

• 成果类型: Article
• 署名作者: Longmire, Pierce; Chen, Han; McKinzey, David R.; Savanagouder, Mamata; Kosarek, Noelle N.; Pesola, Jean M.; Bobak, Carly A.; Bosco, Giovanni; Goodrum, Felicia; Coen, Donald M.
• 署名单位: University of Pennsylvania; Pennsylvania Medicine; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Arizona; University of Arizona Health Sciences; University of Arizona; University of Arizona Health Sciences; Harvard University; Harvard Medical School; Dartmouth College; Dartmouth College; Dartmouth College
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2618057123
• 发表日期: 2026-08-25
• 页码: e2618057123
• 关键词: antiviral resistance; herpesvirus; cytomegalovirus; DNA damage and repair; nucleoside analog; HUMAN CYTOMEGALOVIRUS DNA; POLYMERASE GENE; NUCLEAR EGRESS; LESION-BYPASS; GANCICLOVIR; cells; inhibition; infection; recombination; cytotoxicity

摘要

How host functions affect resistance to antiviral drugs is poorly understood. Ganciclovir, a chain-terminating nucleoside analog, is a first-line therapy against human cytomegalovirus, a widespread herpesvirus that causes life-threatening disease in immunocompromised individuals and newborns. Ganciclovir resistance, which is caused by mutations that affect the viral kinase, UL97, and/or the viral polymerase, UL54, can cause treatment failures. Among these mutations, those reducing the exonuclease activity of the viral DNA polymerase permit ganciclovir incorporation without chain termination. However, the fate of DNA strands containing the incorporated nucleotide analog is unknown. We show here that template DNA containing ganciclovir fails to support DNA synthesis of the complementary strand by exonuclease-mutant polymerase. Moreover, while DNA synthesis and ganciclovir incorporation are limited in drug-treated fibroblasts infected by virus with wild-type polymerase, an exonuclease-resistant mutant virus can better synthesize full-length genomes and incorporate substantially more ganciclovir into DNA. Notably, ganciclovir is lost from DNA when drug is removed, suggesting that ganciclovir-containing templates are repaired. We identify the host nucleotide excision repair component, xeroderma pigmentosum group A (XPA), and the repair enzyme, polymerase kappa, as each being necessary for mutant virus ganciclovir resistance and polymerase kappa as being required for the mutant's cidofovir resistance, demonstrating a role for host DNA repair machinery in a mechanism of antiviral resistance. We propose a model for this mechanism, which has relevance for other antiviral drugs and other nucleoside analog therapeutics, that highlights the participation of host DNA repair machinery during human cytomegalovirus DNA replication.