Understanding Genetic Diversity of Human Cytomegalovirus (HCMV), Drug Resistance Testing and the Prevalence of Resistance Mutations

Camilla Debette^*
*Correspondence: Camilla Debette, Department of Human Genetics, Ohio State University, Columbus, OH, 43210, USA, Email:

Introduction

Human Cytomegalovirus (HCMV) is a widespread herpesvirus that infects a large portion of the human population worldwide. Despite often remaining asymptomatic in healthy individuals, it poses significant risks to immunocompromised individuals such as transplant recipients, HIV/AIDS patients, and unborn babies when contracted during pregnancy. The emergence of drug-resistant strains of HCMV presents a growing concern in clinical management, emphasizing the importance of understanding its genetic diversity and the prevalence of resistance mutations. This article explores the genetic diversity of HCMV, methodologies for drug resistance testing, and the prevalence of resistance mutations.

Description

HCMV exhibits considerable genetic diversity owing to its complex genome structure and its ability to undergo rapid evolution. The viral genome comprises Unique Long (UL) and Unique Short (US) regions, each flanked by inverted repeats, facilitating genetic recombination and mutation. HCMV isolates are classified into genotypes based on sequence variations in genes such as UL55 (glycoprotein B) and UL73 (glycoprotein N). Genotyping studies have revealed multiple genotypes (gB1, gB2, gB3, gN1, gN2, etc.), with variations in geographic distribution and clinical outcomes [1].

Moreover, intrastrain diversity exists within HCMV populations, attributed to mutations, recombination events, and selective pressures imposed by host immune responses and antiviral therapies. Understanding this diversity is crucial for predicting disease progression, designing effective vaccines, and developing antiviral drugs. The emergence of drug-resistant HCMV strains complicates treatment strategies, particularly in immunocompromised patients. Drug resistance testing plays a pivotal role in guiding clinical management by identifying resistance mutations and selecting appropriate antiviral therapies [2].

Polymerase Chain Reaction (PCR) amplification followed by Sanger sequencing or Next-Generation Sequencing (NGS) enables the detection of mutations associated with drug resistance. Whole-genome sequencing provides comprehensive information on viral diversity and resistance mutations. These assays evaluate viral susceptibility to antiviral drugs by measuring viral replication in the presence of different drug concentrations. Phenotypic assays, such as plaque reduction assays and growth inhibition assays, provide direct evidence of drug resistance but are labor-intensive and time-consuming [3].

Combining genotypic and phenotypic approaches enhances the accuracy of drug resistance testing. These assays correlate genotypic mutations with phenotypic resistance profiles, facilitating the interpretation of resistance mutations in clinical settings. The prevalence of drug-resistant HCMV strains varies geographically and among different patient populations. Resistance mutations primarily target viral genes essential for viral replication, including UL97 (phosphotransferase) and UL54 (DNA polymerase). The most common mutations associated with resistance to antiviral drugs are: Mutations in the UL97 gene, encoding the viral kinase responsible for phosphorylating nucleoside analogues such as ganciclovir and valganciclovir, confer resistance to these drugs. Common UL97 mutations include M460V/I, L595S, and C592G [4].

Mutations in the UL54 gene, encoding the viral DNA polymerase targeted by drugs like foscarnet and cidofovir, result in reduced drug susceptibility. Mutations such as D413E and A987G are associated with resistance to nucleoside analogues. The prevalence of resistance mutations varies depending on factors such as antiviral drug usage, treatment duration, and patient immune status. Immunocompromised patients, particularly transplant recipients and HIV/AIDS patients, are at higher risk of developing drug-resistant HCMV infections due to prolonged antiviral therapy and frequent viral reactivation [5].

Conclusion

Understanding the genetic diversity of HCMV and the prevalence of resistance mutations is crucial for effective clinical management and the development of novel therapeutic strategies. Drug resistance testing methodologies provide valuable insights into the selection of appropriate antiviral therapies and monitoring treatment efficacy. Continuous surveillance of resistance mutations and the implementation of personalized treatment approaches are essential in combating the challenges posed by drug-resistant HCMV strains in clinical practice.

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