Viral Genomic Variation and the Severity of Genital Herpes Simplex Virus-2 Infection as Quantified by Shedding Rate: A Viral Genome-Wide Association Study

Abstract

Background: The clinical severity of genital herpes simplex virus-2 (HSV-2) infection varies widely among infected persons with some experiencing frequent genital lesions while others are asymptomatic. The viral genital shedding rate is closely associated with, and has been established as, a surrogate marker of clinical severity.

Methods: To assess the relationship between viral genetics and shedding, we assembled a set of 145 persons who had the severity of their genital herpes quantified through determination of their HSV genital shedding rate. An HSV-2 sample from each person was sequenced and biallelic variants among these genomes were identified.

Results: We found no association between metrics of genome-wide variation in HSV-2 and shedding rate. A viral genome-wide association study identified the minor alleles of 3 individual unlinked variants as significantly associated with higher shedding rate (P < 8.4 × 10-5): C44973T (A512T), a nonsynonymous variant in UL22 (glycoprotein H); A74534G, a synonymous variant in UL36 (large tegument protein); and T119283C, an intergenic variant. We also found an association between the total number of minor alleles for the significant variants and shedding rate (P = 6.6 × 10-7).

Conclusions: These results add to a growing body of literature for HSV suggesting a connection between viral genetic variation and clinically important phenotypes of infection.

Keywords: HSV-2; genital herpes; genital shedding rate; genome-wide association study; linkage disequilibrium.