Abstract
Acute human alpha-herpesvirus 1 (HSV-1) infection culminates in a latent infection of neurons in trigeminal ganglia (TG) and the central nervous system. Following infection of mucosal epithelial cells, certain neurons survive infection and life-long latency is established. Periodically, stressful stimuli trigger reactivation from latency, which result in virus shedding, transmission to other people, and, occasionally, recurrent disease. The glucocorticoid receptor (GR) and Krüppel-like factor 15 (KLF15) comprise a feed-forward transcriptional loop that cooperatively transactivate key HSV-1 promoters that drive expression of infected cell protein 0 (ICP0), ICP4, and ICP27. Silencing KLF15 significantly reduces HSV-1 replication in cultured mouse neuroblastoma cells. Consequently, we hypothesized that KLF15 mediates certain aspects of reactivation from latency. To test this hypothesis, we compared HSV-1 replication in KLF15(-/-) mice versus wild-type (wt) parental C57BL/6 mice. Virus shedding during acute infection was reduced in KLF15(-/-) mice. Male KLF15(-/-) mice shed higher titers of virus during late stages of reactivation from latency compared to KLF15(-/-) females and wt mice regardless of sex. At 15 d after explant-induced reactivation, virus shedding was higher in male KLF15(-/-) mice relative to wt mice and female KLF15(-/-) mice. These studies confirm KLF15 expression enhances viral replication during acute infection and reactivation from latency.