Abstract
Herpes simplex virus type 1 (HSV-1), a member of the herpesviridae, causes a variety of human viral diseases globally. Although a series of antiviral drugs are available for the treatment of infection and suppression of dissemination, HSV-1 remains highly prevalent worldwide. Therefore, the development of novel antiviral agents with different mechanisms of action is a matter of extreme urgency. During the proliferation of HSV-1, capsid assembly is essential for viral growth, and it is highly conserved in all HSV-1 strains. In this study, small interfering RNAs (siRNAs) against the HSV-1 capsid protein were screened to explore the influence of silencing capsid expression on the replication of HSV-1. We designed and chemically synthesized siRNAs for the capsid gene and assessed their inhibitory effects on the expression of target mRNA and the total intracellular viral genome loads by quantitative real-time PCR, as well as on the replication of HSV-1 via plaque reduction assays and electron microscopy. Our results showed that siRNA was an effective approach to inhibit the expression of capsid protein encoding genes including UL18, UL19, UL26, UL26.5, UL35 and UL38 in vitro. Interference of capsid proteins VP23 (UL18) and VP5 (UL19) individually or jointly greatly affected the replication of clinically isolated acyclovir-resistant HSV-1 as well as HSV-1/F and HSV-2/333. Plaque numbers and intracellular virions were significantly reduced by simultaneous knockdown of UL18 and UL19. The total intracellular viral genome loads were also significantly decreased in the UL18 and UL19 knockdown groups compared with the viral control. In conclusion, interfering with UL18 and UL19 gene expression could inhibit HSV-1 replication efficiently in vitro. Our research offers new targets for an RNA interference-based therapeutic strategy against HSV-1.
Highlights
Herpes simplex virus type 1 (HSV-1), a member of the herpesviridae family, is a linear double-stranded DNA virus that only infects humans naturally, with no known animal host [1]
The results showed that knockdown of major capsid proteins VP5 and VP23 encoded by UL19 and UL18, respectively, could greatly affect HSV-1 proliferation
We found that interference of UL18 and UL19 expression could significantly affect the proliferation of HSV-1 and that VP23 and VP5 capsid proteins play crucial roles in the process of capsid assembly and DNA packaging of HSV
Summary
Herpes simplex virus type 1 (HSV-1), a member of the herpesviridae family, is a linear double-stranded DNA virus that only infects humans naturally, with no known animal host [1]. HSV-1 primarily affects the mucocutaneous surfaces and leads to persistent lesions. It can infect the central nervous system or visceral organs and lead to disseminated infections, such as hepatitis, esophagitis, pneumonia and meningoencephalitis. HSV-1 establishes long-term latency in the ganglia of sensory nerves. It can reactivate when the immune system is deficient or stimulated by various factors. In patients with human immunodeficiency virus type 1 (HIV-1) infection or in recipients of organ transplants, herpetic lesions can be extensive, persistent and more disseminated with increased recurrences [7]. The development of new anti-HSV agents with different mechanisms of action is a matter of great urgency
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