Pathogenesis and Chemotherapy of Herpesvirus Infection

National Institute Of Allergy And Infectious Diseases

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Abstract

Herpesviruses, including herpes simplex (HSV) and varicella-zoster virus, establish lifelong latent infection in nerve cells. HSV type 1 can reactivate to cause cold sores, and HSV-2 can reactivate to cause genital herpes. Although these infections are usually mild, they can cause encephalitis and severe disease in newborn infants. In addition, HSV-2 is a risk factor for transmission and acquisition of HIV. The mechanism by which these viruses establish latency is not understood. A better understanding of latency might result in novel ways to prevent latent infections or prevent the virus from reactivation once it establishes latency. [unreadable] HSV expresses a predominant viral RNA, termed the latency-associated transcript (LAT), when the virus is latent in nerve cells. Animal models, using viruses deleted for HSV LAT, indicate that LAT is important for regulating HSV reactivation. While the function of the HSV LAT in reactivation is uncertain, LAT has been postulated to increase the ability of the virus to establish or maintain latency, likely by increasing the survival of latently infected nerve cells. We have been studying other mechanisms whereby the LAT might affect latency or reactivation.[unreadable] Recently a number of very small RNAs (termed microRNAs) have been found in mammalian cells. These microRNAs share similar sequences to cellular genes, and the microRNAs have been shown to be important for regulating expression of viral proteins. More recently microRNAs have been found to be encoded by several herpesviruses including Epstein-Barr virus, cytomegalovirus, and Kaposis sarcoma-associated herpesvirus. At the time we initiated our study, while microRNAs had been predicted to be encoded by HSV, no microRNAs had been detected. [unreadable] We found that the HSV-2 LAT encodes a microRNA. We found that the microRNA is expressed in cells transfected with the LAT gene, in cells infected with HSV-2 in vitro, in acutely and latently HSV-2 infected nerve cells of guinea pigs in vivo, and in human nerve cells of persons who are latently infected with HSV-2. [unreadable] The microRNA is located in the region of the LAT that encodes a protein important for virulence of the virus (termed ICP34.5). When we tranfected cells in vitro, or infected cells with HSV-2, we found that the microRNA reduced the expression of ICP34.5. Therefore, the microRNA may regulate the virulence of the virus in the nervous system, and may act as a molecular switch to regulate expression of ICP34.5.[unreadable] In addition, we found that the HSV-1 LAT also encodes a similar microRNA, in a location similar to that present in the HSV-2 LAT. This implies that there is a conserved function in HSV-1 and HSV-2 for the microRNA to regulate expression of the ICP34.5 neurovirulence factor.