Grant: Project Grant

Herpesviruses include the common human pathogens, herpes simplex virus (HSV) types 1 and 2, and varicella zoster virus. Herpesviruses cause lifelong infections and once an individual is infected there is no cure. HSV-2, the focus of this proposal, is the main cause of HSV genital infections, devastating neonatal infections, and is fueling the epidemic transmission of HIV in Africa. It is estimated that roughly 500 million people are infected with HSV-2. While antiviral drugs are available to treat some herpesvirus infections, the emergence of drug resistant viruses is a serious problem. One goal of our studies is to identify new targets for antiviral interventions. This proposal focuses on an essential early step in the assembly of HSV-2 virus particles. The initial stages of herpesvirus assembly take place in the cell nucleus where virus DNA is replicated and packaged into a protein shell called a capsid. DNA-containing capsids must exit the nucleus into the cell cytoplasm where final steps in virus assembly take place. This process is referred to as nuclear egress. During the past funding period we identified two new viral molecules, pUL16 and pUL21, that are required for nuclear egress and discovered that a third viral molecule previously known to be involved in nuclear egress, pUs3, has a unique and unexpected activity. We hypothesize that pUL16, pUL21 and pUs3 act sequentially in the nuclear egress of HSV-2 capsids. The goals of the experiments described in this proposal are to understand the mechanisms by which pUL21 and pUs3 function to promote HSV-2 assembly. These studies are expected to reveal vulnerabilities that may be exploited for the treatment of HSV-2 disease.