Title: Studies to improve and expand the protective capacity of replication-defective type 2 herpes simplex viruses
Description: Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) cause a variety of clinical syndromes including life-threatening infections such as neonatal herpes and herpes encephalitis and HSV-2 has been shown to increase susceptibility to HIV-1 acquisition and increase HIV-1 viral load in dually infected individuals. A vaccine against HSV would be the most efficient and cost-effective measure to reduce morbidity and mortality caused by HSV infections and may prove to be an effective means of combating the HIV-1 pandemic. While much effort has been put into producing a HSV vaccine, to date no candidate has shown efficacy in the general population. The classical viral vaccine approaches have failed; therefore, new types of vaccines are needed to combat HSV disease. Replication-defective mutant viruses represent a new class of vaccines that are highly attractive as they can elicit robust, long-lived immune responses involving both humoral and cellular arms of the immune system, while retaining a high safety profile. Here we undertake studies to improve and expand the protective capacity of current replication-defective HSV-2 mutant viruses by (1) determining if disruption of the U L 41 gene locus increases the virus's protective capacity, (2) expanding the specificity of a replication-defective HSV-2 virus to elicit immune responses against HIV-1 by expressing HIV-1 gag from within the U L 41 gene locus, (3) determining if the genomic background of the HSV-2 virus used to produce a replication-defective virus affects its protective capacity against different strains of HSV-2.