Recurrent herpes simplex virus type I (HSV-1) infection is a major cause of viral induced blindness. Although the HSV-1 LAT gene is essential for efficient spontaneous reactivation, it remains unclear whether LAT's main latency related function takes place during establishment of latency or reactivation from latency. Although LAT can enhance the rate at which latency is established by 2-3 fold, it can enhances spontaneous reactivation by up to 10-fold. In addition, a mutation in a gene other than LAT has been shown to reduce establishment of latency by 20-fold without altering spontaneous reactivation. We hypothesize that LAT has an important function during the reactivation stage of the HSV-1 latency reactivation cycle. This would make LAT an excellent target for therapeutic intervention to block recurrent disease, and would have tremendous clinical significance.
Our specific aim i s to construct and then infect rabbits with an HSV-1 mutant in which LAT is expressed only when Dox is present.in the rabbit's water supply. Dox will be fed either (i)just prior to and then throughout the first 21 days of infection (LAT will be active only during the time of establishment of latency) or (ii)continuously from days 22 to 60 post infection (pi) (LAT will be active only during the time of reactivation from latency). Spontaneous reactivation will be determined from 30 to 60 days pi. We expect these two complementary experiments to show that LAT is important during reactivation. Thus, (i)when LAT is active only during establishment we expect spontaneous reactivation to be reduced to LAT null mutants levels; and (10when LAT is active only during reactivation we expect wild type spontaneous reactivation levels. These results would confirm that LAT is important at the reactivation step and suggest that blocking LAT's function would be an outstanding therapeutic approach for eliminating or reducing recurrent HSV-1 ocular disease in individuals with a history of recurrent ocular HSV-1.
