This proposal outlines a series of experiments designed to study the phenotypic differences between herpes simplex virus (HSV) strains that produce frequent recurrences of ocular, herpetic disease and strains that do not produce recurrent disease, with the general goal of correlating determinants of the disease pattern in prototype strains with those observed in fresh clinical isolates obtained from our patient population. The ability of the virus to establish latency in the trigeminal and superior cervical ganglia is well-documented, and recurrences of frank disease, as well as asymptomatic shedding of the virus, occur with variable frequency, although the mechanism(s) controlling this variability are not understood. The research proposed here is based on the differences in reactivation patterns determined by the genetics of the latent virus. It appears that corneal lesions are most likely to follow the reactivation and shedding of a virus strain that grows well at the lower corneal temperature, compared with strains that prefer higher core body temperature, and may grow well on the lip or at other sites. Additionally, the effect of host and external stimuli on the frequency of reactivation will be investigated, as well as how host factors may affect the development of lesions at the peripheral site. Various facets of this work will involve comparing growth of the various virus strains at 33 degrees C (external corneal temperature) and 39 degrees C (host core temperature) in terms of number and size plaques, total virus yield, and growth patterns; determining TK phenotype and enzyme activity at 33 degrees C and 39 degrees C in recurrent and non-recurrent strains; examining the effect of iontophoresis on latent, non-recurrent, non-shedding virus strains; determining the effect of antibodies produced after primary infection in the development of recurrent disease; attempting to increase production of HSV-specific antibodies by ocular immmunization with the proper immunogen and determining the effectiveness of this immunization on the rate of recurrent herpetic lesions; and obtaining DNA profiles of the HSV prototypes and clinical isolates by restriction endonuclease analysis, to identify subtle differences in the genomes of strains with various pattern of recurrence. If the mechanism of reactivation of the hypervirus from ganglionic latency can be elucidated, it may be possible to find ways of therapeutically preventing or reducing the rate of recurrant ocular herpetic disease, which can lead to severe and permanent corneal damage and loss of sight.
