PROJECT SUMMARY This proposal brings together three observations: 1) the increasing incidence of zoster in the United States, 2) the decreasing seroprevalence of HSV-1 and HSV-2, and 3) the discovery of extensive T cell cross-reactivity between HSV and VZV. HSV and VZV cause very distinct illnesses, but do share a low degree of sequence at the amino acid level that underlies immune cross-reactivity. It is widely accepted that the risk of zoster is inversely correlated with VZV- specific T cell immunity. We hypothesize that the increasing incidence of zoster over time reflects decreased cross-reactive immunity elicited by HSV, due to decreasing rates of HSV infection. We propose a nested case-control study to examine this hypothesis. We will test baseline samples of participants who developed zoster, and matched controls, from the placebo arm of the Shingles Prevention Study. This previously-completed study of a candidate zoster vaccine has a suitable Specimen Repository. We will determine if the seroprevalence of HSV is lower among cases than among controls. HSV antibody status will be measured with the University of Washington Western blot, the most accurate test available. Because there is a large degree of T cell cross-reactivity between VZV and both HSV-1 and HSV-2, Western blot assays will detect infection with both HSV types. Our Specific Aims are: 1) to test whether persons who develop zoster are less likely to have prior HSV infection than age, sex and health- matched persons without zoster, and 2) to test whether among persons who develop zoster, the disease is less severe among those that have prior HSV infection than those that are HSV seronegative. Power calculations indicate that we will be able to detect a 1.8 odds ratio of HSV infection in the control arm using serum samples from 200 persons that developed zoster and 400 controls for Aim 1, and a 92% power to detect 1.4X increase in zoster pain for Aim 2. This project will shed light on whether the population-wide temporal changes in the epidemiology of one herpesvirus have an impact on the morbidity of a distantly sequence-related pathogen.