DESCRIPTION (provided by applicant): The cytomegalovirus (CMV) has been associated to T-cell aging, impaired immunity, reduced residual lifespan and increased morbidity of cardiovascular diseases. It was recently shown by our group that old mice, infected in youth with CMV, but not other viruses, exhibit defects in immune responsiveness to third-party infections, and alterations in na�ve T cell receptor (TCR) repertoire. Yet, the precise mechanism by which CMV impairs na�ve T cell responses remains incompletely understood. This proposal seeks to define the cost, if any, of persistent CMV infection on host immune function (and lifespan) in aging and to begin to define ways to intervene against negative effects of CMV in aging. Lifelong CMV infection could adversely impact the development of new immune responses (i) by precipitating additional loss of na�ve T cell diversity; and (ii) by interference of inflated, CV-specific effector memory (EM) T cells with na�ve T cell responses against new infection. Further, improved control of CMV and/or reduction of CMV-specific EM accumulation could be beneficial for immune defense. The aims will assess (i) the role of CMV in constriction of T cell receptor (TCR) repertoire and immune defense in mice; (ii) Inhibition of protective immunity by CMV and/or by CMV-specific T cells; and (iii) whether improved CMV control determine human immune responsiveness to vaccination,

PUBLIC HEALTH RELEVANCE: By 2050, cytomegalovirus (CMV) will infect 70 million and over 1 billion people > 65y in the US and the world. The cost, if any, of persistent CMV infection on host immune function, lifespan and healthspan in aging remains poorly defined. This is particularly pertinent because older adults are highly vulnerable to bioterror infectious agents and emerging infections. This proposal will decisively determine the impact of CMV upon immune defense against WNV in mice and successful vaccination with influenza virus in humans, paving way for therapeutic intervention.