PROJECT SUMMARY Age-related macular degeneration (AMD) is the major cause of visual impairment and blindness in persons >65 years of age in the United States and the 3rd leading cause of blindness worldwide. Several lines of evidence implicate immune activation and inflammation in the pathogenesis of AMD, including biomarkers of systemic inflammation as risk factors for AMD, complement deposition in drusen, complement and chemokine genetic polymorphisms as risk factors for AMD and circulating activated monocytes in patients with AMD. Antiretroviral (ART)-treated, immune-restored, HIV-infected persons have accentuated and accelerated aging, an age-adjusted shortened lifespan due to age-related diseases, and immune system changes similar to those seen in >70 year-old HIV-uninfected persons (immunosenescence). Data from the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) cohort show an ~4-fold increased prevalence and a 1.75-fold increased incidence of intermediate-stage AMD vs. that seen in HIV-uninfected cohorts. Preliminary data from LSOCA suggest that monocyte activation and systemic inflammation are risk factors for AMD. Cryopreserved blood specimens from LSOCA will be evaluated for inflammatory biomarkers and chemokines as risk factors for AMD, using nested case-control design and time-updated analyses. Blood biomarkers and chemokines evaluated will be those known to be operative in ART-treated, HIV-infected persons and in HIV-uninfected older persons focusing on those related to monocyte activation. Biomarkers identified as relevant to AMD in the LSOCA cohort will be evaluated in HIV- uninfected persons using cryopreserved specimens from the Age-Related Eye Disease Study (AREDS) cohort. Levels of biomarkers and chemokines will be correlated with AMD risk gene polymorphisms in both cohorts. A discovery-based approach will be used to identify plasma proteomic risk factors for AMD in both the LSOCA and AREDS cohorts. These studies will lead to an improved understanding of the roles of inflammation, immune activation, and immune- senescence in the pathogenesis of AMD and of the biology of aging.