SUMMARY The overall goal of this proposal is to elucidate the mechanisms by which chronic HIV infection promotes telomere attrition and T cell aging, leading to hepatitis B virus (HBV) vaccine hypo-responsiveness. To this end, we will use a model that emulates HBV vaccine response in the setting of HIV infection. Since co-infection of HBV with HIV is common and associated with an increased morbidity and mortality, HBV vaccine is required to prevent HBV co- infection in HIV patients. However, HBV vaccine response in HIV-infected patients is often blunted with only 30-60% seroconversion (HBsAb > 10 IU/ml) compared to 90-95% success rate in age-matched healthy subjects (HS). This poor vaccine response is also observed with influenza and pneumococcal vaccinations in HIV patients and other immunocompromised hosts, including the elderly. Recently, we have found that chronic HIV or HCV infection can cause premature T cell aging, as evidenced by overexpression of the aging markers KLRG1, DUSP6, CD57, and p16ink4a, dysregulation of age-associated noncoding RNAs GAS5/miR21 and, in particular, accelerated telomere attrition - suggesting excessive proliferative turnover or inadequate telomere maintenance. Telomere integrity is a key feature of linear chromosomes that preserves genomic stability and function, whereas telomere attrition is a hallmark of cell aging or senescence that drives cell dysfunctions and apoptosis. While telomere length is maintained in most cases by a telomerase that prolongs telomeric DNA, telomere-associated proteins (shelterins) protect telomeres from unwanted DNA damage response (DDR). We investigated the mechanisms of telomere attrition in the setting of HCV and HIV infections and discovered that the cellular expression and activity of telomerase are intact, whereas the telomeric repeat binding factor 2 (TRF2) is significantly inhibited in CD4 T cells derived from HCV- or HIV-infected patients. Since the role of TRF2 is to protect telomeres from unwanted DNA damage and recruit DNA repair enzymes (e.g., telomerase) access/function at telomeres, we hypothesize that: i) the mechanisms involved in TRF2 inhibition may accelerate telomere attrition and CD4 T cell aging during HIV infection; ii) TRF2 inhibition may result in poor access/function of telomerase at telomeres during HIV infection; and iii) TRF2-mediated telomere attrition and CD4 T cell aging may play a pivotal role in the failure of HBV vaccine in HIV-infected patients. To test this hypothesis, we will 1) define the mechanisms involved in TRF2 inhibition and telomere attrition in T cell aging during HIV infection; 2) determine how TRF2-mediated telomerase transport to telomeres affects T cell aging during HIV infection; and 3) determine the impact of telomere attrition and T cell aging on HBV vaccine failure during HIV infection and whether restoring TRF2-mediated telomere sheltering and telomerase homing machinery can rescue CD4 T cells from telomere attrition and restore ...