The two major oral diseases of mankind are chronic infections that result in dental caries and periodontitis. There is evidence of specific dynamics of alterations in commensal and pathogenic bacteria related to periodontitis within the normal population that appears to differ with aging and in diabetes. It is unclear, however, how HIV-1 infection and current management with antiretroviral drugs may affect the microbiome and disease. It is also unclear how differences in this oral microbial ecology and systemic viral environment together with host responses contribute to the destruction of the periodontium. Since characteristics of the immune system repertoire are critical for maintaining general health, congenital or acquired disruptors of development of normal immune functions are reflected in altered microbiota across body niches within the population. While extensive literature has been acquired over the last 3+ decades on the features of the oral microbial biofilms in health and periodontitis, these have primarily been reported from cross-sectional studies in adults with chronic periodontitis. The interaction of a microbial dybiosis and dysregulated response in periodontitis coincident with HIV-1 infection and response to antiretroviral therapy (ART) remains unknown. This proposal engages a multi-disciplinary and multi-institutional collaborative approach for the determination of the interaction of the chronic oral infection and inflammatory disease, periodontitis, with the course and characteristics of SIV infections and response to ART. The study will use a nonhuman primate model of ligature-induced periodontitis, which is a well-established model of oral infection, inflammation, and mucosal disease, in Macaca mulatta. The experimental design will address specific knowledge gaps about the interaction of the chronic infection and dysregulated immune responses of periodontitis with the immunological and biologic changes occurring with SIV infection, including: (i) Periodontitis effects on the viremia and CD4+ levels from SIV infection; (ii) SIV effects on the oral microbiome and salivary and serum responses; and (iii) Interaction of periodontitis on ART efficacy. Our over-arching hypothesis is that “Periodontitis and age will synergize to negatively impact parameters of SIV infection and will deleteriously affect the efficacy of ART in managing the SIV infection.” Our proposed studies will be examined in three Specific Aims: Specific Aim 1: To delineate age effects on the oral microbiome and targeted salivary biomarkers in health, changes that occur with experimental periodontitis, and impact of a subsequent SIV infection. Specific Aim 2: To delineate the effect of experimental periodontitis and age on the efficacy of ART treatment for an SIV infection. Specific Aim 3: To delineate the effect of severe periodontitis on the efficacy of existing ART treatment to control an SIV infection.