Periodontitis as a Comorbidity in SIV Infection and Antiretroviral Therapy

Periodontitis as a Comorbidity in SIV and Antiretroviral Therapy Abstract 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. However, how HIV infection and current management with HAART drugs may impact the microbiome and disease is minimal. Additionally, how differences in this oral microbial ecology and systemic viral environment interfaces with host responses that can be triggered to result in destruction of the periodontium remains unclear. The fundamental basis underlying this project is related to the concept of host-microbial interactions that control the occurrence and extent of disease outcomes. The expressed features immune phenotype plasticity reflecting an individual’s genotype can be modulated by a variety of intrinsic and extrinsic factors. As such, both local and systemic responses are found to be modified by the host microbiome, physiologic/metabolic conditions, and viral infections. 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 microbiomics 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 reported on cross-sectional studies in chronic periodontitis in adults. The interaction of a microbial dysbiosis and dysregulated response in periodontitis coincident with HIV infection and response to HAART therapy 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 antiretroviral drugs (HAART). The study will use a nonhuman primate model of ligature-induced periodontitis, which is a well-established Macaca mulatta model of oral infection, inflammation, and mucosal disease and is a continuation of a long-standing collaborative research activity of the team. 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 HAART efficacy. The General Hypothesis is that “Periodontitis and age will synergize to negatively impact parameters of SIV infection and will undercut the efficacy of HAART in managing the SIV infection” that will be examined with 3 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 HAART treatment for an SIV infection. Specific Aim 3: To delineate the effect of severe periodontitis on the efficacy of existing HAART treatment to control an SIV infection.