Intersection of Periodontitis with HIV-Antiretroviral Therapy-Induced Immune Reconstitution Bone Loss, on Alveolar Bone and Tooth Loss, in People Living with HIV - PROJECT ABSTRACT This work is anchored on the findings by our group, and others, showing that prior to treatment, the HIV virus inflicts bone mineral density (BMD) loss in People living with HIV (PLH) due to multifactorial mechanisms. Furthermore, Antiretroviral therapy (ART) inflicts additional aggressive, but acute, bone loss within a defined window (~6 months) following ART initiation. Although some first line ART drugs cause mild bone loss due to direct effects, the aggressive bone loss characteristic of most highly immunosuppressed PLH, is an indirect effect of adaptive immune system reconstitution and reactivation, driven in large measure through CD4 T cell activation which is supported by microbial factors. Because this intense, but acute, BMD loss is driven by inflammatory events related to immune regeneration, even newer ART drugs cause severe bone loss in severely immunocompromised patients. Importantly, although we and others have documented this immune reconstitution bone loss (IRBL) in the long bones and spine, it may not be limited to these compartments and new preliminary data using our mouse model of IRBL, suggest that the alveolar bone of the jaw anchoring the teeth, is also severely degraded. This is an important finding given that our extended group has reported that periodontal infection (periodontitis) is 3-fold higher in PLH. Periodontitis is a chronic inflammatory disease, in which bacteria such as the periodontal pathogen P. gingivalis, overrun the oral compartment, a likely consequence of impaired immune surveillance due to HIV-induced immunodeficiency. Like IRBL, periodontitis also causes loss of the alveolar bone anchoring the teeth, leading to tooth loosening and eventual loss. Periodontal infection and tooth loss in people is a cause of morbidity, pain, and self-image issues, leading to a decline in quality of life. We hypothesize that ART-induced IRBL, drives significant alveolar lone loss in PLH, that exacerbates, or is exacerbated by, HIV-induced periodontal infection, leading to poor oral health that culminates in tooth loosening and eventual tooth loss. In this application, we propose to study alveolar IRBL and the intersection of IRBL with periodontitis in a clinical study in PLH (Specific Aim 1) and in a complementary mechanistic basic science study (Specific Aim 2) using animal models of IRBL and periodontal infection. Findings from this work will contribute to efforts aimed at identifying PLH at risk of poor oral health leading to tooth loss. The outcomes will provide strong rationale for exploring targeted prophylaxis including antibiotics and anti- resorptive drugs to protect the alveolar bone and the teeth from ART-associated IRBL.
