FIV as a model to study pathogenesis and treatment of HIV-induced oral disease in children

Colorado State University, Fort Collins CO

Investigators

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Abstract

Project Summary Objectives. The goal of this project is to train a DVM/PhD anatomic pathologist in the field of translational biomedical research to facilitate transition to an independent established investigator. The research questions addressed in this fellowship application focus on the paucity of information regarding the pathogenesis of HIV- and FIV-induced oral disease in juveniles, and the corresponding lack of effective therapies to treat these syndromes. The aims described in this proposal will investigate the virologic impact, contributing factors, and pathogenic mechanisms of this juvenile condition, thereby providing baseline data to establish a novel approach and more efficacious treatment strategy in HIV-infected children. Specific Aims. 1) Characterize oral kinetics of in vivo FIV infection and the relationship to oral dysbiosis, immune dyscrasia, and oral lesion development. 2) Evaluate treatment response of retroviral-induced oral lesions to HAART and microbial-targeted therapy. Relevance to Public Health. Common therapies used to treat HIV-induced oral disease in adults are often unsuccessful in children, resulting in frequent disease recurrence and resistant microbial infections. There is a lack of information regarding virologic effects and HAART on the oral microbiota. It is of exceptionally high impact to define the pathogenesis of juvenile HIV associated oral disease, and test practical, attainable therapies for outcomes that result in reversal of underlying pathologies. Functional understanding of the pathogenic effects of virus-induced immunosuppression on oral disease in HIV-infected children is the first objective of this proposal. Implications of HAART and symptomatic therapy for gingival-stomatitis will be tested in Aim 2 to guide appropriate therapies for this complex disease syndrome. Collectively, this proposal will provide a focused analysis of both cause and cure, aimed to substantially improve management of this condition for more than 2.5 million HIV-infected children. Experimental design. Specific pathogen free (SPF) cats will be orally inoculated with a strain of FIV that reproducibly produces oral lesions. FIV viral and proviral loads in blood and saliva will be monitored over time and compared with hematologic data. Oral lesion development will be evaluated grossly and histologically, and changes in the oral microbiota and cytokine expression will be evaluated by 16S rRNA NGS and MIA, respectively. Following collection of baseline data, changes in viral/proviral status, oral microbiota, oral cytokine expression, and oral lesions will be measured in the presence and absence of highly active antiretroviral therapy (HAART). The synergistic effect of HAART on the resolution of oral lesions will be subsequently measured in the presence and absence of a novel microbial-targeted therapy comprised of dental hygiene, antimicrobial, and probiotic treatments.