Short Chain Fatty Acids: Route for Facilitation of Oral HPV via Inflammasome Dysregulation in People Living with HIV

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PROJECT SUMMARY/ABSTRACT The oral microbiota and inflammasome protein complex are essential factors for maintaining immune homeostasis, which are altered by an HIV infection and have been observed in the pathogenesis of oropharyngeal cancer. Short chain fatty acids (SCFA) in the oral cavity, such as butyrate, exacerbates periodontal tissue damage, which can act as an oncometabolite and lead to the development of HPV-related oral and pharyngeal carcinogenesis. Furthermore, butyrate has been found to regulate the transcription of immune-related genes. Particularly, it upregulates local inflammation while downregulates the expression of interferon-related genes and upregulates inflammasome-related markers, necessary for the innate immune response to a viral infection. Therefore, butyrate could play an essential role on immune dysfunction by dysregulating the inflammasome and facilitating oral HPV infection, increasing cancer risk in people living with HIV (PLWH). Therefore, our overall objective is to quantify oral SCFA in PLWH with an without HPV infection with the central hypothesis that PLWH with oral HPV infection will have higher levels of butyrate, which will be associated with periodontal disease, dysbiosis of the oral microbiome, more inflammation and more inflammasome dysregulation. This supplement plans to use samples from 50 virologically suppressed PLWH (25 HPV+ and 25 HPV-), aged ≥21 and<49 years old from the parent study. The specific aims of this proposal is (i) to quantify the levels of microbial SCFA in saliva of PLWH and assess their relationship with infection and HPV genotypes (high-risk vs. low-risk) and (ii) To determine the association between the levels of SCFA with periodontal disease, oral microbiome dysbiosis, inflammasome dysregulation and levels of inflammation markers. SCFA will be measured by liquid chromatography followed by mass spectrometry. We will leverage HPV genotyping (PCR), oral microbiome data (16s rDNA profiling), inflammasome proteins levels (western blot) and inflammatory markers (multiplex ELISA) from the parent study. This award will directly support Mr. Yabdiel Ramos-Valerio in achieving expertise in microbiome research and data analysis, including large-scale metagenomics data and statistical analysis and epidemiological research focused on HIV, HPV, and cancer. He will also take courses and focused mentorship on expanding his knowledge and experience in designing, implementing, and completing a clinical/translational research study. Finally, he will further develop the academic skills that will ensure his successful, independent research career, including responsible conduct of research, scientific writing, oral communication skills, grantsmanship, and collaborative interdisciplinary research. This supplement will provide him with resources toward achieving his goal of being accepted in MD/PhD programs and eventually become an independent research physician specializing in pathogen-driven cancers.