Doctor of Philosophy (PhD)
Interdisciplinary Graduate Program in Biomedical Sciences
Siddappa N. Byrareddy
HIV, Microbiota, Gut-Brain Axis, Analgesics Opioid, Antibodies Monoclonal
Despite significant advancements in combination antiretroviral therapy (cART), ongoing inflammation in the brain and gut remain two of the most significant hurdles in the health of people living with human immunodeficiency virus (HIV). Additionally, a viral reservoir in each compartment inhibits cure efforts by allowing rapid viral rebound following cART interruption. Emerging understanding of the gut-brain axis (GBA) implicates each compartment in the modulation of the other in a complex bi-directional interaction mediated by vagus innervation, circulating lymphocytes, and microbiome composition and biproducts. Using multiple models of the simian (and simian-human) immunodeficiency virus (SIV/SHIV) and therapeutic intervention, I present how differences in each model depend on modulation of the neuroimmune interactions and the microbiome composition. First, we found that opioids, commonly used to treat chronic pain in HIV-infected individuals, may exacerbate dysbiosis and influence peripheral immune activity, thereby modulating viral reservoir size. Next, we determined that anti-a4b7 monoclonal antibody therapy directed against gut integrins reduces the myeloid cell turnover in the duodenum, thereby influencing the viral tissue loads in the gut. This reduction was associated with butyrate-producing bacteria like Roseburia, suggesting that microbiome composition may be an independent factor in the efficacy of this therapy. Finally, it was found that a new mucosal vaccination strategy modulates immune response at mucosal sites and protects against acute dysbiosis, and the efficacy was associated with microbial taxa such as Helicobacter. These models improve our understanding of HIV/SIV pathogenesis, providing nuance to the complex GBA interactions and offering new targets for further development of novel interventions.
Johnson, Samuel, "Gut Commensals Modulate SIV/SHIV Pathogenesis and Therapeutics" (2022). Theses & Dissertations. 652.
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