Graduation Date

Fall 12-17-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Immunology, Pathology & Infectious Disease

First Advisor

Byrareddy Siddappa

Second Advisor

Courtney Fletcher

MeSH Headings

C23 Pathological Conditions, Signs and Symptoms

Abstract

The significant challenge towards a successful HIV cure lies in eradicating persistent viral reservoirs across diverse tissue niches. As a result, HIV-infected individuals have to resort to lifelong antiretroviral therapy. Recent news of supposed HIV eradication in a second patient has further re-invigorated the fields of HIV cure. However, a few barriers remain, such as the lack of currently available assays to accurately quantify viral reservoirs, limited information on cellular factors associated with persistence, and varied dynamics of the viral reservoir in various body compartments. Lastly, HIV-infected individuals live different lifestyles stemming from comorbid substance abuse including consumption of morphine, cocaine, and heroin, various cultural and sexual practices which collectively could alter host immune and virus dynamics. As a result, this further complicates the development of a universal HIV cure. To address these issues, we formulated a three thematic approach that first sought to improve peripheral quantification of viral reservoirs by overcoming limited activation hurdles. By incorporating retinoic acid to immune modulate peripheral CD4+ T cells towards augmented activated phenotypes, we were able to obtain higher readouts using diverse viral reservoir assays in rhesus macaque models. Secondly, we addressed whether CD4+ T cells play a detrimental or supportive role during SIV pathogenesis. By turning our focus towards CD4+ CTLs, we identified a novel CD29 marker that may be useful to identify this cell phenotype in rhesus macaque models. In addition, we noted that peripheral loss of this phenotype was associated with increased virus replication during SIV/SHIV infection. In addition, we noted that the functionality of this phenotype was modulated by the microbiome and could influence the size of the replication-competent viral reservoir in the periphery. Lastly, we studied SHIV persistence drivers in the Central Nervous System and the gut. We noted that SHIV persistence, particularly in specific sites of neurogenesis in the brain, was exacerbated by morphine and was accompanied by altered myeloid cell activation, microbial dysbiosis, and regulatory loss of inflammation. Our findings highlight the crucial role that the microbiome plays in orientating immune responses towards limiting persistence in diverse tissue compartments.

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