Potential Treatments for HIV Neuroretinal Disorder in People Living with HIV-1 Restricted; Files Only

Abstract

People living with HIV (PLWH) are able to live otherwise healthy lives with the use of antiretroviral therapy (ART). Although ART is able to confer peripheral viral suppression, patients cannot be cured of HIV due to the presence of Integrated HIV DNA in host cell genomes (latent HIV reservoirs). The presence of latent HIV reservoirs lead to persistent, chronic inflammation in PLWH due to elevated levels of pro-inflammatory cytokines such as IL-7 and IL-15, IL-6, TNF-a, D-dimer, IFN-g and others, which lead to the proliferation and expansion of the latent HIV reservoir. This chronic inflammation also leads to many HIV-related disorders such as neuroretinal disorder, which has been observed in up to 27% of PLWH. People with HIV neuroretinal disorder (HNRD) have abnormal retina and optic nerve function, which typically leads to decreased contrast sensitivity, hazy vision, and loss of retinal nerve fiber. Although there is no consensus for what occurs in patients with HNRD or what causes the disorder, it is thought to be caused by poorly matured vasculature due to increased cell proliferation from consistently low-levels of inflammatory cytokines. As a result, there exists a major unmet clinical need to block this inflammation and reduce the levels of pro-inflammatory cytokines in PLWH, to prevent or reverse this inflammatory driven neuroretinal pathology in PLWH. This project aims to replicate the inflammatory environment observed in the eyes of individuals living with HIV (PLWH) in-vitro. Our hypothesis suggests that the chronic low-level inflammation observed in pharmacological sanctuaries arises from the activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. We propose to simulate this inflammatory state by introducing inflammatory cytokines that mimic the low levels of HIV present in PLWH. By emulating the inflammation observed in pharmacological sanctuaries, we can evaluate the efficacy of anti-inflammatory drugs in reducing inflammation. 

Table of Contents

Abstract……………………………………………………………………………………………4

Table of Contents………………………………………………………………………………….7

Background and Significance……………………………………………………………………..8

Methodology……………………………………………………………………………………..14

Results………………………………………………………………………………………..…..24

Discussion and Conclusion…………………………………………………………………..…..36

Future Directions…………………………………………………………………………….…..38

About this Honors Thesis

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School	Emory College
Department	Quantitative Science
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Statistics Biology, Cell Health Sciences, Pharmacology
Keyword	neuroretinal AIDS HIV antiretroviral inflammation HIV reservoir
Committee Chair / Thesis Advisor	Christina Gavegnano, Emory University Wen Wei Loh, Emory University
Committee Members	Arri Eisen, Emory University

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