Fundamentals and control of stochastic decision-making in HIV

Human immunodeficiency virus (HIV), the virus responsible for the current acquired immunodeficiency syndrome (AIDS) epidemic, infects and destroys many different cell types in the human immune system. While usually HIV does not directly result in death, patients are highly susceptible to other pathogens if HIV is left untreated and develops into AIDS. Current treatment for HIV infection involves highly active antiretroviral treatment (HAART) that inhibits multiple elements in the viral life cycle, including cellular entry, reverse transcription, protease and integrase activities, therefore stopping HIV infections from progressing into AIDS. However, HIV can establish a silent state upon infection called latency, where the infected cell hosts the HIV genome but does not express it immediately. These cells are undetectable by the immune system, evade drug treatments, and can spontaneously and stochastically initiate viral production through a process called reactivation. HIV latency forces patients to life-long HAART, and is a major barrier to a cure. This thesis focuses on studying HIV latency and its dependency on fluctuations in HIV gene expression (or “noise”). Chapter 1 and 2 provides an overview of HIV latency and noise. Chapter 3 explores the relationship between host cell size and the likelihood of HIV reactivation through theoretical and experimental analysis of noise in HIV. Chapter 4 investigates whether the responsiveness of latent HIV to external stimuli is inherited from mother cell to daughter cells. This is achieved by measuring noise in responsiveness among colonies cultured from single cells. Chapter 5 demonstrates noise modulation of HIV through external drug perturbations. Chapter 6 examines the potential of utilizing noise modulation to bias HIV decision making in reactivation from latency. Overall, my work deepens our understanding of how gene expression noise shapes the behavior of latent HIV, and provided novel small molecule compounds that may help advance efforts to a cure to HIV.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Bioengineering

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2022

Author dc:creator

• Lu, Yiyang

Contributors dc:contributor

• Maslov, Sergei
• Dar, Roy David
• Lu, Ting
• Golding, Ido

• HIV
• gene expression
• noise
• stochasticity
• latency
• LPA
• LRA
• microscopy
• flow cytometry
• drug screen

Statement dc:rights

• Copyright 2022 Yiyang Lu

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/115365

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F115365