Modeling HIV-1 Infection in the Brain: The Effect of the Blood-Brain Barrier

Despite the advancement of antiretroviral therapy (ART), the development of HIV associated neurocognitive disorders (HAND) remains a major concern among HIV infected patients. As many ART drugs may fail to penetrate the blood-brain barrier (BBB), the long-term presence of viral RNA in the brain is considered to be associated with these disorders, such as early-onset dementia. \textit{In vivo} study of HIV infection in the brain is extremely difficult, and thus mathematical modeling can help to further the analysis of the viral dynamics of HIV in the brain. In this dissertation we develop a mathematical model to help investigate the viral dynamics of HIV in the brain. Our model can explain containing viral loads in the plasma and in the cerebral spinal fluid from SIV-infected macaques. We then extend this model to study the treatment of HIV in the brain. Furthermore we develop a new stochastic model to analyze any stochastic effects that may underlie HIV-viral dynamics in the brain. Using our models, we show that the rate of transport of infected macrophages into the brain greatly exceeds the rate of transport out of the brain. We also show that viral replication occurs in the brain, suggesting that the brain can act as a viral reservoir. We also show that the basic reproduction number largely depends on the overall effectiveness of ART, but it is not strongly affected by the rate of drug penetration through the blood-brain barrier. The effectiveness of ART depends on both pharmacodynamic parameters and a drug's ability to penetrate through the BBB. In particular, for drugs with a high dose-response curve, the BBB penetration strongly affects the post-treatment control of the virus in the brain. Through examination of the stochastic model we illustrate a prolonged higher likelihood of infection and viral production in the brain compared to the plasma. Results in this dissertation may be useful to develop HIV control strategies to target the virus hiding in the brain.

Name thesis:degree_name

Ph.D. (Doctor of Philosophy)

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Mathematics (UMKC)

Grantor

University of Missouri--Kansas City

Year dc:date.issued

2019

Author dc:creator

• Barker, Colin T.

Advisor dc:contributor.advisor

• Vaidya, Naveen K.

Handle dc:identifier.uri

https://hdl.handle.net/10355/73689

OAI identifier oai:identifier

oai:mospace.umsystem.edu:10355/73689