Graduation Date

Summer 8-9-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Courtney Fletcher

Second Advisor

Kim Scarsi

Third Advisor

Anthony Podany

Fourth Advisor

DJ Murry

Abstract

Soon after viral infection, viruses like Human Immunodeficiency Virus (HIV) and SARS-CoV-2 can disseminate throughout the body and establish reservoirs in the central nervous system (CNS). The persistence of viruses in cells of these reservoirs is a major obstacle to virus eradication. This is due to the abundance of cells/receptors that these viruses utilize to gain entry into cells found at these various reservoir sites. Consequently, these same anatomical sites also may be pharmacologic sanctuaries, as evidenced by concentrations of antiretroviral drugs (ARVs) and antivirals (AVs) that are lower in reservoirs than those in peripheral blood; in some cases, these low ARV concentrations have been associated with evidence for low-level ongoing virus replication in the CNS. Neurological complications associated with viral infection are well recognized with both HIV and SARs-CoV-2 infection and are a continuing problem. Ensuring that ARVs/AVs can cross the blood-brain barrier (BBB) and maintain adequate exposure to inhibit viral replication in the CNS is a pharmacotherapeutic challenge that requires attention, especially in recent years (i.e., NeuroHIV, Long COVID). Strategies to maximize these efforts include optimizing the selection of an ARV/AV and increased dosing/intervals of ARV/AV in hopes of achieving optimal pharmacodynamic (PD) endpoints in the CNS. The inhibitory concentration is commonly the level at which 50%, 90%, or 95% (IC50-95) of in-vitro viral replication is inhibited utilizing wild-type viruses. Pharmacokinetic/pharmacodynamic (PK/PD) endpoints are further complicated as no clear exposure thresholds have been identified in the CSF or CNS. The lack of such information leaves gaps in our understanding of the relative efficacy of various ARVs/AVs in the CSF/CNS. Further, assessing drug concentrations in the CNS in patients is difficult as it requires invasive methods for CSF (i.e., lumbar puncture) and tissue collection. This brings to light the utilization of pre-clinical models for potential CNS penetration. The work conducted in this dissertation highlights novel pharmacologic methods used to assess CSF and CNS penetration of various ARVs for HIV and AVs for SARs-CoV-2 using both pre-clinical and clinical models.

Comments

2024 Copyright, the authors

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