# Combining In Vitro and In Silico Models to Investigate Antiretroviral Drug Transport Across the Blood Brain Barrier for the Treatment of HIV-1 Infection in the Brain

> **NIH NIH R21** · UNIVERSITY OF COLORADO · 2023 · $396,541

## Abstract

SUMMARY
HIV-1 establishes latent reservoirs throughout the body in the earliest stages of infection and can remain hidden
and inactive inside long-lived immune cells for years, impeding our ability to cure HIV. Early treatment with
antiretrovirals (ARVs) is considered the most effective means of reducing the total latent HIV reservoir size and
can do so by up to 100-fold compared to untreated individuals after three years. One common location for HIV
reservoirs to form is in the brain. Unfortunately, the ability of ARVs to penetrate and treat HIV infection in the
brain is significantly limited by their poor ability to transport across the blood-brain barrier (BBB) and their
tendency to be bound and cleared by BBB-embedded efflux proteins. Despite knowledge that such transport
barriers exist, a detailed understanding of how ARVs interact with the BBB lipid membrane and BBB efflux
proteins is still lacking, due in part to the oversimplification of past computational models that do not consider
key interactions between ARVs and BBB lipids or BBB efflux proteins and the lack of relevant experimental
transport data. The overarching goal of this proposal is to uncover the fundamental mechanisms and key
features governing the interactions between ARVs and BBB components by testing the hypothesis that key
physicochemical and/or structural properties of ARVs give rise to both their differential molecular-scale
interactions with BBB efflux proteins and their differential abilities to diffuse across the BBB. To test our
hypothesis, we will employ a physiologically relevant in vitro BBB model combined with atomistic simulations to
identify properties of two classes of ARVs often used for treating HIV—protease inhibitors (PIs) and nucleoside
reverse transcriptase inhibitors (NRTIs)—that mediate their transport across the BBB. We will determine the
molecular mechanisms of ARV binding to the BBB lipid membrane (Aim 1) and efflux proteins (Aim 2) using
molecular dynamics simulations. Drawing on the literature and our significant experience with vascular
microfluidic models, we will optimize our in vitro BBB model to include a model brain microvasculature with efflux
transporters, supported by pericytes and astrocytes, and will use it to quantify ARV transport across the BBB
(Aim 1) and determine the effect of ARV/efflux protein interactions (Aim 2), validating our in silico results and
generating new data for our machine learning model. Finally, we will develop machine learning models to identify
properties and/or dynamical features of ARV/BBB interactions that govern transport and will use this model for
forward-design and testing of novel ARVs. This collaborative, iterative approach will allow for the direct
measurement of parameters needed to create accurate computational models and direct testing of predictions
from the computational models, using a novel in vitro BBB system. In turn, this will increase the relevance and
power of our findings and greatly fac...

## Key facts

- **NIH application ID:** 10838759
- **Project number:** 1R21MH132159-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Laurel Erin Hind
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $396,541
- **Award type:** 1
- **Project period:** 2023-09-18 → 2026-09-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10838759

## Citation

> US National Institutes of Health, RePORTER application 10838759, Combining In Vitro and In Silico Models to Investigate Antiretroviral Drug Transport Across the Blood Brain Barrier for the Treatment of HIV-1 Infection in the Brain (1R21MH132159-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10838759. Licensed CC0.

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