# Accelerating to the Cure: A Novel IVIVE Model for Advancing HIV Eradication Strategies

> **NIH NIH R21** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $192,295

## Abstract

Project Summary
Problem: Despite remarkable advances in HIV treatment over the last 2 decades, viral suppression in people
living with HIV (PLWH) still requires lifelong adherence to expensive, multidrug, daily dosing regimens. The stark
reality of this challenging treatment modality is that almost 50% of PLWH in the US are not virologically
suppressed. An HIV cure that achieves sustained, medication-free remission is desperately needed. The
main obstacle to this cure is the latent reservoir, a subset of long-lived, latently infected cells harboring
replication-competent virus.
 Investigational cure strategies seek to activate then clear (Target and Clear) this reservoir by pairing
latency-reversing agents (LRAs) with immunomodulators. Over 50 small molecules across 7 mechanistic classes
have been identified as potential LRAs. Yet in the last decade of research, none have advanced past early stages
of clinical development due to unacceptable toxicity or inadequate efficacy. A critical component of drug
development that has been widely overlooked in the development of LRAs, is identification of PK/PD indices
(e.g. Cmax/EC50) associated with drug effect. These targets are essential for optimizing doses to achieve a
concentration profile within the therapeutic window.
Overarching Goal: By leveraging the predictive power of PK/PD modeling and simulation, we aim to accelerate
the advancement of LRAs from the Laboratory to the Patient. We have developed an in vitro to in vivo
extrapolation (IVIVE) system that incorporates a cellular model of latency and can simulate human PK. We will
employ this system to identify PK/PD indices for latency reversal.
Study Design: We have selected 6 promising LRAs from 3 mechanistic classes to assess using our novel IVIVE
model. We identified these LRAs based on published human PK data, and prioritized LRAs with existing or
anticipated clinical study results in PLWH. In AIM 1 we will use established cellular models of latency to
characterize the LRA concentration vs latency reversal relationship across a 4-log concentration range by fitting
sigmoid Emax models to estimate the following parameters for each LRA: EC25, EC50, EC75, and EC90. In AIM 2
we will identify PK/PD indices for HIV latency reversal by simulating the human PK profile for each LRA and
conducting dose fractionation studies. We will fit sigmoid Emax models for 12 combinations of PK/PD indices
(Cmax/IC50, AUC/EC90, Time>EC75, etc.) vs HIV latency reversal and determine the best fitting models. We will
validate our model (where possible) by cross-referencing our predictions with clinical trial results.
Anticipated Outcome: This work will guide dose optimization for a broad portfolio of LRAs and assist in selecting
effective doses for animal and human studies. Through clinical validation, we will establish our novel IVIVE model
as a new paradigm to accelerate the development of HIV cure strategies.

## Key facts

- **NIH application ID:** 10468902
- **Project number:** 5R21AI157853-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Mackenzie Cottrell
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $192,295
- **Award type:** 5
- **Project period:** 2021-08-12 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468902

## Citation

> US National Institutes of Health, RePORTER application 10468902, Accelerating to the Cure: A Novel IVIVE Model for Advancing HIV Eradication Strategies (5R21AI157853-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10468902. Licensed CC0.

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