# Modeling the HIV latent reservoir, latency reversal and immunotherapeutics for HIV cure

> **NIH NIH R01** · TRIAD NATIONAL SECURITY, LLC · 2020 · $603,470

## Abstract

SUMMARY
A major barrier to HIV cure is the reservoir of latently infected cells that persists in patients treated
with highly potent antiretroviral treatment (ART). Activation of these latently infected cells can lead
to HIV rebound in the absence of ART. In clinical trials, HIV exhibits widely different dynamics
after ART cessation. HIV rebounds rapidly in most individuals, whereas in a small fraction of
individuals, prolonged HIV remission or post-treatment control (PTC) is achieved. Despite
intensive research, we lack a clear and coherent understanding of the determinants of viral control
or the duration of HIV remission after ART, which hinders the development of effective therapeutic
strategies to achieve a ‘functional’ cure and ultimately a sterilizing cure.
This grant addresses this gap in knowledge. Our central hypothesis is that PTC is not solely driven
by a single factor; rather, it is a phenomenon emerging from complex nonlinear interactions
between the immune response and the latent reservoir, including both the replication competent
reservoir and the defective reservoir. Understanding this dynamical interaction will be key to
develop effective interventions to achieve favorable clinical outcomes. We will first delineate the
roles of these interactions in determining viral control through integration of recent biological
findings into a mechanistic mathematical model. We will validate this model using clinical data
from post-treatment controllers and non-controllers, correlate estimated model parameters with
measured biological and immunological markers to identify patient characteristics that predict
PTC. Further, we will estimate the mode of action and quantify the efficacy of a next-generation
latency reversing agent (LRA), AZD5582, and a class of promising bispecific antibody-based
immunotherapeutics, the Dual-Affinity Re-Targeting molecules. Finally, we will integrate models
of how these agents work with a model of the interaction of the latent reservoir with the immune
system to evaluate and predict the impact of combinations of LRAs and immunotherapeutics on
the reservoir and on clinical outcomes.
Altogether, our work will provide a theoretical foundation for 1) understanding HIV control and
rebound dynamics after ART, 2) identifying patients who are likely to achieve PTC, 3)
estimating/predicting the impact of therapeutic interventions such as LRAs and/or
immunotherapeutics, and 4) suggesting effective interventions to achieve a ‘functional’ cure
according to patient characteristics.

## Key facts

- **NIH application ID:** 10083086
- **Project number:** 1R01AI152703-01A1
- **Recipient organization:** TRIAD NATIONAL SECURITY, LLC
- **Principal Investigator:** Ruian Ke
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $603,470
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10083086

## Citation

> US National Institutes of Health, RePORTER application 10083086, Modeling the HIV latent reservoir, latency reversal and immunotherapeutics for HIV cure (1R01AI152703-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10083086. Licensed CC0.

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