# Targeted delivery of cytopathicity enhancing agents, and co-ordination with shock and kill, to reduce HIV reservoirs

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $793,988

## Abstract

Project Abstract
Although modern therapies have dramatically improved the outlooks for people living
with HIV they are unable to cure infection, leaving these individuals burdened by a
lifelong commitment to antiretroviral (ARV) medication. For any given individual,
maintaining lifelong adherence to medication can present substantial challenges.
Moreover, these expensive medications are not accessible for many individuals, in
particular those in resource poor settings. It would therefore be of tremendous value to
develop novel therapies that can drive HIV into remission, by which we mean into a state
where levels of virus remain low or undetectable even when one stops taking ARV
medication. At present, no such therapeutic intervention exists. Recent studies have
shown that a type of molecule called BCL-2/BCL-XL antagonists is able to promote the
death of HIV-infected cells, which could potentially lead to remission. A concern of these
BCL-2/BCL-XL antagonists, however, is that they are associated with side-effects that
are likely to be considered unacceptable. Relatedly, these molecules are not highly
specific to HIV-infected cells and can also cause the death of some uninfected
'bystander' cells. We have developed a technology that allows for the selective targeting
of drug-loaded gold nanoparticles to certain cell populations in vivo. In the current
proposal we aim to use this technology to more selectively target BCL-2/BCL-XL
antagonists to infected cell populations. In Aim 2, this targeting will be relatively broad –
for example, targeting all memory CD4+ T-cells. In Aim 3, we will test approaches to
specifically target delivery to only HIV infected cells. For both of these approaches
'latency reversing agents (LRAs)' may also be needed to induce some expression of HIV
and promote the death of infected cells. In Aim 2, these LRAs will be provided along with
BCL-2/BCL-XL antagonist be co-loading gold nanoparticles. In Aim 3, LRAs will be
provided first in order to induce HIV expression, allowing subsequent specific targeting
of BCL-2/BCL-XL antagonists to HIV-infected cells. Our proposal will take both of these
complementary approaches from in vitro experiments through to an in vivo preclinical
model. Our ultimate objective is to observe efficacy of the novel therapeutics developed
by this project in these preclinical models. If observed, this would enable future clinical
trials of these new therapies in people living with HIV, and potentially leading to viral
remission without the need for ongoing ARV therapy.

## Key facts

- **NIH application ID:** 9972851
- **Project number:** 5R01AI147845-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Darrell J Irvine
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $793,988
- **Award type:** 5
- **Project period:** 2019-07-05 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972851

## Citation

> US National Institutes of Health, RePORTER application 9972851, Targeted delivery of cytopathicity enhancing agents, and co-ordination with shock and kill, to reduce HIV reservoirs (5R01AI147845-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9972851. Licensed CC0.

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