# In Vivo Evaluation of HIV Latency Reversal Strategies

> **NIH NIH R56** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $621,932

## Abstract

Elimination of the persistent reservoir of resting latently HIV-infected cells is the greatest challenge to HIV
eradication. Estimates indicate that complete clearance of HIV from the body would require >70 years of
continuous fully suppressive antiretroviral treatment (ART). However, induction of HIV from its dormant
state could accelerate the decline of the latent reservoir shortening the time to eradication. Initial efforts to
induce HIV focused on latency reversing agents (LRAs) that stimulate HIV transcription by activating T cells.
However, in clinical trials these agents failed to reduce the HIV reservoir and were toxic. Recent efforts
have focused on polyclonal T cell stimulants at doses that induce minimal-to no-side effects in patients (e.g.
PKC agonists) or agents that use alternative pathways to induce HIV transcription without T cell activation
(e.g. HDAC inhibitors). However, while transient increases in HIV in peripheral blood (PB) have been
detected in clinical trials, no LRA has reduced the latent HIV reservoir in vivo. Furthermore, previous
attempts to induce HIV from patients and animal models focused on PB. Their systemic effect in tissues has
been poorly described. Our long-term goal is to accelerate HIV eradication by identifying LRAs that are
easy to administer, safe, have little-to-no immune stimulatory activity, induce HIV in PB and tissues, and
effectively reduce the latent HIV reservoir. Recently, it was shown that induction of the non-canonical NF-B
(ncNF-B) signaling pathway by AZD5582, a peptide mimetic with second mitochondrial activator of
caspases (SMAC)-like activity, reverses HIV latency in vitro and ex vivo. Based on these data, we evaluated
AZD5582 in vivo in BLT humanized mice and observed robust target cell engagement and HIV induction.
Our preliminary data shows that AZD5582 administration to ART-suppressed BLT mice induced
reproducible plasma HIV RNA. These results were confirmed in SIV-infected, ART suppressed non-human
primates. Analysis of resting CD4+ T cells from AZD5582-treated BLT mice revealed robust (up to 24 fold)
systemic HIV induction in virtually all tissues analyzed including lymph nodes, thymus, bone marrow, liver,
and lung. Importantly, we observed no overt toxicity or T cell activation. To our knowledge, this is the first
demonstration of widespread HIV induction in resting cells from tissues by a LRA. Based on our
preliminary data, our hypothesis is that SMAC mimetics will induce HIV expression in resting latently
infected CD4+ T cells in vivo thereby reducing the latent HIV reservoir. Our objective here is to evaluate
and compare the in vivo LRA activity of a panel of SMAC mimetics by analyzing their: 1) PK profile,
safety and target engagement in vivo, 2) effect on HIV RNA levels in plasma and in latently-infected resting
CD4+ T cells from tissues, and 3) effect on the latent HIV reservoir in vivo. These data will be used to select
the best candidates for further evaluation leading to...

## Key facts

- **NIH application ID:** 10237476
- **Project number:** 1R56AI148089-01A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** J. Victor Garcia-Martinez
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $621,932
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10237476

## Citation

> US National Institutes of Health, RePORTER application 10237476, In Vivo Evaluation of HIV Latency Reversal Strategies (1R56AI148089-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10237476. Licensed CC0.

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