# Understanding HIV latency reversal and clearance of infected cells in vivo

> **NIH NIH R01** · NORTHERN CALIFORNIA INSTITUTE/RES/EDU · 2020 · $383,250

## Abstract

Project Summary/Abstract:
 Latently-infected CD4+ T cells are thought to be the main barrier to HIV eradication or functional cure,
and viral reactivation from these cells likely contributes to the organ inflammation and damage observed on
antiretroviral therapy. Major impediments to the development of more effective latency-reversing agents
(LRAs) include the lack of knowledge about the mechanisms that govern latency and latency reversal in vivo,
and the degree to which these are recapitulated by latency models in vitro. The lack of agreement between
latency models and the incomplete success of human trials with LRAs suggest that it is critical to understand
why different LRAs do or do not work in vivo. We have developed a new “transcription profiling” approach that
can simultaneously measure the degree to which different mechanisms contribute to reversible inhibition of
HIV transcription in vivo. By applying this approach to cells from ART-suppressed patients, we have generated
preliminary data suggesting a new paradigm in which latency is not (as commonly assumed) due to a block to
HIV transcriptional initiation, the block to proximal elongation is greater and more pervasive than previously
realized, and the main reversible blocks to HIV transcription are a previously-unrecognized block to distal
transcription/polyadenylation (completion) and a block to multiple-splicing. In addition, we have intriguing new
data suggesting that LRAs may act selectively on the different mechanistic blocks to HIV transcription. This
study will utilize samples from clinical trials of humans treated with LRAs (aims 1 and 2) to better understand
how they reverse the mechanisms of latency in vivo and to identify the optimum model to test new agents in
vitro (aim 3). In aim 1, we will apply our transcription profiling approach to samples from humans treated with
disulfiram, vorinostat, panobinostat, and romidepsin. We hypothesize that these agents preferentially increase
HIV transcriptional initiation and elongation but have less ability to overcome blocks to completion and splicing.
In aim 2, we will apply our approach to blood and gut samples from clinical trials of humans treated with
agonists of toll-like receptor (TLR) 7 and 9 to understand how these agents reverse latency and lead to death
of infected cells in vivo. We hypothesize that TLR agonists can overcome later blocks to HIV transcription,
increasing the completed transcripts (and HIV protein/antigen) that may facilitate clearance by intrinsic cell
defenses or immune killing. In aim 3, we will compare in vitro models of latency based on the degree to which
they recapitulate in vivo mechanisms of latency and responses to LRAs. We will then select the best model
and test new combinations of agents for their ability to increase completed/spliced transcripts and lead to death
of infected cells. The results from these 3 aims should provide critical new insights on the degree to which
existing LRAs reverse the ...

## Key facts

- **NIH application ID:** 9975686
- **Project number:** 5R01AI132128-04
- **Recipient organization:** NORTHERN CALIFORNIA INSTITUTE/RES/EDU
- **Principal Investigator:** Joseph K Wong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,250
- **Award type:** 5
- **Project period:** 2017-07-21 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975686

## Citation

> US National Institutes of Health, RePORTER application 9975686, Understanding HIV latency reversal and clearance of infected cells in vivo (5R01AI132128-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9975686. Licensed CC0.

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