# The heterogeneous HIV expressing reservoir: dynamics, persistence mechanisms, tissue distribution, and contribution to rebound

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $1,578,386

## Abstract

Abstract: While the latent and intact HIV reservoirs pose theoretical barriers to cure, it is also critical to
understand those cells that are reactivated and/or express HIV in vivo, which contribute to immune activation
and may have more potential to initiate rebound after ART interruption. However, prior studies of the
“transcriptionally active reservoir” have not been able to fully characterize the heterogeneity of these cells, which
vary in terms of whether they transcribe incomplete or completed and spliced HIV RNA, whether the HIV RNA
is transcribed from defective or intact proviruses, and whether it is translated into HIV protein. This P01 focuses
on the novel hypothesis that subsets of cells expressing different types of HIV RNA and/or protein will differ in
terms of their frequency, survival or clearance rate, contribution to immune activation, cellular gene expression,
differences across tissues, rebound potential, and susceptibility to new therapies aimed at HIV cure. To test
these hypotheses, the three synergistic projects in this P01 will employ an array of new and cutting-edge
technologies that can distinguish HIV-expressing cells based on the processivity of the HIV RNA, presence or
absence of deletions or hypermutations, translation into HIV protein, and human transcriptome/proteome.
Project #1 will measure the changes in blocks to HIV transcription and levels of defective or intact HIV RNA and
protein over time in the blood of elite controllers and individuals who initiate ART during acute or chronic infection
(aim 1), determine how they relate to immune responses and immune activation/inflammation (aim 2), and
determine how differential expression of host cell genes relates to the ability of these cells to express HIV and
survive in blood and lymph nodes (aim 3). In Project #2, we will measure the total burden of intact/defective
proviruses and intact/defective HIV RNA across the full spectrum of different organs and tissues in vivo (aim 1),
define the frequencies and phenotypes of cells expressing different types of HIV RNA transcripts across tissues
(aim 2), and determine the in situ impact of HIV burden and residual transcriptional activity on host cell factors
in tissue-resident lymphoid and myeloid cells (aim 3). Project #3 will determine which reservoirs of HIV-
expressing cells (as well as the intact and inducible reservoir) and host factors best predict the timing of rebound
in individuals who initiated ART during acute vs. chronic infection (aim 1), define the features of the rebounding
virus and earliest detectable infected cells during treatment interruption (aim 2), and assess the effects of
immune-based cure interventions on these HIV reservoirs (aim 3). To achieve these goals, the Bioinformatics
Core will help analyze transcriptomic, proteomic, and high dimensional data, while the Administrative Core will
facilitate scientific crosstalk and collaboration, coordinate allocation of resources, and track and evaluate
p...

## Key facts

- **NIH application ID:** 10459929
- **Project number:** 1P01AI169606-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Steven A Yukl
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,578,386
- **Award type:** 1
- **Project period:** 2022-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459929

## Citation

> US National Institutes of Health, RePORTER application 10459929, The heterogeneous HIV expressing reservoir: dynamics, persistence mechanisms, tissue distribution, and contribution to rebound (1P01AI169606-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10459929. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*