# Integrative Single-Cell Analysis of Transcriptome, Epigenome, and Lineage in HIV Latency and Activation

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $657,841

## Abstract

Abstract
With the development of triple combination antiretroviral therapy, routine HIV treatment eliminates nearly all
actively infected cells. Nevertheless, the small reservoir of latently infected cells, which can remain dormant for
long periods of time before becoming active and producing new virus particles, represents a crucial barrier to
completely curing the disease. Identifying markers that identify latently infected cells or the biochemical factors
that control latency activation could enable the effective use of a “shock and kill” strategy, where specific targeting
or activation of latently infected cells eliminates the viral reservoir. Our recent work suggests that the global
transcriptomic and epigenomic changes during hematopoietic differentiation affect viral latency and activation.
Additionally, we recently found that global inhibition of histone deacetylase activity increases viral activation in
these cells, further implicating epigenomic changes in activation. These results raise fundamental questions:
What are the markers of latently infected cells? How do the transcriptomic and epigenomic state of a cell affect
latency and activation? How does differentiation state relate to viral latency? Here, we leverage our experimental
platform for identifying latently and actively infected cells, single cell transcriptome and epigenome sequencing,
and our recently developed computational integration methods to investigate these questions. Our
interdisciplinary team combines expertise in HIV basic science, HIV clinical treatment, and bioinformatics to
develop an experimental and computational framework for integrated gene expression, chromatin accessibility,
and lineage into a single picture of viral latency and activation. Specifically, this project will (1) use single-cell
RNA-seq and single-cell ATAC-seq to map diversity of infected cells, (2) investigate the relationship between
hematopoietic differentiation state and viral activation, (3) determine viral integration sites through single-cell
RNA-seq, (4) computationally integrate single cell transcriptome and epigenome profiles, and (5) computationally
infer cell lineage relationships among viral genomes and infected cells. To accomplish these goals, we will carry
out the following aims: (1) Characterize lineage, transcriptomic and epigenomic diversity of single latently and
actively infected primary cells. (2) Investigate latency and activation during in vitro differentiation. (3) Survey
single cell diversity of re-activated and in vitro infected cells from cART-suppressed patients. Together, these
aims will produce a comprehensive, integrated transcriptomic and epigenomic atlas of the HIV reservoir, identify
DNA and RNA biomarkers of latency, and characterize clonal expansion patterns. Our work also develops a
broadly applicable experimental and computational framework, laying a foundation for the discovery of novel
insights into HIV latency and activation.

## Key facts

- **NIH application ID:** 10306389
- **Project number:** 5R01AI149669-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Kathleen L. Collins
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $657,841
- **Award type:** 5
- **Project period:** 2019-12-19 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10306389

## Citation

> US National Institutes of Health, RePORTER application 10306389, Integrative Single-Cell Analysis of Transcriptome, Epigenome, and Lineage in HIV Latency and Activation (5R01AI149669-03). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10306389. Licensed CC0.

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