# Role of clonal expansion in HIV-1 persistence

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $444,620

## Abstract

Project summary
Despite effective antiretroviral therapy (ART), HIV-1 persists in memory CD4+ T cells as the major barrier to cure.
It was recently proposed that HIV-1 can drive the aberrant proliferation of the infected cells through integration
into cancer-related genes. The clonally expanding latent reservoir, if present, hampers HIV-1 eradication efforts
and should be targeted specifically. However, it remains unclear whether HIV-1 proviruses integrated into
cancer-related genes are intact or defective, and how HIV-1 may drive the clonal expansion through integration
into cancer-related genes. Several challenges prevent the study of HIV-1 persistence. First, the rarity of HIV-1
infected cells and the lack of reliable markers which can distinguish cells containing inducible HIV-1 (~1-10 per
million resting CD4+ T cells) from cells containing defective HIV-1 (~100-1000 per million resting CD4+ T cells)
and uninfected cells makes HIV-1-specific analysis difficult. Second, transcriptome analysis of bulk CD4+ T cells
from HIV-1-infected individuals captures mostly the transcriptome of HIV-1 uninfected cells. Third, methods
studying HIV-1 integration sites disrupt the HIV-1 genome, while methods studying HIV-1 full-length sequences
and replication competence exclude HIV-1 integration sites from amplification. To this end, we developed the
innovative, cutting-edge HIV-1 RNA SortSeq which identifies cells containing inducible HIV-1 for single
cell RNAseq analysis and the integration site of inducible HIV-1. From blood samples obtained from virally
suppressed individuals, we identified HIV-1-host chimeric RNA which depicts inducible HIV-1 RNA and
HIV-1 integration sites at the same time. Further, we identified three patterns of HIV-1-host interactions: 1)
read-through transcription, 2) host RNA splicing into HIV-1 RNA, creating novel transcription variants encoding
a host-HIV-1 fusion protein, and 3) HIV-1 RNA splicing into host RNA, indicating HIV-1 driven host (cancer-
related) gene expression. We hypothesize that HIV-1 which are integrated into cancer-related genes may
drive the proliferation of the infected cells and promote HIV-1 persistence through HIV-1-host RNA
interactions. Our goal is to examine whether HIV-1 integration into cancer-related genes causes clonal
expansion (Aim 1) and to identify the mechanisms of HIV-1-driven proliferation (Aim 2). In Aim 1, we will obtain
blood samples from virally suppressed individuals at different time points to determine whether inducible HIV-1
which are integrated into cancer-related genes undergo clonal expansion using HIV-1 RNASortSeq. We will
determine whether HIV-1 integration into cancer-related gene changes the host cell transcriptome at the single
cell level. We will examine the contribution of T cell activation, antigen-driven proliferation and homeostatic
proliferation in HIV-1 clonal expansion. In Aim 2, we will use our established cell line model to examine HIV-1-
host RNA interactions and clo...

## Key facts

- **NIH application ID:** 10458573
- **Project number:** 5R01AI141009-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Ya-Chi Ho
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $444,620
- **Award type:** 5
- **Project period:** 2018-08-17 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458573

## Citation

> US National Institutes of Health, RePORTER application 10458573, Role of clonal expansion in HIV-1 persistence (5R01AI141009-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10458573. Licensed CC0.

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