# Single cell transcriptomics of HIV persistence and latency

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $628,679

## Abstract

Summary
 Antiretroviral therapy (ART) in HIV-1 infection suppresses viral replication, preserves and improves the
CD4+ T cell count and prevents disease progression. However, treatment with ART is not curative, and
interruption of therapy consistently unleashes viral relapse. The persistence of a viral reservoir following ART
is the major obstacle to an HIV cure. Proposed “shock and kill” strategies to activate and eliminate the HIV
reservoir are currently not informed by a knowledge of the T cell states or lineages that support latency. One
of the greatest challenges in latency research is to distinguish latent cells from non-latent cells, which is
inherently difficult to do without perturbing the latent state of the cells. With current approaches, cellular
activation is required to enumerate latent cells, which disrupts the very state that we would like to study. To
overcome this major roadblock to latency studies, we have developed an HIV-induced lineage tracing model
(HILT) in humanized mouse that irreversibly genetically marks infected cells. When combined with single cell
RNA sequencing (scRNAseq) approaches in HIV-infected, ART-treated animals, the result is an emerging
genomic resolution view of transcriptional states associated with HIV infection and latency. Preliminary studies
presented here begin to provide an unprecedented, single cell genomic classification of HIV-infected CD4 T
cell lineages and states during acute infection and during early antiretroviral treatment. In this proposal, we
explore single cell multi-omics of persistently infected human CD4 T cells in humanized mice and examine how
it responds to oligoclonal TCR activation versus homeostatic proliferation. The systems biology of T cells will
be used to dissect latent reservoirs in novel small animal models for HIV to understand how a reservoir is
generated and maintained in distinct cell states. Genomic analysis may be used to identify drugs or biologic
interventions that can push cells towards active HIV expression and are independent of cellular activation
state. These could be used to develop cure strategies aimed at enhancing expression and the progressive
decay of the latent reservoir. We hypothesize that a single cell multi-omics approach will elucidate
developmentally diverse T cell lineages and transcriptional states that harbor HIV reservoirs, and that each
cluster may display unique gene programs associated with HIV persistence. Reversing the expression of
factors associated with HIV persistence may reactivate the reservoir. Single cell multi-omics may unveil new
targeted strategies to purge HIV from different T cell states. The proposed study leverages a team with
expertise in HIV immunopathogenesis, humanized mice, single cell genomics, to deeply phenotype human T
cell reservoirs in novel small animal models.

## Key facts

- **NIH application ID:** 10375603
- **Project number:** 5R01AI162223-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** BENJAMIN K CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $628,679
- **Award type:** 5
- **Project period:** 2021-03-19 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375603

## Citation

> US National Institutes of Health, RePORTER application 10375603, Single cell transcriptomics of HIV persistence and latency (5R01AI162223-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10375603. Licensed CC0.

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