# T-cell depletion and maintenance of the HIV-1 latent reservoir in distinct tissue compartments

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $823,537

## Abstract

The primary challenge in curing HIV-1 is the persistence of a latent viral reservoir (LVR) in resting CD4+ (rCD4)
T cells that harbor stably integrated latent HIV. Examining changes in the LVR composition is incredibly difficult
due to the long half-life. Recent data show that clonal expansion of latently infected rCD4 T cells through a
combination of antigenic stimulation, homeostatic proliferation, and integration site promotor disruption are
major contributors to LVR maintenance. It is unclear which tissue source is the primary driver of LVR
maintenance, as well as what level of contribution each of these three potential mechanisms driving proliferation
may play in that process. Solid organ transplantation in people living with HIV and the associated different T
cell induction strategies prescribed for prophylactic allograft rejection treatment provide a unique opportunity to
examine how the LVR rebounds after a large proportion of the T cell repertoire is destroyed. The HOPE in
Action HIV+ kidney organ transplantation trial provides access to >120 matched flash frozen lymph nodes (LN),
renal allograft tissue, and longitudinally collected peripheral blood mononuclear cells (PBMC) from PLWH. We
hypothesize that the LVR is primarily maintained through antigen stimulation of latently infected cells in micro
foci within lymph nodes, which subsequently migrate into the circulation and other tissues in the body, thereby
reestablishing the LVR post-T cell depletion therapy.
Aim 1: Examine long-term LVR dynamics post-renal transplantation and its association with clinical outcomes.
We will measure the HIV LVR annually for up to 10 years using the intact proviral DNA assay (IPDA), which
distinguishes fully intact HIV from defective, deleted, and hypermutated proviral DNA, in individuals receiving
transplant-related immunosuppressive drugs that are of interest to HIV cure strategies. Aim 2: Develop a tissue
specific atlas of the LVR in LN, blood, and organ tissue (kidney) pre-transplantation, and examine reseeding of
the circulating, LN, and kidney allograft LVR post T cell induction. We will assemble a multi-modal atlas of HIV+
LN by integrating the CODEX multiplexed immunofluorescence (mIF) platform to phenotype lymphoid cells and
laser capture microdissection (LCM) and site-directed next-generation sequencing of the proviruses in cells
isolated from distinct LN zones. HIV SMRTcap, a novel HIV-specific single molecule sequencing assay will
provide simultaneous resolution of proviral sequences and matched integration sites, to evaluate clonality and
intactness of latent provirus within the LN, PBMC and kidney. Aim 3: Determine the relative contribution of
homeostatic proliferation, antigenic stimulation, and integration site promoter disruption on LVR maintenance
and re-establishment post-transplant.
These proposed studies will enable us to characterize the longitudinal LVR spatially, genetically, and
phenotypically in multiple compartments. This proje...

## Key facts

- **NIH application ID:** 10480980
- **Project number:** 1R01DK131926-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Melissa Laird Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $823,537
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10480980

## Citation

> US National Institutes of Health, RePORTER application 10480980, T-cell depletion and maintenance of the HIV-1 latent reservoir in distinct tissue compartments (1R01DK131926-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10480980. Licensed CC0.

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