# Cellular Reservoirs of HIV

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $656,609

## Abstract

Antiretroviral medications suppress viral replication but do not eradicate cellular sources of integrated proviral
genomes that are a major barrier to a cure. CD4+ hematopoietic stem and progenitor cells (HSPCs) have the
capacity for life-long survival, self-renewal and the generation of daughter cells. They are also susceptible to
HIV infection in vitro and in vivo. Combination antiretroviral therapy effectively suppresses viremia in HIV-
infected people. However, residual plasma virus (RPV) can be detected with very sensitive assays. Recently
published studies demonstrate that clusters of identical proviruses from HSPCs and their likely progeny often
match RPV and are sometimes infectious. A higher proportion of these sequences matched RPV than proviral
genomes from peripheral blood mononuclear cells that lacked evidence of clonal expansion. Furthermore, we
provide examples of proviral genomes from progenitors that were latent in peripheral blood T cells while
simultaneously contributing to RPV. The cellular source of RPV in these cases is not known but is unlikely to
be peripheral blood T cells, which required latency reactivation for gene expression. We have developed a
model based on these data. In this model, we propose that heterogeneous differentiated progeny of infected
progenitors can support either active or latent infection depending on progeny epigenetic and transcriptional
programs. The overall objective of this application is to test this hypothesis by comprehensively characterizing
intact HIV in peripheral blood and tissue reservoirs. A secondary objective is to determine whether infected
HSPCs are required for clonal provirus and RPV and to identify any alternative proliferative sources of non-
HSPC generated clonal genomes. To accomplish this, we will: 1. Analyze intact near full length viral genomes
to identify sources of clonally amplified proviral genomes in peripheral blood and to determine their
relationship to proliferative sources such as HSPCs; 2. use viral outgrowth assays to confirm relationships
amongst sources of infectious virus; and 3. determine the active and latently infected tissue sources of
infectious virus and their relationships to proliferative sources such as HSPCs. Results from these aims will
comprehensively identify sources of functional virus and RPV across multiple disparate tissue sites. They will
determine the extent to which multipotent and/or restricted progenitors or other proliferative sources serve as
the source for clonally expanded HIV proviral genomes present in the peripheral blood and tissue sites. These
studies will provide important new information that has the potential to change the way we think about the
source of functionally relevant HIV reservoirs.

## Key facts

- **NIH application ID:** 10469656
- **Project number:** 5R01AI148084-04
- **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:** $656,609
- **Award type:** 5
- **Project period:** 2019-09-23 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469656

## Citation

> US National Institutes of Health, RePORTER application 10469656, Cellular Reservoirs of HIV (5R01AI148084-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10469656. Licensed CC0.

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