# Unraveling the Mechanisms of HIV Persistence and Rebound

> **NIH NIH P01** · NORTHWESTERN UNIVERSITY · 2024 · $1,548,481

## Abstract

PROJECT SUMMARY/ABSTRACT (Overall)
The persistence of HIV infection despite long term suppression of viremia by cART constitutes the major obstacle
to HIV cure. This is unfortunately true even for patients initiated on cART during acute infection. Thus, long-term
persistent HIV reservoirs are seeded rapidly post infection, and this was confirmed in the nonhuman primate
(NHP) model of HIV. In addition, data from several groups and ours strongly suggest that residual viral replication
is ongoing despite in tissues despite full suppression of viremia by cART. Our on-going studies investigate the
“eclipse phase” of viral rebound in the NHP model after cART interruption. This “eclipse phase” is key to
understand the rebound process since the virus is spreading in tissues before viremia and it is influenced by
adaptive and innate responses as well as the host microenvironment. In our studies of early (4 days post-
infection) cART initiation, our innovative SIV-env ImmunoPET-CT guided analysis and sampling led to several
important, sometimes unexpected findings: 1) we detected SIV expansion throughout the entire host for >1 week
post cART initiation, with signal decreasing thereafter; 2) Even after 6-8 months of cART, immunoPET/CT was
sensitive enough to detect residual viral (protein) signal in tissues in spite of undetectable viremia in the blood;
3) upon ART interruption, viral signals rebounded as early as 4 days post cART interruption (ATI) but also 2
weeks before detection of virus in plasma; 4) analysis of the tissues collected at rebound through our PET-CT
guided necropsy workflow surprisingly showed that the majority of infected cells were of myeloid cells. After
extensive analysis, these cells revealed to be mast cells (MC), a predominantly tissue resident granulocytes that
we demonstrate expresses CD4 and CCR5. By teaming up with a local MC expert, we were able to demonstrate
that primary tissue MC are susceptible to HIV infection in vitro and their susceptibility and ability to support viral
replication is heavily influenced by environmental stimuli. In this PPG, we will leverage several important insights
and innovative techniques developed during our current PPG to investigate the hypothesis that MC contribute to
HIV persistence in tissues during cART and/or contribute to viral rebound upon cART interruption. Moreover, we
will clarify virus-host dynamics through phyloanatomical analysis of viral populations in tissues using tissues and
cells isolated through our innovative PET-CT guided sampling workflow. These tissues will be identified also
through the analysis of additional features of “rebound tissues” that we have recognized through our current
studies. This PPG comprises of 3 independent, although highly interconnected projects, 1 scientific NHP core
and 1 administrative core. The 3 projects will all use in different ways tissues from the NHP studies as well as
resources unique to each project and will address different although comp...

## Key facts

- **NIH application ID:** 10834289
- **Project number:** 5P01AI169600-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Thomas Hope
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,548,481
- **Award type:** 5
- **Project period:** 2022-07-15 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834289

## Citation

> US National Institutes of Health, RePORTER application 10834289, Unraveling the Mechanisms of HIV Persistence and Rebound (5P01AI169600-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10834289. Licensed CC0.

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