# Investigating antigen-driven clonal proliferation to target HIV-1 persistence

> **NIH NIH DP5** · JOHNS HOPKINS UNIVERSITY · 2022 · $409,375

## Abstract

PROJECT SUMMARY
Antiretroviral therapy (ART) greatly reduces HIV morbidity and mortality. However, it has no effect on the HIV
reservoir, a small pool of latently infected cells that rekindles infection upon treatment interruption. Due to the
persistence of this reservoir, ART must be continued indefinitely, requiring public health systems to deliver
medications to all 38 million people living with HIV for life. This research program has the long-term goal of
helping develop new therapeutic approaches to eliminate or control the HIV reservoir, leading to a drug-free
remission. The proliferation of infected cells is a major mechanism of HIV persistence, as it results in expanded
CD4+ T cell clones that carry proviral DNA. Recent studies suggest that antigen-specific immune responses
contribute largely to this phenomenon. The overall objective of this application is to understand the role of chronic
antigens in determining the structure and dynamics of the clones that constitute the HIV reservoir. The underlying
central hypothesis is that adaptive immune responses impose selective pressure on HIV-infected cells. The
rationale for the project is that, if clonal expansion is one of the major mechanisms of HIV persistence, targeting
this process will reduce the reservoir size and accelerate its decay. The central hypothesis will be tested by
pursuing three specific aims: 1) Determine the effect of antigens on HIV latency reversal; 2) Identify the factors
responsible for the expansion and maintenance of HIV-infected, antigen-specific clones; and 3) Determine the
role of chronic antigens from commensal pathogens in driving reservoir persistence. Under the first aim, CD4+
T cells reactive to Cytomegalovirus (CMV, the virus responsible for a common chronic infection) will be isolated
from individuals with HIV and expanded ex vivo. Upon stimulation of T cells with cognate CMV antigens, HIV
latency will be studied at the single-cell level and compared to non-specific maximal T cell stimulation, commonly
used to reverse latency in vitro. For the second aim, CMV-responsive clones harboring HIV will be tracked
longitudinally in individuals with CMV replication around the time of ART introduction, in the effort to understand
the events underlying their expansion. For the third aim, Candida albicans, a pathogenic commensal yeast that
plays a major role in driving antifungal immune responses, will be used to demonstrate whether chronic exposure
to commensal microbes shapes the repertoire of CD4+ T cells, including those part of the HIV reservoir. The
research proposed in this application is innovative because, compared to the status quo, it focuses on
physiological T cell stimulation and ubiquitous immune responses to study latency reversal and HIV dynamics.
The proposed research is significant because it is expected to result in a better understanding of the interaction
between adaptive immunity and HIV persistence, and will provide new insight on how to target ...

## Key facts

- **NIH application ID:** 10488649
- **Project number:** 5DP5OD031834-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Francesco Roberto Simonetti
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $409,375
- **Award type:** 5
- **Project period:** 2021-09-14 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488649

## Citation

> US National Institutes of Health, RePORTER application 10488649, Investigating antigen-driven clonal proliferation to target HIV-1 persistence (5DP5OD031834-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10488649. Licensed CC0.

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