# Deciphering Mechanisms of HIV Latency Reversal in Perinatal Infections

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $769,890

## Abstract

Latent HIV prevents cure for the nearly 37 million persons living with HIV worldwide, of whom 1.7 million are
children. Elimination of the latent reservoir (LR) is critical for antiretroviral therapy (ART)-free remission, where
viral rebound does not occur when ART is stopped. Latency reversal agents (LRAs) can therapeutically target
the LR and render it susceptible to elimination. Clinical trials of LRAs in adults are ongoing and planned for
perinatally-infected children. Critically, however, our recent in vitro studies reveal that the kinetics of latency
reversal are slower and of lower magnitude when the LR is established in infancy (through perinatal infection)
compared with during adulthood. Our findings suggest that this major therapeutic approach requires further ex
vivo studies to decipher mechanisms of HIV latency reversal in perinatal infections in order to guide clinical
trials of LRAs in this population. We hypothesize that the immune environment in which the LR is established
and exists in perinatal infection renders it intrinsically more resistant to latency reversal than in adult infection.
The specific aims of this application are: 1) Determine and compare the size, composition, and
inducibility of the latent HIV reservoir in perinatal and adult infection, and characterize their differences;
2) Identify correlates of susceptibility to proviral reactivation through transcriptomic analyses of CD4+
T cells in perinatal and adult infections; and 3) Define the contribution of regulatory T cells (Tregs) to the
latent HIV reservoir in perinatal HIV infection and explore the utility of single-cell RNA-seq approaches
to examine differential responses of CD4+ T cell subsets to latency reversal. We will enroll perinatally HIV-
infected children, adolescents, and adults cared for in the US and Uganda, and comprehensively characterize
and compare the size of the latent reservoir, as measured by total and intact proviral DNA (including sites of
integration). We will determine susceptibility to latency reversal under maximum T cell activating conditions and
clinically relevant latency reversal therapeutics (TLR-7 agonist GS-9620, the IL-15 superagonist N-803, or the
SMAC mimetic-AZD5582), and when analyzed by mode of infection, LRA class, duration of virologic
suppression, proviral load, and subtype. Correlations between baseline states of immune activation, along with
baseline transcriptomes of CD4+ T cells as a function of mode of infection, geographic region/HIV subtype, and
size of the induced reservoir will be determined. We will further examine contribution of Tregs and non-Tregs to
the LR in perinatal infections, with exploratory studies of single-cell RNA-seq in defining baseline transcriptional
profiles of the different CD4+ memory T cell subsets, including Tregs, and their differential responses to the
LRAS. The systematic characterization proposed here will inform mechanistic insights into perinatal HIV latency,
including the contribu...

## Key facts

- **NIH application ID:** 10247079
- **Project number:** 5R01AI150412-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Deborah Persaud
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $769,890
- **Award type:** 5
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247079

## Citation

> US National Institutes of Health, RePORTER application 10247079, Deciphering Mechanisms of HIV Latency Reversal in Perinatal Infections (5R01AI150412-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10247079. Licensed CC0.

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