# Immune responses to HSV-2 recurrence replenish HIV tissue reservoirs during ART

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2020 · $478,209

## Abstract

Project Summary/Abstract
Functional cures of HIV have been documented, but rebound of plasma HIV RNA from the “Mississippi baby”6
and Boston bone marrow transplant recipients7 from latent reservoirs after post-ART aviremia confirms HIV
reservoirs are a significant barrier to a cure. This proposal will examine one model of an immune mediated
mechanism that replenishes HIV tissue reservoirs, i.e. cellular proliferation. We will determine whether antigen
(Ag)-specific responses to recurrent herpes simplex viruses (HSV) replenish HIV reservoirs by increasing HIV
DNA concentrations and HIV env diversity via cellular proliferation and recruitment of Treg and Ag-specific
CD4+ T cells to sites of recurrence and to the surrounding tissues. The role of Ag-specific responses to chronic
HSV, which are prevalent in HIV infected subjects (~45-90%), has not been studied in humans during
suppressive antiretroviral therapy (ART). HSV-2 episodically reactivates in tissues throughout subject’s life
even during suppressive ART for HIV.[5-7]
We will recruit 40 HIV(+) HSV-2(+) subjects that are currently receiving suppressive combination antiretroviral
therapy (ART, <30 copies/mL) for HIV from the University of Washington Virology Research Clinic (UW-VRC)
in Seattle, Washington. All subjects will be instructed to collect 28-days of anogenital samples that will be
assayed using HSV real-time PCR to generate an HSV shedding rate. Women will also collect cervical
secretions using the Instead Softcup™ to determine whether subclinical HSV shedding at the uterine cervix
induces HIV expression. Subjects will return to clinic to have blood, anogenital, cervical (women) or rectal
(men) biopsies collected. HIV(+) HSV(+) subjects will receive four months of valacyclovir 500 mg daily to
suppress HSV recurrences. After four months, subjects will return to the clinic for collection of blood,
anogenital and cervical or rectal biopsies. Specimens will be assessed for HIV DNA concentrations, HIV env
diversity, and the frequency of CD4+ Ag-specific T helper and Treg cells associated with HIV DNA and RNA.
Any HSV clinical recurrences after stopping Val throughout one year of follow-up will be biopsied. HSV
shedding/recurrence will be used in a linear regression model as the predictor for the following outcomes: HIV
DNA concentrations, HIV env diversity, and the frequency of CD4+ Treg and Ag-specific T cells. Comparisons
within HIV(+) HSV(+) subjects that have recurrences will be performed using a paired Wilcoxon sign rank test.
Understanding whether cellular proliferation, as part of the normal immune response to herpes recurrences,
replenishes or promotes the seeding of HIV tissue reservoirs (e.g. uterine cervix) is critical to our
understanding immune mechanisms that could pose a barrier to HIV eradication. These studies may suggest
therapeutic interventions to improve the health of HIV/HSV co-infected individuals and inform whether the
immune response to chronic viral infection shoul...

## Key facts

- **NIH application ID:** 9955152
- **Project number:** 5R01AI124770-05
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Lisa M Frenkel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $478,209
- **Award type:** 5
- **Project period:** 2016-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955152

## Citation

> US National Institutes of Health, RePORTER application 9955152, Immune responses to HSV-2 recurrence replenish HIV tissue reservoirs during ART (5R01AI124770-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9955152. Licensed CC0.

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