# Mechanisms Underlying the HIV-HSV-2 Syndemic

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $509,551

## Abstract

The HIV and HSV-2 syndemic is well recognized, but the biological mechanisms that contribute are not
understood. The recent recognition that HSV-2 is characterized by a frequent state of subclinical shedding
suggests that the virus might contribute to persistent immune activation and prompted us to examine the
impact of HSV-2 on peripheral blood T cells and on HIV reservoirs. Taking advantage of our biorepository of
peripheral blood mononuclear cells (PBMC) from well-characterized HIV+ women on antiretroviral therapy who
were or were not HSV-2 seropositive (HIV+/HSV-2+ vs. HIV+/HSV-2-), we found a significant difference in the
phenotype of CD4+ (but not CD8+) T cells in HIV+/HSV-2+ compared to HIV+/HSV-2- women. These changes
included an increase in the frequency of activated cells, but a paradoxical decrease in the expression of IL-32,
an intracellular cytokine presumed to be associated with inflammation. Moreover, when CD4+ T cells isolated
from virally suppressed HIV+/HSV-2+ women were stimulated with latency reversal agents, the addition of
recombinant IL-32 to the cultures blocked HIV reactivation. These observations suggest that IL-32 plays a
pivotal role in controlling HIV reactivation and suggest a new paradigm underlying the HIV-HSV-2 syndemic.
We hypothesize that HSV-2 triggers changes in local (at the site of HSV-2 genital skin outbreaks) and
peripheral blood CD4+ T cells including a reduction in intracellular IL-32 levels that promote HIV reactivation.
Conversely, high levels of IL-32 contribute to the maintenance of HIV reservoirs suggesting that IL-32 blockade
may synergize with strategies to reactivate HIV as part of a “shock and kill” approach to cure. To test these
hypotheses, we will analyze serial samples of PBMC from HIV infected women before and after HSV-2
acquisition from two unique cohorts: women enrolled in Microbicides Trial Network (MTN)-015, a longitudinal
study of African women who seroconverted to HIV while participating in pre-exposure prophylaxis trials, and
U.S. women with established HIV infection enrolled in the Bronx Women's Interagency Study (WIHS). We will
also compare PBMC in HIV-infected men who are or are not coninfected with HSV-2. We will phenotype
immune cell subpopulations to define the changes that occur in association with HSV-2 acquisition and the
impact of these changes on plasma viral loads and HIV reservoirs. We will prepare CD4+ T cell libraries of IL-
32lo cells and determine whether these subpopulations are enriched in HSV-2 and/or HIV reactive cells and
whether decreased IL-32 interferes with immune functions. We will also take advantage of our repository of
genital skin biopsies (herpes lesion and unaffected contralateral side) and analyze the CD4+ T cells to
determine whether they are enriched for cells of specific phenotypes in situ. We will determine how IL-32
blocks the response to latency reactivating stimuli and how IL-32 antagonists promote HIV reactivation. These
studies will identif...

## Key facts

- **NIH application ID:** 9825515
- **Project number:** 5R01AI134367-04
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Betsy C. Herold
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $509,551
- **Award type:** 5
- **Project period:** 2017-12-05 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9825515

## Citation

> US National Institutes of Health, RePORTER application 9825515, Mechanisms Underlying the HIV-HSV-2 Syndemic (5R01AI134367-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9825515. Licensed CC0.

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