# Project 1-Peruzzi

> **NIH NIH P20** · LSU HEALTH SCIENCES CENTER · 2022 · $257,330

## Abstract

Accumulating evidence indicate that people living with HIV (PLWH) are at higher risk of developing cancer
compared to the general population. In addition, the ability of HIV to imprint epigenetic changes in myeloid cells
may paly acritical role in reshaping the overall immune performance of PLWH. This is important since it will
address a gap of knowledge on the link between epigenetic modifications underlying a dysfunctional immune
response and susceptibility to cancer development in HIV+ individuals with low or undetectable viral load. Our
data indicate the presence of specific epigenetic modifications found in the genome of monocytes isolated from
HIV+ patients. These epigenetic changes can be subsequently linked to monocyte abnormal function and
abnormal differentiation. When challenged with environmental signals, such as β-glucan or LPS, normal
monocytes are expected to execute a type of innate program called either “trained immunity” or “tolerance”,
characterized by hyper-responsiveness or hypo-responsiveness to secondary stimuli, respectively. This delicate
balance between trained immunity and tolerance, characterized by epigenetic and metabolic reprogramming, is
defective in HIV+ monocytes, and represents the major focus of this proposal. Our model involves isolation of
CD14+ monocytes from HIV+ individuals and healthy controls, which are analyzed in vitro following polarization
toward a pro-inflammatory (M1-like) phenotype. Upon LPS stimulation, which activates toll-like receptor 4
(TLR4), the cells from HIV+ individuals demonstrated a significant increase in the pro-inflammatory expression
of IL6, TNFα and IL1B. In parallel, we observed a significantly lower expression of miR-146a-5p, a miRNA
involved in the negative regulation of LPS-induced inflammation, in HIV-derived cells. By contrast, a pro-
inflammatory and oncogenic miRNA, miR-155-5p, was upregulated in HIV-derived cells compared to controls.
In addition, our ChIP-seq data show a differential enrichment of chromatin activation marks at promoters
(H3K4me3) and distal enhancers (H3k4me1) of freshly isolated HIV-derived cells compared to controls. We also
found lower expression of transcriptional repressors and inhibitors of TLR4 signaling pathway, which suggests
inability of HIV-derived cells to establish a negative feedback mechanism required to dampen inflammation
following LPS. Therefore, our experimental plan proposed here is intended to test the overall hypothesis that
epigenetic marks and specific metabolic features found in HIV-derived monocytes prime these immune cells to
hyper-responsiveness following secondary insults, leading to increased cytokine production and immune
dysfunction, contributing to cancer susceptibility in PLWH.

## Key facts

- **NIH application ID:** 10520699
- **Project number:** 2P20GM121288-06
- **Recipient organization:** LSU HEALTH SCIENCES CENTER
- **Principal Investigator:** Francesca Peruzzi
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $257,330
- **Award type:** 2
- **Project period:** 2017-08-15 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10520699

## Citation

> US National Institutes of Health, RePORTER application 10520699, Project 1-Peruzzi (2P20GM121288-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10520699. Licensed CC0.

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