# Mechanisms of Trained Immunity in HIV Immune Responses

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $234,000

## Abstract

PROJECT SUMMARY / ABSTRACT
Acute HIV infection is characterized by a robust innate immune response that determines the ultimate clinical
disease course. Innate immune activation and transcriptional changes can persist beyond the acute infection
period. Cells of the innate immune system can be reprogrammed or “trained” by prior exposures, and this
lasting changes influence future immune responses. This phenomenon, termed trained immunity or innate
immune memory, is epigenetically encoded, allowing stimulus-dependent transcription factors to bind not only
to available cell type-specific enhancers, but also to previously inaccessible regions of the chromatin in the
genome. Despite the importance of early innate responses in determining HIV disease course, the role of
trained immunity in HIV infection has not been explored. Moreover, the effects of substance use on these
early innate immune responses are not known. This project will leverage expertise in HIV immunology and
substance use (Dr. Fulcher), innate immune memory epigenetic mechanisms (Dr. Cheng), and HIV
immunology and cytotoxic T lymphocytes (Dr. Yang) to investigate mechanisms of trained immunity in shaping
HIV immune responses and how HIV itself may reprogram innate immune cells. We hypothesize that
exposure to certain stimuli during monocyte differentiation will lead to differential ability to produce cytokines
and stimulate HIV-specific CD8+ T cell responses. In the setting of HIV infection, we hypothesize that HIV
exposure induces monocyte reprogramming resulting in heightened secondary responses that may contribute
to chronic inflammation and immune exhaustion. To test these hypotheses we will: (1) identify innate immune
stimuli that train monocytes for optimal HIV-specific immune responses, including examining the effects of
drugs of abuse on these responses and (2) characterize the innate immune memory produced by HIV
infection and determine the viral factors and host signaling pathways required for training. We will train
primary human monocytes, obtained from persons who do or do not use drugs, with different ligands during
differentiation to macrophages then expose to HIV and compare outcomes using functional immune assays.
Pathways will be interrogated using RNAseq. We will next train monocytes with HIV then examine epigenetic
and transcription changes following secondary stimulus (LPS) using RNAseq and ATACseq. Results from
these studies will advance understanding of how trained immunity shapes HIV immune responses, and how
HIV may affect later immune responses. This knowledge can lead to novel immune targets for therapeutics to
improve HIV prevention and treatment.

## Key facts

- **NIH application ID:** 10535270
- **Project number:** 1R21AI172059-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Quen J Cheng
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $234,000
- **Award type:** 1
- **Project period:** 2022-07-14 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10535270

## Citation

> US National Institutes of Health, RePORTER application 10535270, Mechanisms of Trained Immunity in HIV Immune Responses (1R21AI172059-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10535270. Licensed CC0.

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