# Trained immunity induced by Nef-containing extracellular vesicles

> **NIH NIH R21** · GEORGE WASHINGTON UNIVERSITY · 2022 · $242,250

## Abstract

Abstract
Findings that certain infections induce immunity not only against the causing agent, but also against an unrelated
pathogen have intrigued investigators for many years. During recent years, underlying mechanisms of this
phenomenon have started to come to light. It was found that the key cells responsible for heterologous protection
are innate immune cells such as natural killer cells (NKs), dendritic cells, and monocytes/macrophages. These
cells are ‘primed’ by initial infection, allowing them to provide enhanced response to subsequent infection by the
same or unrelated agent. This phenomenon of innate immune memory was termed trained immunity. The
proposed mechanism for trained immunity involves activation by the first stimulus of metabolic pathways that
lead to epigenetic changes, which maintain the cell in a "trained" state allowing enhanced responses to a
subsequent stimulus. Innate immune memory can lead either to enhanced responses or to suppression of
subsequent responses (‘tolerance’), depending on the strength and length of the initial stimulation of the immune
cells. In the context of HIV infection, it remains unknown whether innate memory is induced by infection, although
limited evidence suggests a lasting activation of NK cells following HIV exposure. In this application, we present
the first evidence that extracellular vesicles carrying the HIV-1 protein Nef (exNef) induce trained immunity in
human monocytes, characterized by increased response to stimulation. The mechanism of this training appears
to depend on exNef-mediated effect on cholesterol homeostasis. Given that exNef are released into the blood
even after HIV replication had been suppressed by ART, trained monocytes/macrophages can be maintained
for a long time after virus suppression. We propose to investigate the mechanism of exNef-induced innate
immune memory training and its effect on susceptibility of macrophages to HIV infection. The proposed aims
address the two scientific questions in the FOA: ‘Does HIV exposure or infection induce innate immune memory?’
and ‘What mechanisms regulate innate immune memory which impact HIV acquisition?’. The study also involves
a specific approach mentioned in the FOA: ‘Metabolic changes leading to reprogramming of innate immune
cells’.

## Key facts

- **NIH application ID:** 10534002
- **Project number:** 1R21AI172028-01
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** MICHAEL Ilya BUKRINSKY
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $242,250
- **Award type:** 1
- **Project period:** 2022-07-12 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10534002

## Citation

> US National Institutes of Health, RePORTER application 10534002, Trained immunity induced by Nef-containing extracellular vesicles (1R21AI172028-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10534002. Licensed CC0.

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