# How HIV-related proteins increase the susceptibility to lung injury despite anti-retroviral therapy

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $390,000

## Abstract

Infection by the human immunodeficiency virus (HIV) remains a major global threat with ~34 million individuals
living with HIV worldwide. Although combination antiretroviral therapy is effective at slowing disease
progression, it fails to eradicate latent viral reservoirs. In parallel, HIV integrates into target tissues and the
chronic expression of HIV-related proteins, including gp120 and Tat, can induce alveolar macrophage and
epithelial dysfunction even when ART limits viral replication to undetectably low levels. Consequently,
individuals living with HIV are remarkably susceptible (perhaps 10-fold or greater) to serious pneumonias, such
as from Pseudomonas aeruginosa, and lung injury. Using clinically relevant HIV-1 transgenic rodent models
and cell culture systems we discovered that HIV-related proteins induce oxidative stress by inhibiting Nrf2
(Nuclear factor (erythroid-derived 2)-like 2), the master transcription factor that activates anti-oxidant and
immune defenses. Our preliminary studies for the first time show that HIV-1 transgenic mice have an impaired
clearance of P. aeruginosa with exacerbated lung injury and inflammation compared to wild type mice.
Additionally, the relative loss of Nrf2 signaling results in unrestrained inflammatory signaling in macrophages
including the activation of Triggering Receptor Expressed on Myeloid cells-1 (TREM-1), a member of the super
immunoglobulin family expressed on myeloid cells. These intriguing findings led us to hypothesize that chronic
exposure to HIV-related viral proteins dysregulates the normal balance between Nrf2 and TREM-1 signaling.
This imbalance, in which Nrf2 is suppressed and TREM-1 is induced, promotes a pathophysiological
environment that impairs innate immune responses to bacterial invasion and renders the lung susceptible to
infection and injury. We further hypothesize that targeting the balance between Nrf2 and TREM-1 signaling is
a novel therapeutic approach to enhance lung health in individuals living with HIV. We propose to test these
hypotheses in three integrated aims: 1) Investigate the molecular basis for the dysfunctional signaling of Nrf2
and TREM-1 in macrophages in response to HIV-related viral proteins. 2) Define the functional consequences
of TREM-1 induction in alveolar macrophages by HIV-related proteins on both epithelial barrier integrity and
macrophage-epithelial interactive innate immunity against Pseudomonas aeruginosa. 3) Determine the impact
of modulating Nrf2-TREM-1 signaling in vivo on lung bacterial clearance in HIV-1 transgenic mice challenged
with Pseudomonas aeruginosa. It is imperative that we elucidate the mechanisms by which HIV-related
proteins impair innate immunity within the lung, including how they promote an environment in which latent
viral reservoirs may be established within the alveolar macrophage pool. In parallel, understanding the discrete
molecular and cellular mechanisms by which HIV-related proteins impair alveolar macrophage im...

## Key facts

- **NIH application ID:** 10442363
- **Project number:** 5R01HL144478-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** David Marshall Guidot
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2019-01-15 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442363

## Citation

> US National Institutes of Health, RePORTER application 10442363, How HIV-related proteins increase the susceptibility to lung injury despite anti-retroviral therapy (5R01HL144478-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10442363. Licensed CC0.

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