# Mechanisms of SARS-CoV-2 pathogenesis during HIV/SIV infection

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $785,351

## Abstract

PROJECT SUMMARY/ABSTRACT
COVID-19 vaccination reduces the risk of SARS-CoV-2 infection and severe disease, but almost half of
hospitalized breakthrough cases are in immunocompromised individuals. HIV infection is an independent risk
factor for severe COVID-19, hospitalization, and mortality. Immunocompromised individuals are more likely to
have prolonged SARS-CoV-2 infection and viral shedding, increasing the risk of viral transmission and allowing
for rapid evolution of more virulent strains. Therefore, investigating SARS-CoV-2 pathogenesis in the context of
immunosuppression is urgently needed to reveal factors driving severe COVID-19. SARS-CoV-2 lung
pathogenesis is characterized by infiltration of innate and adaptive immune cells into the lung and induction of
an inflammatory immune response. Similar mechanisms of inflammation and immune dysfunction during HIV
infection contribute to systemic HIV pathogenesis and lung pathology. Therefore, dysregulation of immune
responses during HIV infection could induce severe disease outcomes during SARS-CoV-2 coinfection. SARS-
CoV-2 replication occurs in both respiratory and gastrointestinal mucosal sites and enteric symptoms are
associated with COVID-19. There is a defined link between gastrointestinal microbial dysbiosis with accelerated
HIV disease progression and an emerging role of lung and intestinal microbial dysbiosis with severe COVID-19.
Given that the microbiome plays an important role in maintaining mucosal function and homeostasis, shifts in
microbial communities due to HIV infection could contribute to inflammation and immune activation that would
drive exacerbated SARS-CoV-2 pathogenesis. Here, we will test the hypothesis that increased immune
dysfunction and exhaustion, inflammation, and microbial dysbiosis during HIV infection promote enhanced
SARS-CoV-2 lung pathogenesis. We will leverage the pigtail macaque simian immunodeficiency virus (SIV)
model of rapid HIV/AIDS and will test this hypothesis during a state of inflammatory untreated SIV infection and
during primary and secondary SARS-CoV-2 viral challenges. We will evaluate the roles of SIV-induced
immunosuppression and altered alveolar macrophage and neutrophil function on SARS-CoV-2 pathogenesis
and pulmonary pathology. We will determine whether HIV infection causes gastrointestinal tract and lung
microbial dysbiosis and its association with SARS-CoV-2 disease severity. Lastly, we will determine whether
increased immune exhaustion during HIV infection promotes deficits in the generation of primary anti-viral SARS-
CoV-2 responses that impairs protection from heterologous SAR-CoV-2 re-challenge. These studies will
contribute to our understanding of how normal immunity drives SARS-CoV-2 lung pathophysiology and will
dissect how perturbations of immune responses during HIV infection contribute to enhanced disease.

## Key facts

- **NIH application ID:** 10914834
- **Project number:** 5R01HL165933-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Megan A O'Connor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $785,351
- **Award type:** 5
- **Project period:** 2023-08-28 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914834

## Citation

> US National Institutes of Health, RePORTER application 10914834, Mechanisms of SARS-CoV-2 pathogenesis during HIV/SIV infection (5R01HL165933-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10914834. Licensed CC0.

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