# Impact of NETosis on SIV Pathogenesis and Response to Treatment

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $781,335

## Abstract

Antiretroviral therapy (ART) has dramatically changed the landscape of chronic HIV infection and massively
reduced mortality in persons living with HIV (PWH). Yet, many PWH present with intestinal dysfunction, residual
immune activation and inflammation, incomplete immune restoration and a hypercoagulable state, all of which
drive a poor prognosis and development of non-AIDS comorbidities, such as the cardiovascular disease (CVD).
The pathways involved in the development of CVD in PWH and SIV-infected macaques are not completely
elucidated. We recently reported that neutrophil dysfunction may be a key driver of this process, through
overwhelming activation and excessive production of neutrophil extracellular traps (NETs). By studying the
dynamics and functions of NETs in SIV infection, we showed that they may contribute to disease progression
and comorbidities: (a) proinflammatory NETosis increases throughout untreated SIV infection, and is only
partially reduced by ART, (b) NETs may be a determinant of the indiscriminate depletion of immune cells that
are not virus targets, and of the incomplete CD4+ T cell restoration observed in PWH on ART, and (c) NETosis
may promote thrombosis in the thrombocytopenic environment of HIV/SIV infections by capturing platelets and
expressing tissue factor. We thus propose a project to assess the role of NETosis in HIV disease progression
and response to ART through a direct intervention in vivo. We will use an SIVsab/PTM model developed in our
laboratory that faithfully reproduce both key aspects of SIV pathogenesis on ART and the CV disease. We will
also use a NET inhibitor that has been validated in vivo by numerous studies in murine animal models. In
preliminary studies, we demonstrated that this drug has the ability to inhibit ex vivo production of NETs by
neutrophils isolated from our SIV-infected PTMs. We will first test the hypothesis that NETosis is involved in
driving SIV pathogenesis and disease progression. To this goal, we will administer the NET inhibitor during
chronic infection to untreated SIV-infected PTMs and assess its impact on the natural history of SIV infection,
including CV comorbidities. These experiments are designed to model those PWH who either do not receive
ART or do not achieve complete virus suppression on ART. Second, we will test the hypothesis that NETosis
is involved in driving the response to ART and development of CV comorbidities. To this goal, we will
administer a NET inhibitor to ART-treated SIV-infected PTMs and assess the consequences of this intervention
on the CD4+ T cell restoration, inflammation, coagulation and CV disease development. These experiments are
designed to model PWH, who receive ART. This highly innovative project will improve our understanding of HIV
pathogenesis and mechanisms of HIV-related comorbidities, particularly the CVD, a major cause of death in
PWH, and thus may have a critical impact on the clinical management and survival of the PWH.

## Key facts

- **NIH application ID:** 10402152
- **Project number:** 2R01HL123096-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Ivona Vasile Pandrea
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $781,335
- **Award type:** 2
- **Project period:** 2015-07-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10402152

## Citation

> US National Institutes of Health, RePORTER application 10402152, Impact of NETosis on SIV Pathogenesis and Response to Treatment (2R01HL123096-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10402152. Licensed CC0.

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