# Role of caspase-1 activation in HIV-1 associated atherogenesis

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2021 · $612,974

## Abstract

Project summary/Abstract: Atherosclerosis-associated cardiovascular disease (CVD) is currently one of the
leading causes of mortality among people living with HIV (PLWH) on effective antiretroviral therapy (ART). Our
current understanding of the pathogenesis of HIV-associated atherosclerosis is limited and largely obtained
from clinical observations. The distinct pathologic features of HIV-induced atherosclerosis are noncalcified
inflammatory plaques that are more vulnerable to rupture. In patients on ART treatment, HIV infection not only
activates immune cells, such as macrophages (MC), but also activates an array of molecular pathways, such
the inflammasome pathway, including caspase-1 (casp-1) activation. However, the exact cellular and
molecular mechanisms underlying HIV-associated atherogenesis have not been extensively investigated.
Understanding these mechanisms will help to better develop and design novel therapeutic interventions for the
treatment/prevention of HIV-associated CVD. To achieve this unmet goal, we have formed a multidisciplinary
team consisting of multiple PIs Dr. Qin (innate immunity and CVD expert) and Dr. Burdo (expert in HIV-1 CVD
and macrophage (Mɸ) biology), and Co-I Dr. Gordon (expert in HIV-1 infection). Through this joint effort, we
have utilized HIV-transgenic mice (Tg26 on a B6 background) carrying a 7.4-kb proviral HIV DNA construct
carrying a deletion, encompassing most of the gag and pol genes, to render it noninfectious. Tg26 mice mimic
chronic HIV patients on ART in which there is no viral replication, but viral proteins are still produced. In order
to introduce Tg26 to an atherogenic background, we crossed this line with Apolipoprotein E (ApoE-/-) mice, a
common mouse strain used for studying atherogenesis for the last 25 years to generate Tg26/ApoE-/- mice.
Our preliminary results show that 1) Tg26/ApoE-/- developed an accelerated atherogenesis with normal renal
function, 2) Tg26/ApoE-/- had significantly higher casp-1 activation in peripheral blood mononuclear cells
(PBMC) and plaques than ApoE-/-, 3) The HIV-1 transgene in Tg26/ApoE-/- fostered MC to form the foam cells,
a hallmark of atherogenesis, and 4) Casp-1 is activated on MC in the plaques of HIV-1-infected patients, and
5) serum IL-1β and IL-18 are elevated in Tg26 and IL-18 is elevated in HIV+ patients and correlates with
coronary plaque. Therefore, we hypothesize that chronic HIV infection induces MC activation via casp-1
pathway, contributing to HIV-associated atherogenesis. To test this hypothesis, we propose to investigate
the pathogenesis of HIV-1-associated atherosclerosis by using animal models and available HIV specimens. We
will use several novel models and approaches including our newly established HIV-1 Tg-26 transgenic mice
maintained under hyperlipidemia conditions as well as standard approaches including our established in vitro model
systems for foam cell formation. The proposed studies will provide important insights into our und...

## Key facts

- **NIH application ID:** 10162645
- **Project number:** 5R01HL141132-04
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Tricia Helen Burdo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $612,974
- **Award type:** 5
- **Project period:** 2018-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10162645

## Citation

> US National Institutes of Health, RePORTER application 10162645, Role of caspase-1 activation in HIV-1 associated atherogenesis (5R01HL141132-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10162645. Licensed CC0.

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