# CCL2/CCR2 modulates HIV-associated ischemic stroke by regulating blood brain barrier monocyte recruitment

> **NIH NIH R21** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $422,125

## Abstract

ABSTRACT
HIV infection results in increased susceptibility to ischemic stroke by enhancing the injury volume and decreasing
post-stroke recovery. Stroke is the second leading cause of death worldwide with a mortality rate higher than 5
million deaths per year. However, the specific factors involved in HIV-induced potentiation of ischemic stroke
have not been defined. Inflammatory chemokine CCL2 is known to play a crucial role in HIV infection by acting
via the CCR2 receptor, inducing inflammatory responses, including the release of CCL5, and enhancing the
blood brain barrier (BBB) disruption during ischemic stroke. Importantly, it has been shown that astrocytes are
responsible for the exacerbated CCL2 release post-ischemic stroke. The central hypothesis of this proposal
is that astrocyte-specific CCL2/CCR2 signaling modulates HIV-associated stroke severity and functional
recovery by regulating monocyte recruitment to the BBB, inflammasome activation, and modulating
innate immune responses. Consistent with this hypothesis, the Specific Aims are: 1) To evaluate the
hypothesis that astrocyte-derived CCL2 plays a critical role in the recruitment of proinflammatory HIV-infected
monocytes/macrophages into the brain, BBB breakdown, and potentiation of ischemic stroke injury in HIV
infection. 2) To evaluate the hypothesis that therapeutic targeting of the CCR2 and CCR5 receptors protects
against ischemic stroke in HIV-infected brain and accelerates functional recovery via astrocyte-specific innate
immunity mechanisms.
The proposed research will involve a novel conditional and astrocyte-specific CCL2-deficient mice, namely,
CCL2flox/flof;GFAP-Cre conditional knockout mice generated in our lab. Mice will be infected with a mouse adapted
to HIV strain called EcoHIV. We will investigate whether conditional ablation of CCL2 in astrocytes can reduce
exacerbated neuroinflammatory response. Moreover, we will therapeutically target the CCL2 signaling in
humanized mouse model of HIV infection by using the dual CCR2/CCR5 inhibitor cenicriviroc, which can prevent
BBB dysregulation through NLRP3 inflammasome inhibition. Next, we will assess both the acute and long-term
effects of cenicriviroc on ischemic stroke outcomes. This proposal is conceptually innovative by being the first to
study mechanism-targeted therapeutic approaches for BBB protection in the context of stroke in HIV infection.
The results of this proposal will significantly contribute to a better understanding of the interplay between the
recruitment and infiltration of monocyte subsets into the ischemic brain and the severity of ischemic stroke
outcomes in HIV patients. The findings resulting from this proposal will help to establish associated pathways
that may be identified as promising new therapeutic targets.

## Key facts

- **NIH application ID:** 11085498
- **Project number:** 1R21NS141704-01
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Silvia Torices
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $422,125
- **Award type:** 1
- **Project period:** 2024-09-18 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11085498

## Citation

> US National Institutes of Health, RePORTER application 11085498, CCL2/CCR2 modulates HIV-associated ischemic stroke by regulating blood brain barrier monocyte recruitment (1R21NS141704-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11085498. Licensed CC0.

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