# Functional Cure of HIV Neurocognitive Disease by Induction of Innate Immunity

> **NIH NIH R21** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $253,500

## Abstract

Despite suppressive antiretroviral therapy in HIV infected human beings that maintains their
immunocompetence, brain dysfunction develops and impairs their quality of life. To investigate
HIV residence, disease, and recovery in the central nervous system (CNS) we have studied the
infection of conventional mice by EcoHIV, a chimeric HIV with tropism switched from human to
rodent. Infected mice reliably develop neurocognitive impairment (NCI). We found that innate
immune responses to Toll-like receptor ligand polyinosinic-polycytidylic acid (poly I:C) reduce
virus burden and restore cognitive function in mice chronically infected by EcoHIV. Remarkably,
poly I:C also induces a long-lived response that largely prevents EcoHIV infection and NCI. Here,
we shall exploit these successful treatments to achieve functional EcoHIV cure in the murine CNS
as a complement to existing antiretroviral therapies. The Specific Aims are 1) to exploit reversal
of HIV NCI through intermittent poly I:C treatment of chronically infected mice to identify the
changes in gene expression underlying both the essential antiviral responses and the critical
neuronal genes restored to normal function. Of particular interest is the identification of specific
cell types mediating protective immunity and their specific products, since all brain cell types can
respond to poly I:C. 2) to investigate reversal of HIV NCI through long-lived poly I:C responses
by chronically infected mice. Poly I:C induces both immediate and long-lived antiviral programs
that prevent EcoHIV infection and the development of HIV NCI. Our overall goal in this application
is to bring genomics and imaging techniques to expose the routes of HIV NCI as well as the
antiviral routes that restore function. Here, we will test whether chronically infected mice can
mount a long-lived poly I:C response that restores normal cognitive function. It will be critical to
compare the gene expression programs initiated by intermittent poly I:C treatment, likely Type I
interferon, to those comprising the long-lived poly I:C response that may include the canonical
innate immune training program. To monitor EcoHIV infection and disease in the brain we shall
employ QPCR to measure virus burden and radial arm water maze (RAWM) to detect cognitive
defects, brain RNA-seq to reveal cellular gene dysregulation, RNAscope to assign brain infection
to cell types, and confocal microscopy to determine cell types mounting protective innate
responses. Since innate immunity is not pathogen specific, this exploratory program may reveal
approaches to induce innate responses that protect against other viruses invading the brain.

## Key facts

- **NIH application ID:** 10548392
- **Project number:** 1R21NS129460-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** MARY Jane POTASH
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $253,500
- **Award type:** 1
- **Project period:** 2022-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10548392

## Citation

> US National Institutes of Health, RePORTER application 10548392, Functional Cure of HIV Neurocognitive Disease by Induction of Innate Immunity (1R21NS129460-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10548392. Licensed CC0.

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