# Examining HIV-mediated disruption of CNS immune homeostasis using a triple humanized mouse

> **NIH NIH R21** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $230,250

## Abstract

ABSTRACT
 Currently, the lack of adequate animal models to replicate the events of HIV-1 infection in humans
presents a critical barrier to study HIV pathology of the central nervous system (CNS). Eradicating HIV-1 infection
has become a priority. Contemporary, highly active antiretroviral therapy (ART) has significantly prolonged the
lives of those infected, but it has not resolved the incidence of HIV-associated neurocognitive disorders (HAND).
HIV persists in the human hemato-lymphoid compartments and in the central nervous system (CNS). Persistent
HIV reservoirs both in the periphery and CNS result in chronic inflammation and end-organ diseases. Clinical
observations reveal that the virus is present in CNS-resident immune cells and in non-immune cells of the CNS,
such as astrocytes. The CNS viral reservoir is life-long. Still, knowledge on the nature of persistent CNS viral
reservoirs and their influence on neuroimmune homeostasis is limited because of deficiencies in existing small
animal models. We aim to establish a new TRIPLE humanized mouse model reconstituted with autologous
human blood/ hematolymphoid system, microglia, and astrocytes to study the interaction of peripheral HIV-
infection and immune activation with human brain glial cells in developing CNS immune and neuronal
dysfunction. Mice that possess both peripheral blood/immune cells and human brain cells (HuBB-mice) are
expected to provide a comprehensive model to study NeuroAIDS. The model is best suitable to study the
research areas that fall within the scope of the current RFA. Using the new HuBB-mice, we aim to study: 1). HIV
glial reservoirs during suppressive ART and the dysregulation of neuroimmune homeostasis using single-cell
transcriptomic analysis, and 2). the altered neuronal integrity and function as a consequence of dysregulated
neuroimmune homeostasis. Animals treated with ART suppress peripheral viral replication in all tissues and cell
types, including astrocytes and microglia, facilitating virologic, immunologic, and neuropathologic assessments.
The proposed work is expected to lay the groundwork on the new HuBB-mice for future evaluations of multiple
aspects of HAND pathology in the context of chronic infection/ immune activation, persistent HIV reservoirs in
CNS, and neuroinflammation. The mouse model will be an important tool to develop therapeutics to alleviate
HAND and for designing HIV eradication strategies from CNS reservoirs.

## Key facts

- **NIH application ID:** 10536487
- **Project number:** 1R21MH131220-01
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Santhi Gorantla
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $230,250
- **Award type:** 1
- **Project period:** 2022-09-16 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536487

## Citation

> US National Institutes of Health, RePORTER application 10536487, Examining HIV-mediated disruption of CNS immune homeostasis using a triple humanized mouse (1R21MH131220-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10536487. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*