# Validating a Humanized Mouse HIV Model for Cognitive Deficits and Novel Treatments

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

Abstract
Approximately half of the roughly 40 million people with HIV (PHIV) worldwide develop HIV
associated neurocognitive disorders (HAND), regardless of whether they receive combined
antiretroviral therapy (cART). Mild forms of HAND, which are most common in PHIV on cART,
ultimately progress to dementia. Treatment strategies to eradicate HIV are ongoing, but in
reality the brain will remain an HIV reservoir for the foreseeable future. Therefore, developing
adjunctive treatments for HAND is important while simultaneously advancing eradication
strategies. Another important point is targeting treatments to mild forms of HAND [prior to
dementia], when treatment is more likely to stabilize or reverse HAND. To best accomplish this,
an animal model must be used that is practical, displays cognitive deficits and pathology
consistent with mild HAND in humans, and preferably employs replicating HIV so that long-term
effects of treatments and eradication strategies can be optimally investigated. However,
currently there is no model that incorporates all of these important features. Recently it has
been shown that humanized (BLT) mouse models of HIV infection exhibit trafficking of human
cells to mouse brain, including T cells and mononuclear phagocytes (MP), which are the cell
types infected by HIV. HIV-infected human MP and T cells have been demonstrated in BLT
brains, HIV DNA and RNA can be quantitated in brain, and there is a mouse MP reaction similar
that seen in humans with mild HAND. Importantly the BLT model exhibits long lived brain
infection, which enables testing of novel treatments in sufficient numbers of animals to
determine statistically significant, prolonged effects and tolerability in BLT mice that can also be
simultaneously treated with cART. However, BLT mice have not been shown to have cognitive
deficits or neuronal abnormalities, which are hallmarks of HAND. The proposed studies will test
BLT mice for cognitive deficits using techniques that are established in our current short term
SCID mouse HAND model. Essential pathological parameters to be monitored will be brain HIV
load, mouse and human brain MP inflammatory activity, and neuronal dendritic integrity in
important regions such as frontal cortex, hippocampus and the basal ganglia. These are also
established techniques in our current short-term HAND model. Therefore, the first aim is to
validate the BLT model according to important features of HAND including cognitive deficits and
associated neuronal pathology. The second major aim of the proposal is to validate novel
treatments previously shown to be effective in the short-term HAND model with long-term
testing for efficacy in HAND, safety and potentially brain HIV eradication. It is predicted that this
model will be validated along with novel treatments as detailed in the proposal, providing a
direct conduit to human clinical trials.

## Key facts

- **NIH application ID:** 10123545
- **Project number:** 1I01BX005402-01
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** WILLIAM R TYOR
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123545

## Citation

> US National Institutes of Health, RePORTER application 10123545, Validating a Humanized Mouse HIV Model for Cognitive Deficits and Novel Treatments (1I01BX005402-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10123545. Licensed CC0.

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