# Routes to enhanced HIV neuropathogenesis through expression of subclinical levels of endogenous amyloid-beta

> **NIH NIH RF1** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $2,475,013

## Abstract

This is a resubmission of a collaborative project between HIV and Alzheimer’s Disease (AD) laboratories to
investigate potential synergy between HIV infection and amyloid β (Aβ), a hallmark of AD, in promoting memory
impairment. Half of HIV patients on antiretroviral therapy develop neurocognitive impairments (NCI) despite low
HIV brain burdens. Age is the most consistent factor affecting NCI progression. We reproduced HIV-NCI
pathogenesis in conventional mice infected with EcoHIV, a mouse-tropic HIV. The Project MPI, Dr. Arancio,
reported that non-synaptotoxic doses of exogenous oligomeric Aβ (oAβ) and Tau, another AD hallmark,
cooperate in synaptic dysfunction and memory impairment in mice, suggesting that AD proteins have pathogenic
potential at their subclinical concentrations. Our revised preliminary results show such cooperation between
EcoHIV and oAβ in multiple formats including after EcoHIV infection of AD mouse models prior to their cognitive
decline. The models included transgenic APP/PS1 mouse model of familial AD (FAD) and two late onset AD
(LOAD) mouse models expressing humanized AD proteins. We propose that HIV and subclinical oAβ processes
cooperate in disrupting synaptic plasticity to exacerbate HIV-NCI beyond each agent alone. The Specific Aims
are to: 1) Characterize enhanced HIV-NCI pathogenesis in FAD and LOAD mouse models prior to onset of their
AD symptoms. (A) optimize the onset of memory deficits with EcoHIV infection in preclinical APP/PS1 mice; (B)
determine HIV-NCI severity at disease onset by infected APP/PS1 mice by hippocampal LTP, synaptodendritic
injury, apoptosis, APP processing, and amyloid pathology (C) Conduct similar studies by EcoHIV infection of
LOAD model mice expressing various humanized AD genes and select one LOAD model for further studies 2)
Using APP/PS1 mice and one LOAD strain, conduct next generation RNA sequencing (RNA-seq) in EcoHIV
infected mice upon reaching HIV disease state (A) generate transcriptome from hippocampus (HPC), prefrontal
cortex (PFC), and striatum (STR), and define biological processes specifically associated with memory defects
caused jointly by HIV and oAβ; B) confirm some gene modulation by RT-QPCR in HPC and STR extracts or by
immunostaining in brain section; and C) conduct limited nuclear-RNA-seq analysis in HPC to assign altered HIV-
oAβ processes/transcripts to specific cell types. 3) Study molecular mechanisms responsible for promoting HIV-
NCI pathogenesis in the setting of naturally produced subclinical levels of human oAβ in mice. (A) since both
HIV and Aβ disturb wnt signaling and cause dendritic pruning, examine how HIV infection of myeloid cells works
with Aβ in dysregulating Wnt function in dendritic integrity. B) since EcoHIV downmodulates CaMKII and CREB
in mice study potential Aβ-HIV convergence in oAβ dysregulation of the CREB role in synaptic strengthening.
Studies will include EcoHIV infection of moderate and late onset AD mice, tests of learning and memory,...

## Key facts

- **NIH application ID:** 10415699
- **Project number:** 1RF1NS119438-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** OTTAVIO ARANCIO
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,475,013
- **Award type:** 1
- **Project period:** 2022-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10415699

## Citation

> US National Institutes of Health, RePORTER application 10415699, Routes to enhanced HIV neuropathogenesis through expression of subclinical levels of endogenous amyloid-beta (1RF1NS119438-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10415699. Licensed CC0.

---

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