# Leveraging Directly Reprogrammed Human Neurons to Investigate the Molecular Impact of Age and Distinct Antiretroviral Therapies in Individuals Living with HIV-1

> **NIH NIH R21** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $214,500

## Abstract

PROJECT SUMMARY/ABSTRACT
Despite advances in clinical care, people living with HIV-1 (PLWH) on long-term antiretroviral therapy (ART) still
present with cognitive and behavioral deficits and the prevalence of HIV-1 associated neurocognitive disorders
(HANDs) is 30%-50%. The mechanisms underlying HIV-induced central nervous system (CNS) dysfunction in
these patients are complex, multifactorial and difficult to study using current methods. In this proposal, we will
investigate modifiable mechanistic pathways of neuronal aging in HIV-1 using physiologically relevant,
participant-derived cell models. In recent years, the ability to generate directly induced neurons (iNs) from
patient-derived fibroblasts has been demonstrated. Unlike the immature neuronal populations generated from
induced pluripotent stem cells (iPSCs), iNs retain neuron-specific, aging-associated gene-expression
characteristics of the donor. As a result, these iNs represent a major technological advance. Our preliminary
data demonstrates our ability to generate iNs from the skin biopsies of PLWH. To our knowledge, this makes us
the first group to apply this technology to study of neuronal health in HIV-1. We now propose to use these tools
to determine if differences in gene expression reflective of accelerated age- and/or additional HIV disease-
associated transcriptional signatures are evident through the transcriptional phenotyping of iNs derived from
age-matched young and older HIV-negative and HIV-positive cohorts. Functional analyses of the iNs will test
hypothesized pathomechanisms of neuronal aging. A growing body of scientific evidence also suggests that
antiretroviral drugs (ARVs) widely used in HIV-1 therapy and known to cross the blood-brain barrier to varying
degrees may have class- and/or drug-specific deleterious effects on neuronal health. We therefore, in
exploratory secondary analyses, hypothesize that there are potentially modifiable, mechanistic pathways of
neuronal injury in HIV-1 that are also ARV class dependent. We will investigate our hypotheses in two specific
aims. In AIM 1, we will generate patient-derived iNs from clinically well-characterized participants. We will
generate iNs as per Mertens et al. (Cell Stem Cell, 2015) from the skin biopsies of 6 clinically well-defined cohorts
stratified by age, HIV-1 status and use of protease-inhibitor (PI)- versus Integrase strand
transfer inhibitor (INSTI)-based ART. In AIM 2, we will determine neuronal-associated gene-expression
pathways modulated by age, HIV-1 status and cART usage through transcriptional profiling of iNs from well-
defined clinical cohorts. Differential gene expression analysis will be performed across cohorts in attempts to
determine, age (old vs. young), and in secondary exploratory analyses, HIV-1 (positive vs. negative) and ARV
(PI vs. INSTI) effects on gene transcription. We will then determine if age-dependent nucleocytoplasmic
compartmentalization (NCC) impairments characterize iNs from ...

## Key facts

- **NIH application ID:** 10414084
- **Project number:** 5R21AG071433-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Teresa Evering
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $214,500
- **Award type:** 5
- **Project period:** 2021-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10414084

## Citation

> US National Institutes of Health, RePORTER application 10414084, Leveraging Directly Reprogrammed Human Neurons to Investigate the Molecular Impact of Age and Distinct Antiretroviral Therapies in Individuals Living with HIV-1 (5R21AG071433-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10414084. Licensed CC0.

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