# Role of PERK haplotypes in HIV-Associated Neurocognitive Disorders

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $522,061

## Abstract

HIV-Associated Neurocognitive Disorder (HAND) continues to affect ~50% of HIV(+) patients despite widespread
implementation of antiretroviral therapy (ART) and successful viral suppression. Several risk factors including
older age, low nadir CD4+ cell count, metabolic syndrome, depression and hepatitis C co-infection associate with
HAND. Early interventions and complete viral suppression are most likely to improve neurocognitive (NC)
prognosis; the Mind Exchange Program recommends consideration of risk factors for diagnosis and treatment
within the first six months. Many of the mechanisms implicated in HAND persistence, including unremitting CNS
viral replication, age-related pathologies, comorbidities (e.g., drug abuse, ART-associated toxicities) can induce
the unfolded protein response (UPR), which results in activation of one or more of the 3 initiators, PERK, ATF6,
and IRE1α, when cellular stressors disrupt their binding to the chaperone, binding protein (BiP), with wide
ranging consequences. Most pertinent here is PERK-mediated phosphorylation of eukaryotic translation initiation
factor 2α (eIF2α) slows global translation, while selectively enhancing translation of a subset of genes including
the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). Chronic and/or sustained UPR activation
may have detrimental outcomes, supported by multiple studies. Consistently, UPR is implicated in several
neurodegenerative diseases, including Alzheimer and Parkinson. We previously showed UPR activation in
HAND prefrontal cortex. Based on multiple lines of evidence from in vitro and in vivo models of HIV-induced
neurodegeneration, suggesting that the dysregulation of the PERK arm of the UPR pathway may be contributing
to HIV- as well as antiretroviral-mediated neurodegenerative processes, we propose a role for PERK
dysregulation as a mechanism for the continuing neuronal perturbations still observed in HAND patients despite
ART’s success. We propose that PERK activation contributes to HAND development, and a genetic variant
of PERK with increased activity is a predictive risk factor for HAND. In this application, we will examine
whether a protein-coding PERK haplotype resulting from three single nucleotide polymorphisms (SNPs), which
may confer increased kinase activity, may underlie the alteration/s of PERK’s protein function and/or changes in
its amount. We will determine: 1) the mechanisms of PERK-mediated neurotoxicity in vitro, 2) the mechanisms
of PERK-mediated neuronal injury in a preclinical rodent model of HIV-induced synaptic damage, gliosis and
behavioral/cognitive deficits, and 3) the associations between PERK genetic haplotype and/or expression with
HAND risk in human adults.

## Key facts

- **NIH application ID:** 9962163
- **Project number:** 5R01MH109382-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Kelly L Jordan-Sciutto
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $522,061
- **Award type:** 5
- **Project period:** 2016-07-16 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962163

## Citation

> US National Institutes of Health, RePORTER application 9962163, Role of PERK haplotypes in HIV-Associated Neurocognitive Disorders (5R01MH109382-05). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9962163. Licensed CC0.

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