# Tat endolysosome escape and HAND

> **NIH NIH R01** · UNIVERSITY OF NORTH DAKOTA · 2020 · $352,500

## Abstract

Project Abstract
Antiretroviral therapeutic (ART) drugs have greatly increased the lifespan of people living with HIV-1/AIDS.
However, these same people experience ~50% prevalence rates of HIV-1 associated neurocognitive disorders
(HAND). Increasingly noted in HIV-1 infected individuals are clinical manifestations and pathological features of
Alzheimer’s disease (AD) including cognitive impairment, increased levels of amyloid beta protein (Aβ),
increased levels of phosphorylated tau protein (p-tau), and synaptic dysfunction. Not only is the pathogenesis
of HAND unclear, but relatively little is known about the extent to which HIV-1, HIV-1 proteins, and/or ART
drugs act as “aging and AD accelerators”. The objective for this Alzheimer’s-focused Administrative
Supplement (NOT-AG-20-008) is to determine the extent to which and mechanisms by which HIV-1 Tat protein
contributes to the development of AD-like pathology. Our central hypothesis is that HIV-1 Tat interacts with the
SLC38A9 arginine sensor in endolysosomes, promotes the disassembly of the v-ATPase proton pump in
endolysosomes, and causes AD-like pathology. Guided by our preliminary findings, this novel hypothesis will
be tested by pursuing two specific aims. (1) Determine the extent to which and mechanisms by which Tat
causes v-ATPase disassembly. (2) Determine the extent to which and mechanisms by which Tat induced v-
ATPase disassembly causes AD-like pathology in primary cultured neurons. The proposed studies here will
explore novel mechanisms whereby Tat induces disassembly of v-ATPase via a lysosome arginine sensor,
and we will focus on how Tat-induced disassembly of v-ATPase contributes to AD-like pathogenesis. Further,
we expect that promoting the assembly of v-ATPase will attenuate Tat-induced AD-like pathology. The
proposed studies are within the scope of the awarded R01 (MH119000-01) that is focused not on AD or its
related dementias, but rather an involvement of v-ATPase in Tat endolysosome escape and HAND. Results of
the proposed studies will not only lead to novel mechanistic insights into the co-pathogenesis of HAND and
AD, but also provide rationale for developing endolysosome-acidifying agents as novel therapeutic strategies.

## Key facts

- **NIH application ID:** 10094719
- **Project number:** 3R01MH119000-02S1
- **Recipient organization:** UNIVERSITY OF NORTH DAKOTA
- **Principal Investigator:** Xuesong Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,500
- **Award type:** 3
- **Project period:** 2020-07-24 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10094719

## Citation

> US National Institutes of Health, RePORTER application 10094719, Tat endolysosome escape and HAND (3R01MH119000-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10094719. Licensed CC0.

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