HIV-1 Tat-induced VAPB disruption initiates a cascade of organellar failures culminating in neuronal lipid accumulation.

Overview

Authors: Maryline Santerre¹, Sterling P Arjona¹, Kathy Q Cai², Natalia Shcherbik³, Bassel E Sawaya^1,4,5

ORCID iDs: Maryline Santerre, Sterling P Arjona, Bassel E Sawaya

FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine - Temple University, Philadelphia, PA, USA
Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA, USA
Department of Cell and Molecular Biology, School of Osteopathic Medicine, Rowan University, Stratford, NJ, USA
Department of Cancer and Cellular Biology, Lewis Katz School of Medicine - Temple University, Philadelphia, PA, USA
Department of Neural Sciences, Lewis Katz School of Medicine - Temple University, Philadelphia, PA, USA

Institutions: Temple University (United States); Fox Chase Cancer Center (United States); Rowan University (United States)

Journal: Journal of lipid research, volume 67, issue 6, article 101053

Dates: received 15 February 2026; published online 4 May 2026; in print June 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1016/j.jlr.2026.101053 · PMID 42092489 · PMCID PMC13234481 · OpenAlex W7160247700

Open access: gold, a free copy (OpenAlex)

Status: code on request

Categories: human (organism), other condition (population), stroke (population), cellular / molecular (subfield)

Methods: Statistics, Evoked potentials

Keywords: HIV-1 Tat, VAPB, triglycerides, lipid droplets, stroke, HAND, mitochondria-ER contacts

MeSH: HIV-1*, Lipid Metabolism*, Neurons*, tat Gene Products, Human Immunodeficiency Virus*, Humans, Mitochondria, Vesicular Transport Proteins (* major topic)

Topic: HIV Research and Treatment (Virology, Immunology and Microbiology), according to OpenAlex

Funding: National Institutes of Health; National Institute on Aging (AG054411); National Institute of Mental Health (MH093331); National Institute of Neurological Disorders and Stroke (NS076402); NIGMS NIH HHS (R01 GM114308)

Citations: not cited yet (Europe PMC); 72 references in the paper

Abstract

People living with HIV develop persistent neurocognitive impairment despite viral suppression through incompletely defined mechanisms. HIV-1 Tat disrupts VAPB-PTPIP51 coupling at mitochondria-associated ER membranes via PTPIP51 tyrosine phosphorylation, causing VAPB relocalization away from MAMs, a causal mechanism established in our prior work. Here, we define the downstream metabolic consequences and establish VAPB as the critical determinant of neuronal lipid pathology. Lipidomic profiling identified triglycerides as the dominant altered species, comprising polyunsaturated forms normally destined for membrane synthesis or mitochondrial oxidation, consistent with membrane catabolism rather than de novo lipogenesis. Targeted metabolomics revealed bioenergetic collapse consistent with impaired mitochondrial oxidative function. The resulting lipid imbalance, including lipid droplet accumulation, produced secondary organellar dysfunction, including Golgi dispersal and ER stress. Critically, Tat failed to induce lipid droplet accumulation in shRNA-VAPB cells, while PTPIP51 silencing had no such protective effect, establishing that VAPB relocalization is the obligate trigger. Guanosine supplementation reduced lipid droplet accumulation, suggesting a link to bioenergetic failure that warrants further investigation. In postmortem HIV-infected frontal cortex, VAPB was paradoxically elevated yet correlated with worsening dementia severity, consistent with transcriptional upregulation that cannot overcome posttranslational blockade of VAPB-MAM localization. The polyunsaturated triglycerides, depleted plasmalogens, and elevated ceramides documented here closely parallel lipid signatures reported in PLWH with cerebrovascular complications, implicating Tat-driven lipid dysregulation as a candidate mechanism for the incompletely explained elevation in stroke risk in this population.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

No dataset and no data link were found in the paper.

Data availability

Raw lipidomics and metabolomics data, image files, and analysis scripts are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 7 keywords, 7 MeSH terms, 5 funders, 72 references.

Cite

This paper

Santerre, M., Arjona, S. P., Cai, K. Q., Shcherbik, N., & Sawaya, B. E. (2026). HIV-1 Tat-induced VAPB disruption initiates a cascade of organellar failures culminating in neuronal lipid accumulation. Journal of lipid research, 67(6), 101053. https://doi.org/10.1016/j.jlr.2026.101053

BibTeX

@article{santerre2026hiv, author = {Santerre, Maryline and Arjona, Sterling P and Cai, Kathy Q and Shcherbik, Natalia and Sawaya, Bassel E}, title = {{HIV-1 Tat-induced VAPB disruption initiates a cascade of organellar failures culminating in neuronal lipid accumulation}}, journal = {Journal of lipid research}, year = {2026}, month = may, volume = {67}, number = {6}, pages = {101053}, publisher = {American Society for Biochemistry and Molecular Biology}, issn = {0022-2275}, doi = {10.1016/j.jlr.2026.101053}, url = {https://doi.org/10.1016/j.jlr.2026.101053}, pmid = {42092489}, pmcid = {PMC13234481} }

RIS

TY - JOUR AU - Santerre, Maryline AU - Arjona, Sterling P AU - Cai, Kathy Q AU - Shcherbik, Natalia AU - Sawaya, Bassel E TI - HIV-1 Tat-induced VAPB disruption initiates a cascade of organellar failures culminating in neuronal lipid accumulation T2 - Journal of lipid research J2 - J Lipid Res PY - 2026 DA - 2026/05/04 VL - 67 IS - 6 SP - 101053 SN - 0022-2275 PB - American Society for Biochemistry and Molecular Biology DO - 10.1016/j.jlr.2026.101053 UR - https://doi.org/10.1016/j.jlr.2026.101053 LA - en ER -

CSL-JSON

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