Liver-specific Expression of HIV-1 Viral Protein R Causes Hepatic Steatosis and Glucose Intolerance in Male Mice

Authors

Neeti Agarwal
Pradip Saha
Claudia E Ramirez Bustamante
Sean M Hartig
Mark A Herman
Ashok Balasubramanyam
Jordan E Lake

Language

English

Publication Date

10-1-2025

Journal

Journal of the Endocrine Society

DOI

10.1210/jendso/bvaf132

PMID

40980543

PMCID

PMC12445674

PubMedCentral® Posted Date

8-22-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized in people with HIV (PWH), with both HIV and antiretroviral therapy contributing to liver damage and glucose intolerance. However, the role of viral proteins derived from reservoirs in this process remains unclear.

Methods: Adeno-associated virus (AAV) constructs encoding a control protein or HIV-1 viral protein R (Vpr) driven by the thyroxine-binding globulin promoter were administered to male mice (n = 5 per group) fed regular chow or a high-fat diet (HFD). Young adult mice underwent intraperitoneal glucose tolerance testing and magnetic resonance imaging, followed by euthanasia. Liver and adipose tissues were analyzed for mRNA expression, lipid levels, and fat content and plasma samples for triglycerides and liver function.

Results: AAV-Vpr mice on HFD developed exacerbated hepatic steatosis, glucose intolerance, and systemic inflammation compared to AAV-green fluorescent protein control mice. Gene expression indicated enhanced de novo lipogenesis, diminished lipid oxidation and insulin resistance in the liver. These effects were distinct from those observed with HFD alone, confirming a Vpr-specific contribution.

Conclusion: Vpr upregulates the hepatic synthesis of fatty acids and downregulates their oxidation and export as triglycerides. The liver-specific activity of Vpr is sufficient, in synergy with a HFD, to cause hepatic steatosis and impaired glucose tolerance. These findings define a tissue-autonomous role for Vpr in mediating hepatic steatosis in mice, with implications for MASLD development and its complications in PWH.

Keywords

metabolic dysfunction-associated steatotic liver disease, MASLD, Vpr, metabolism, mice, adipose tissue

Published Open-Access

yes

Recommended Citation

Agarwal, Neeti; Saha, Pradip; Ramirez Bustamante, Claudia E; et al., "Liver-specific Expression of HIV-1 Viral Protein R Causes Hepatic Steatosis and Glucose Intolerance in Male Mice" (2025). Faculty and Staff Publications. 4073.
https://digitalcommons.library.tmc.edu/baylor_docs/4073