Increased atherosclerosis in HIV-infected humanized mice is caused by a single viral protein, Nef

Yongsen Wang, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Beda Brichacek, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Larisa Dubrovsky, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Tatiana Pushkarsky, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Kyle Korolowicz, Departments of Oncology and Radiology, Lombardi Comprehensive Cancer Center and Center for Translational Research, Georgetown University Medical Center, Washington, DC, USA.
Olga Rodriguez, Departments of Oncology and Radiology, Lombardi Comprehensive Cancer Center and Center for Translational Research, Georgetown University Medical Center, Washington, DC, USA.
Yichien Lee, Departments of Oncology and Radiology, Lombardi Comprehensive Cancer Center and Center for Translational Research, Georgetown University Medical Center, Washington, DC, USA.
Marta Catalfamo, Georgetown University Medical Center, Washington DC, USA.
Chris Albanese, Departments of Oncology and Radiology, Lombardi Comprehensive Cancer Center and Center for Translational Research, Georgetown University Medical Center, Washington, DC, USA.
Anastas Popratiloff, GW Nanofabrication and Imaging Center, The George Washington University, Washington, DC, USA.
Dmitri Sviridov, Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia.
Michael Bukrinsky, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.

Document Type

Journal Article

Publication Date

4-16-2025

Journal

The Journal of infectious diseases

DOI

10.1093/infdis/jiaf192

Keywords

HIV; Nef; PCSK9; atherosclerosis; humanized mice; inflammation; spectral confocal imaging

Abstract

Antiretroviral therapy (ART) suppresses HIV replication, reverses immunodeficiency, and reduces AIDS-related symptoms, but non-AIDS co-morbidities like cardiovascular diseases remain a major challenge for people living with HIV (PLWH). The pathogenic mechanisms driving these co-morbidities are poorly understood. We previously showed that the HIV protein Nef contributes to chronic inflammation in PLWH. Here, we explored Nef's role in HIV-associated atherosclerosis using a novel model: HIV-infected humanized mice expressing a gain-of-function mutant of proprotein convertase subtilisin/kexin type 9 (PCSK9) and fed a high-fat diet. Comparing atherosclerosis in uninfected mice to those infected with Nef-positive or Nef-deficient HIV-1, we found that Nef exacerbates atherosclerotic changes by increasing inflammation. These results identify Nef as a key driver of HIV-related atherosclerosis and provide a platform for testing therapeutic interventions targeting Nef to mitigate cardiovascular risks in PLWH.

Department

Biochemistry and Molecular Medicine

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