Extracellular vesicles produced by HIV-1 Nef-expressing cells induce myelin impairment and oligodendrocyte damage in the mouse central nervous system

Authors

Jessica K. Schenck, School of Medicine and Health Sciences, The George Washington University, 2300 I St NW, Ross Hall 624, Washington, DC, 20037, USA.
Molly T. Karl, School of Medicine and Health Sciences, The George Washington University, 2300 I St NW, Ross Hall 624, Washington, DC, 20037, USA.
Cheryl Clarkson-Paredes, School of Medicine and Health Sciences, The George Washington University, 2300 I St NW, Ross Hall 624, Washington, DC, 20037, USA.
Ashley Bastin, School of Medicine and Health Sciences, The George Washington University, 2300 I St NW, Ross Hall 624, Washington, DC, 20037, USA.
Tatiana Pushkarsky, School of Medicine and Health Sciences, The George Washington University, 2300 I St NW, Ross Hall 624, Washington, DC, 20037, USA.
Beda Brichacek, School of Medicine and Health Sciences, The George Washington University, 2300 I St NW, Ross Hall 624, Washington, DC, 20037, USA.
Robert H. Miller, School of Medicine and Health Sciences, The George Washington University, 2300 I St NW, Ross Hall 624, Washington, DC, 20037, USA.
Michael I. Bukrinsky, School of Medicine and Health Sciences, The George Washington University, 2300 I St NW, Ross Hall 624, Washington, DC, 20037, USA. mbukrins@gwu.edu.

Document Type

Journal Article

Publication Date

5-13-2024

Journal

Journal of neuroinflammation

Volume

21

Issue

1

DOI

10.1186/s12974-024-03124-5

Keywords

Astrocyte; Extracellular vesicles; HAND; HIV-1; Microglia; Myelin; Nef; Oligodendrocyte

Abstract

HIV-associated neurocognitive disorders (HAND) are a spectrum of cognitive impairments that continue to affect approximately half of all HIV-positive individuals despite effective viral suppression through antiretroviral therapy (ART). White matter pathologies have persisted in the ART era, and the degree of white matter damage correlates with the degree of neurocognitive impairment in patients with HAND. The HIV protein Nef has been implicated in HAND pathogenesis, but its effect on white matter damage has not been well characterized. Here, utilizing in vivo, ex vivo, and in vitro methods, we demonstrate that Nef-containing extracellular vesicles (Nef EVs) disrupt myelin sheaths and inflict damage upon oligodendrocytes within the murine central nervous system. Intracranial injection of Nef EVs leads to reduced myelin basic protein (MBP) staining and a decreased number of CC1 + oligodendrocytes in the corpus callosum. Moreover, cerebellar slice cultures treated with Nef EVs exhibit diminished MBP expression and increased presence of unmyelinated axons. Primary mixed brain cultures and enriched oligodendrocyte precursor cell cultures exposed to Nef EVs display a decreased number of O4 + cells, indicative of oligodendrocyte impairment. These findings underscore the potential contribution of Nef EV-mediated damage to oligodendrocytes and myelin maintenance in the pathogenesis of HAND.

APA Citation

Schenck, Jessica K.; Karl, Molly T.; Clarkson-Paredes, Cheryl; Bastin, Ashley; Pushkarsky, Tatiana; Brichacek, Beda; Miller, Robert H.; and Bukrinsky, Michael I., "Extracellular vesicles produced by HIV-1 Nef-expressing cells induce myelin impairment and oligodendrocyte damage in the mouse central nervous system" (2024). GW Authored Works. Paper 4937.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/4937

Department

Microbiology, Immunology, and Tropical Medicine