2. Academic Validation
  3. Inhibiting Glycan Degradation Prevents HIV-Induced Inflammaging and Cognitive Impairment

Inhibiting Glycan Degradation Prevents HIV-Induced Inflammaging and Cognitive Impairment

  • bioRxiv. 2025 Nov 17:2025.11.17.688839. doi: 10.1101/2025.11.17.688839.
Leila B Giron 1 2 3,  Alejandra Borjabad 4,  Eran Hadas 4,  Janeway Granche 5,  Erika G Marques de Menezes 6 7,  Thomas A Premeaux 8,  Hongxia He 4,  Stephen T Yeung 8,  Shalini Singh 1 2 3,  Courtney Friday 8,  Joshua Glover 9,  Eric Balboa 9,  Derrick Dopkin 9,  Michelle Burrows 9,  Anthony Secreto 9,  Nicolas Skuli 9,  Hiroaki Tateno 10,  Paul W Denton 11,  Frank Palella 1 3,  Michael J Corley 12,  Lishomwa C Ndhlovu 8,  Philip J Norris 6 7 13,  Katherine Tassiopoulos 5,  David J Volsky 4,  Mohamed Abdel-Mohsen 1 2 3
Affiliations

Affiliations

  • 1 Division of Infectious Diseases, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
  • 2 Center for Human Immunobiology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
  • 3 Potocsnak Longevity Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
  • 4 Icahn School of Medicine at Mount Sinai, New York, NY; USA.
  • 5 Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
  • 6 Vitalant Research Institute, San Francisco, CA, USA.
  • 7 Department of Laboratory Medicine, University of California, San Francisco, CA, USA.
  • 8 Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
  • 9 University of Pennsylvania, Philadelphia, PA, USA.
  • 10 Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.
  • 11 University of Nebraska Omaha, Omaha, NE, USA.
  • 12 University of California San Diego, San Diego, CA, USA.
  • 13 Department of Medicine, University of California, San Francisco, CA, USA.
PMID: 41332691 DOI: 10.1101/2025.11.17.688839
Abstract

Cognitive impairment is a frequent outcome of chronic viral infections linked to premature aging, including HIV. The mechanisms underlying this decline remain poorly understood. Here, we identify pro-inflammatory glycan degradation, characterized by loss of sialic acid and galactose, alterations that are hallmarks of premature aging, as key contributors to HIV-associated cognitive impairment (HIV-CI). In two independent cohorts of people living with HIV, these degradative changes were enriched in individuals with cognitive impairment, particularly females, and correlated with worse cognitive performance. In both a humanized mouse model of HIV and Eco-HIV, a complementary model that allows behavioral testing, pharmacological inhibition of glycan degradation with sialidase inhibitors prevented virally induced inflammation, immune activation, accelerated aging, and memory deficits. These findings implicate glycan degradation as a contributor to inflammation and cognitive impairment in HIV and highlight glycan-preserving therapies as a promising strategy to mitigate inflammation, premature aging, and cognitive decline during viral infections.

Keywords

HIV-associated cognitive impairment (HIV-CI); biological aging; glycosylation; neuroinflammation; sialidase inhibitors.

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