Microbial molecule ingress promotes neuroinflammation and brain CCR5 expression in persons with HIV-associated neurocognitive disorders

William G Branton; Jason P Fernandes; Nazanin Mohammadzadeh; Mathew A L Doan; Jon D Laman; Benjamin B Gelman; Zahra Fagrouch; Ivanela Kondova; Petra Mooij; Gerrit Koopman; Christopher Power

doi:10.1016/j.bbi.2022.09.019

Microbial molecule ingress promotes neuroinflammation and brain CCR5 expression in persons with HIV-associated neurocognitive disorders

Brain Behav Immun. 2023 Jan:107:110-123. doi: 10.1016/j.bbi.2022.09.019. Epub 2022 Oct 3.

Authors

Affiliations

¹ Departments of Medicine, University of Alberta, Edmonton, AB, Canada.
² Medical Microbiology & Immunology, University of Alberta, Edmonton, AB, Canada.
³ Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada.
⁴ Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, Netherlands.
⁵ Departments of Pathology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.
⁶ Department of Virology and Animal Science Department, Biomedical Primate Research Centre, Rijswijk, Netherlands.
⁷ Departments of Medicine, University of Alberta, Edmonton, AB, Canada; Medical Microbiology & Immunology, University of Alberta, Edmonton, AB, Canada; Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada. Electronic address: chris.power@ualberta.ca.

PMID: 36202168
DOI: 10.1016/j.bbi.2022.09.019

Abstract

Background: Systemic inflammation accompanies HIV-1 infection, resulting in microbial translocation from different tissues. We investigated interactions between lentivirus infections, neuroinflammation and microbial molecule presence in the brain.

Methods: Brain tissues from adult humans with (n = 22) and without HIV-1 (n = 11) infection as well as adult nonhuman primates (NHPs) with (n = 11) and without (n = 4) SIV_mac251 infection were investigated by RT-PCR/ddPCR, immunofluorescence and western blotting. Studies of viral infectivity, host immune gene expression and viability were performed in primary human neural cells.

Findings: Among NHPs, SIV DNA quantitation in brain showed increased levels among animals with SIV encephalitis (n = 5) that was associated with bacterial genomic copy number as well as CCR5 and CASP1 expression in brain. Microbial DnaK and peptidoglycan were immunodetected in brains from uninfected and SIV-infected animals, chiefly in glial cells. Human microglia infected by HIV-1 showed increased p24 production after exposure to peptidoglycan that was associated CCR5 induction. HIV-1 Vpr application to human neurons followed by peptidoglycan exposure resulted in reduced mitochondrial function and diminished beta-III tubulin expression. In human brains, bacterial genome copies (250-550 copies/gm of tissue), were correlated with increased bacterial rRNA and GroEL transcript levels in patients with HIV-associated neurocognitive disorders (HAND). Glial cells displayed microbial GroEL and peptidoglycan immunoreactivity accompanied by CCR5 induction in brains from patients with HAND.

Interpretation: Increased microbial genomes and proteins were evident in brain tissues from lentivirus-infected humans and animals and associated with neurological disease. Microbial molecule translocation into the brain might exacerbate neuroinflammatory disease severity and represent a driver of lentivirus-associated brain disease.

Keywords: CCR5; Glia; HIV-1; Neuroinflammation; Peptidoglycan; SIV.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Brain
HIV Infections* / complications
HIV*
Humans
Neurocognitive Disorders
Neuroinflammatory Diseases
Receptors, CCR5 / genetics

Substances

CCR5 protein, human
Receptors, CCR5

Abstract

Publication types

MeSH terms

Substances

Grants and funding