PrPC, the cellular isoform of the human prion protein, is a novel biomarker of HIV-associated neurocognitive impairment and mediates neuroinflammation.
Of the 33 million people infected with the human immunodeficiency virus (HIV) worldwide, 40-60% of individuals will eventually develop neurocognitive sequelae that can be attributed to the presence of HIV-1 in the central nervous system (CNS) and its associated neuroinflammation despite antiretroviral therapy. PrP(C) (protease resistant protein, cellular isoform) is the nonpathological cellular isoform of the human prion protein that participates in many physiological processes that are disrupted during HIV-1 infection. However, its role in HIV-1 CNS disease is unknown. We demonstrate that PrP(C) is significantly increased in both the CNS of HIV-1-infected individuals with neurocognitive impairment and in SIV-infected macaques with encephalitis. PrP(C) is released into the cerebrospinal fluid, and its levels correlate with CNS compromise, suggesting it is a biomarker of HIV-associated neurocognitive impairment. We show that the chemokine (c-c Motif) Ligand-2 (CCL2) increases PrP(C) release from CNS cells, while HIV-1 infection alters PrP(C) release from peripheral blood mononuclear cells. Soluble PrP(C) mediates neuroinflammation by inducing astrocyte production of both CCL2 and interleukin 6. This report presents the first evidence that PrP(C) dysregulation occurs in cognitively impaired HIV-1-infected individuals and that PrP(C) participates in the pathogenesis of HIV-1-associated CNS disease.
Roberts
Toni K
TK
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Eugenin
Eliseo A
EA
Morgello
Susan
S
Clements
Janice E
JE
Zink
M Christine
MC
Berman
Joan W
JW
D000328:Adult; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism*; D001927:Brain Diseases / Q000209:etiology / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2; D003072:Cognition Disorders / Q000209:etiology* / Q000378:metabolism; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism; D008254:Macaca nemestrina; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000150:complications / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000472:pathogenicity
D015415:Biomarkers; D018932:Chemokine CCL2; D018621:PrPC Proteins; D011994:Recombinant Proteins