title: Alarmins and central nervous system inflammation in HIV-associated neurological disorders.
abstract: In the era of highly active antiretroviral therapy (HAART), HIV-1-associated neurocognitive disorders (HAND) persist in infected individuals with adequate immunological and virological status. Risk factors for cognitive impairment include hepatitis C virus co-infection, host genetic factors predisposing to HAND, the early establishment of the virus in the CNS and its persistence under HAART; thus, the CNS is an important reservoir for HIV. Microglial cells are permissive to HIV-1, and NLRP3 inflammasome-associated genes were found expressed in brains of HIV-1-infected persons, contributing to brain disease. Inflammasomes can be triggered by alarmins or danger-associated molecular patterns (DAMPs), which directly stimulate the production of proinflammatory mediators by glial cells, contribute to blood-brain barrier injury through induction of release of various proteases and allow the passage of infected macrophages, and trigger IL-1β release from primed cells. Amongst alarmins involved in HIV-1-induced neuropathogenesis, IL-33 and high-mobility group box 1 (HMGB1) are of particular interest. Neurocognitive alterations were recently associated with dysregulation of the IL-33/ST2 axis in the CNS, leading to the induction of neuronal apoptosis, decrease in synaptic function and neuroinflammation. Specific biomarkers, including HMGB1 and anti-HMGB1 antibodies, have been identified in cerebrospinal fluid from patients with HAND, correlated with immune activation and identifying a very early stage of neurocognitive impairment that precedes changes in metabolites detected by magnetic resonance spectroscopy. Moreover, HMGB1 plays a crucial role in HIV-1 persistence in dendritic cells and in the constitution of viral reservoirs. In this review, the mechanisms whereby alarmins contribute to HIV-1-induced CNS inflammation and neuropathogenesis will be discussed.
authors.affiliation: Institut Pasteur, Antiviral Immunity, Biotherapy and Vaccine Unit, Infection and Epidemiology Department, Paris, France.
authors.forename: M-L
authors.initials: ML
authors.lastname: Gougeon
mesh_terms: D000067531:Alarmins / Q000502:physiology*; D019380:Anti-HIV Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D002493:Central Nervous System Diseases / Q000276:immunology / Q000821:virology*; D002908:Chronic Disease; D004197:Disease Reservoirs; D015699:HIV Envelope Protein gp120 / Q000502:physiology; D015658:HIV Infections / Q000188:drug therapy / Q000209:etiology* / Q000276:immunology; D015497:HIV-1; D024243:HMGB1 Protein / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D058847:Inflammasomes / Q000502:physiology; D000067596:Interleukin-33 / Q000502:physiology; D009443:Neuritis / Q000276:immunology / Q000821:virology*; D019636:Neurodegenerative Diseases / Q000276:immunology / Q000821:virology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000502:physiology
chemical_list: D000067531:Alarmins; D019380:Anti-HIV Agents; D015415:Biomarkers; D015699:HIV Envelope Protein gp120; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D058847:Inflammasomes; D000067596:Interleukin-33; D054322:tat Gene Products, Human Immunodeficiency Virus
keywords: HAND; HIV-1; HMGB1; IL-33; alarmins