title: Molecular and pathologic insights from latent HIV-1 infection in the human brain.
abstract: OBJECTIVE
  We aimed to investigate whether HIV latency in the CNS might have adverse molecular, pathologic, and clinical consequences.
  
  
  METHODS
  This was a case-control comparison of HIV-1 seropositive (HIV+) patients with clinical and neuropathologic examination. Based on the levels of HIV-1 DNA, RNA, and p24 in the brain, cases were classified as controls, latent HIV CNS infection, and HIV encephalitis (HIVE). Analysis of epigenetic markers including BCL11B, neurodegeneration, and neuroinflammation was performed utilizing immunoblot, confocal microscopy, immunochemistry/image analysis, and qPCR. Detailed antemortem neurocognitive data were available for 23 out of the 32 cases.
  
  
  RESULTS
  HIV+ controls (n = 12) had no detectable HIV-1 DNA, RNA, or p24 in the CNS; latent HIV+ cases (n = 10) showed high levels of HIV-1 DNA but no HIV RNA or p24; and HIVE cases (n = 10) had high levels of HIV-1 DNA, RNA, and p24. Compared to HIV+ controls, the HIV+ latent cases displayed moderate cognitive impairment with neurodegenerative and neuroinflammatory alterations, although to a lesser extent than HIVE cases. Remarkably, HIV+ latent cases showed higher levels of BCL11B and other chromatin modifiers involved in silencing. Increased BCL11B was associated with deregulation of proinflammatory genes like interleukin-6, tumor necrosis factor-α, and CD74.
  
  
  CONCLUSIONS
  Persistence of latent HIV-1 infection in the CNS was associated with increased levels of chromatin modifiers, including BCL11B. Alteration of these epigenetic factors might result in abnormal transcriptomes, leading to inflammation, neurodegeneration, and neurocognitive impairment. BCL11B and other epigenetic factors involved in silencing might represent potential targets for HIV-1 involvement of the CNS.
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Desplats
authors.forename: Wilmar
authors.initials: W
authors.lastname: Dumaop
authors.forename: David
authors.initials: D
authors.lastname: Smith
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Ian
authors.initials: I
authors.lastname: Everall
authors.forename: Scott
authors.initials: S
authors.lastname: Letendre
authors.forename: Ronald
authors.initials: R
authors.lastname: Ellis
authors.forename: Mariana
authors.initials: M
authors.lastname: Cherner
authors.forename: Igor
authors.initials: I
authors.lastname: Grant
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000328:Adult; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D016022:Case-Control Studies; D005260:Female; D016655:HIV Core Protein p24 / Q000378:metabolism*; D015658:HIV Infections / Q000473:pathology*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; C479740:BCL11B protein, human; C527276:CXCR4 protein, human; D016655:HIV Core Protein p24; D000949:Histocompatibility Antigens Class II; D054298:Human Immunodeficiency Virus Proteins; D015850:Interleukin-6; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D012097:Repressor Proteins; C569014:SYP protein, human; D016708:Synaptophysin; D025521:Tumor Suppressor Proteins; C045084:invariant chain