title: Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy.
abstract: OBJECTIVE
  To describe a severe form of demyelinating HIV-associated leukoencephalopathy in AIDS patients failing highly active antiretroviral therapy (HAART), its relationship to clinical and neuroimaging findings, and suggest hypotheses regarding pathogenesis.
  
  
  METHODS
  AIDS patients who failed HAART and displayed severe leukoencephalopathy were included. All cases had detailed neuromedical, neuropsychological, neuroimaging and postmortem neuropathological examination. Immunocytochemical and PCR analyses were performed to determine brain HIV levels and to exclude other viruses.
  
  
  RESULTS
  Seven recent autopsy cases of leukoencephalopathy in antiretroviral-experienced patients with AIDS were identified. Clinically, all were severely immunosuppressed, six (86%) had poorly controlled HIV replication despite combination antiretroviral therapy, and five (71%) had HIV-associated dementia. Neuropathologically, all seven had intense perivascular infiltration by HIV-gp41 immunoreactive monocytes/macrophages and lymphocytes, widespread myelin loss, axonal injury, microgliosis and astrogliosis. The extent of damage exceeds that described prior to the use of HAART. Brain tissue demonstrated high levels of HIV RNA but evidence of other pathogens, such as JC virus, Epstein-Barr virus, cytomegalovirus, human herpes virus type-8, and herpes simplex virus types 1 and 2, was absent. Comparison of the stages of pathology suggests a temporal sequence of events. In this model, white matter damage begins with perivascular infiltration by HIV-infected monocytes, which may occur as a consequence of antiretroviral-associated immune restoration. Intense infiltration by immune cells injures brain endothelial cells and is followed by myelin loss, axonal damage, and finally, astrogliosis.
  
  
  CONCLUSIONS
  Taken together, our findings provide evidence for the emergence of a severe form of HIV-associated leukoencephalopathy. This condition warrants further study and increased vigilance among those who provide care for HIV-infected individuals.
authors.affiliation: Department of Pathology, University of California, San Diego, CA, USA.
authors.forename: T Dianne
authors.initials: TD
authors.lastname: Langford
authors.forename: Scott L
authors.initials: SL
authors.lastname: Letendre
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Marcotte
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Ellis
authors.forename: J Allen
authors.initials: JA
authors.lastname: McCutchan
authors.forename: Igor
authors.initials: I
authors.lastname: Grant
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Mallory
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Hansen
authors.forename: Sarah
authors.initials: S
authors.lastname: Archibald
authors.forename: Terry
authors.initials: T
authors.lastname: Jernigan
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D015526:AIDS Dementia Complex / Q000473:pathology; D000163:Acquired Immunodeficiency Syndrome / Q000150:complications / Q000188:drug therapy*; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D001921:Brain / Q000473:pathology* / Q000821:virology; D018791:CD4 Lymphocyte Count; D002555:Cerebrospinal Fluid / Q000821:virology; D003711:Demyelinating Diseases / Q000209:etiology* / Q000473:pathology; D018450:Disease Progression; D005911:Gliosis / Q000209:etiology / Q000473:pathology; D015497:HIV-1 / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000821:virology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000821:virology; D012367:RNA, Viral / Q000032:analysis; D017211:Treatment Failure; D019562:Viral Load; D014779:Virus Replication
chemical_list: D012367:RNA, Viral