Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy.
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.
Langford
T Dianne
TD
Department of Pathology, University of California, San Diego, CA, USA.
Letendre
Scott L
SL
Marcotte
Thomas D
TD
Ellis
Ronald J
RJ
McCutchan
J Allen
JA
Grant
Igor
I
Mallory
Margaret E
ME
Hansen
Lawrence A
LA
Archibald
Sarah
S
Jernigan
Terry
T
Masliah
Eliezer
E
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
D012367:RNA, Viral