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Journal of Virology, November 1998, p. 9045-9053, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Neuronal Death Induced by Brain-Derived Human Immunodeficiency Virus Type 1 Envelope Genes Differs between Demented and Nondemented AIDS Patients

C. Power,1,2,* J. C. McArthur,3,4 A. Nath,5 K. Wehrly,6 M. Mayne,1 J. Nishio,6 T. Langelier,1 R. T. Johnson,3 and B. Chesebro6

Departments of Medical Microbiology1 and Internal Medicine,2 University of Manitoba, Winnipeg, Manitoba R3E 0W3, Canada; Departments of Neurology3 and Epidemiology,4 Johns Hopkins University, Baltimore, Maryland 21287; Department of Neurology, University of Kentucky, Lexington, Kentucky 405365; and Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 598406

Received 12 March 1998/Accepted 28 July 1998

Human immunodeficiency virus type 1 (HIV-1) infection of the brain results in viral replication primarily in macrophages and microglia. Despite frequent detection of viral genome and proteins in the brains of AIDS patients with and without HIV dementia, only 20% of AIDS patients become demented. To investigate the role of viral envelope gene variation in the occurrence of dementia, we examined regions of variability in the viral envelope gene isolated from brains of AIDS patients. Brain-derived HIV-1 V1-V2 envelope sequences from seven demented and six nondemented AIDS patients displayed significant sequence differences between clinical groups, and by phylogenetic analysis, sequences from the demented group showed clustering. Infectious recombinant viruses containing brain-derived V3 sequences from both clinical groups were macrophagetropic, and viruses containing brain-derived V1, V2, and V3 sequences from both clinical groups spread efficiently in macrophages. In an indirect in vitro neurotoxicity assay using supernatant fluid from HIV-1-infected macrophages, recombinant viruses from demented patients induced greater neuronal death than viruses from nondemented patients. Thus, the HIV-1 envelope diversity observed in these patient groups appeared to influence the release of neurotoxic molecules from macrophages and might account in part for the variability in occurrence of dementia in AIDS patients.

* Corresponding author. Present address: Department of Clinical Neurosciences, University of Calgary, 107-3330 Hospital Dr., Calgary, Alberta T2N 4N1, Canada. Phone: (403) 220-5011. Fax: (403) 283-8731. E-mail: power{at}ucalgary.ca.

Journal of Virology, November 1998, p. 9045-9053, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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