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Journal of Virology, February 1999, p. 897-906, Vol. 73, No. 2
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Apoptosis Induced by Infection of Primary Brain
Cultures with Diverse Human Immunodeficiency Virus Type 1 Isolates:
Evidence for a Role of the Envelope
Asa
Ohagen,1,2
Sajal
Ghosh,3
Jianglin
He,1,2
Karen
Huang,1
Youzhi
Chen,1,2
Menglan
Yuan,4
Rapin
Osathanondh,5
Suzanne
Gartner,6
Bin
Shi,1,2
George
Shaw,3 and
Dana
Gabuzda1,7,*
Department of Cancer Immunology & AIDS,
Dana-Farber Cancer Institute,1
Departments of Pathology2 and
Neurology,7 Harvard Medical School,
Division of Neuroscience, Children's Hospital Medical
Center,4 and
Department of
Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard
Medical School,5 Boston, Massachusetts;
Department of Medicine, University of Alabama, Birmingham,
Alabama3; and
Department of
Neurology, Johns Hopkins University, Baltimore,
Maryland6
Received 2 June 1998/Accepted 15 October 1998
Apoptosis of neurons and astrocytes is induced by human
immunodeficiency type 1 (HIV-1) infection in vitro and has been
demonstrated in brain tissue from patients with AIDS. We analyzed a
panel of diverse HIV-1 primary isolates for the ability to replicate
and induce neuronal and astrocyte apoptosis in primary human brain cultures. Apoptosis was induced three- to eightfold by infection with
the blood-derived HIV-1 isolates 89.6, SG3, and ADA. In contrast, the
brain-derived HIV-1 isolates YU2, JRFL, DS-br, RC-br, and KJ-br did not
induce significant levels of apoptosis. The ability of HIV-1 isolates
to induce apoptosis was independent of their replication capacity.
Studies of recombinant chimeras between the SG3 and YU2 viruses showed
that replacement of the YU2 Env with the SG3 Env was sufficient to
confer the ability to induce apoptosis to the YU2 virus. Replacement of
the Env V3 regions alone largely conferred the phenotypes of the
parental clones. The SG3 Env used CXCR4 and CCR3 as coreceptors for
virus entry, whereas YU2 used CCR5 and CCR3. The V3 regions of SG3 and
YU2 conferred the ability to use CXCR4 and CCR5, respectively. In contrast, the 3' region of Env, particularly the C3V4 region, was
required in conjunction with the V3 region for efficient use of CCR3.
These results provide evidence that Env is a major determinant of
neurodegenerative mechanisms associated with HIV-1 infection in vitro
and raise the possibility that blood-derived viruses which emerge
during the late stages of disease may affect disease progression in the
central nervous system.
*
Corresponding author. Mailing address: Dana-Farber
Cancer Institute, JFB712, 44 Binney St., Boston, MA 02115. Phone: (617) 632-2154. Fax: (617) 632-3113. E-mail:
dana_gabuzda{at}dfci.harvard.edu.
Journal of Virology, February 1999, p. 897-906, Vol. 73, No. 2
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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