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, Sajal Ghosh, Jianglin He, Karen Huang, Youzhi Chen, Menglan Yuan, Rapin Osathanondh, Suzanne Gartner, Bin Shi, George Shaw, Dana Gabuzda

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Abstract

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.

Original languageEnglish
Pages (from-to)897-906
Number of pages10
JournalJournal of Virology
Volume73
Issue number2
StatePublished - 23 Jan 1999

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Human immunodeficiency virus 1
HIV-1
apoptosis
Apoptosis
brain
Brain
Infection
infection
viruses
astrocytes
Viruses
Astrocytes
HIV Infections
Virus Internalization
chimerism
immunosuppression
blood
disease course
central nervous system
Disease Progression

Cite this

Ohagen, Asa ; Ghosh, Sajal ; He, Jianglin ; Huang, Karen ; Chen, Youzhi ; Yuan, Menglan ; Osathanondh, Rapin ; Gartner, Suzanne ; Shi, Bin ; Shaw, George ; Gabuzda, Dana. / Apoptosis induced by infection of primary brain cultures with diverse human immunodeficiency virus type 1 isolates : Evidence for a role of the envelope. In: Journal of Virology. 1999 ; Vol. 73, No. 2. pp. 897-906.
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Ohagen, A, Ghosh, S, He, J, Huang, K, Chen, Y, Yuan, M, Osathanondh, R, Gartner, S, Shi, B, Shaw, G & Gabuzda, D 1999, 'Apoptosis induced by infection of primary brain cultures with diverse human immunodeficiency virus type 1 isolates: Evidence for a role of the envelope', Journal of Virology, vol. 73, no. 2, pp. 897-906.

Apoptosis induced by infection of primary brain cultures with diverse human immunodeficiency virus type 1 isolates : Evidence for a role of the envelope. / Ohagen, Asa; Ghosh, Sajal; He, Jianglin; Huang, Karen; Chen, Youzhi; Yuan, Menglan; Osathanondh, Rapin; Gartner, Suzanne; Shi, Bin; Shaw, George; Gabuzda, Dana.

In: Journal of Virology, Vol. 73, No. 2, 23.01.1999, p. 897-906.

Research output: Contribution to journalArticle

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AU - Ohagen, Asa

AU - Ghosh, Sajal

AU - He, Jianglin

AU - Huang, Karen

AU - Chen, Youzhi

AU - Yuan, Menglan

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AU - Shi, Bin

AU - Shaw, George

AU - Gabuzda, Dana

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N2 - 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.

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