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PMID: 12021361 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Increased CCR5 affinity and reduced CCR5/CD4 dependence of a neurovirulent primary human immunodeficiency virus type 1 isolate.

Journal of virology ·Vol. 76 ·No. 12 ·2002-06-00 ·Pages 6277-92

Gorry PR, Taylor J, Holm GH, Mehle A, Morgan T, Cayabyab M, Farzan M, Wang H, Bell JE, Kunstman K, Moore JP, Wolinsky SM, Gabuzda D

Abstract

Most human immunodeficiency virus type 1 (HIV-1) viruses in the brain use CCR5 as the principal coreceptor for entry into a cell. However, additional phenotypic characteristics are necessary for HIV-1 neurotropism. Furthermore, neurotropic strains are not necessarily neurovirulent. To better understand the determinants of HIV-1 neurovirulence, we isolated viruses from brain tissue samples from three AIDS patients with dementia and HIV-1 encephalitis and analyzed their ability to induce syncytia in monocyte-derived macrophages (MDM) and neuronal apoptosis in primary brain cultures. Two R5X4 viruses (MACS1-br and MACS1-spln) were highly fusogenic in MDM and induced neuronal apoptosis. The R5 viruses UK1-br and MACS2-br are both neurotropic. However, only UK1-br induced high levels of fusion in MDM and neuronal apoptosis. Full-length Env clones from UK1-br required lower CCR5 and CD4 levels than Env clones from MACS2-br to function efficiently in cell-to-cell fusion and single-round infection assays. UK1-br Envs also had a greater affinity for CCR5 than MACS2-br Envs in binding assays. Relatively high levels of UK1-br and MACS2-br Envs bound to CCR5 in the absence of soluble CD4. However, these Envs could not mediate CD4-independent infection, and MACS2-br Envs were unable to mediate fusion or infection in cells expressing low levels of CD4. The UK1-br virus was more resistant than MACS2-br to inhibition by the CCR5-targeted inhibitors TAK-779 and Sch-C. UK1-br was more sensitive than MACS2-br to neutralization by monoclonal antibodies (2F5 and immunoglobulin G1b12 [IgG1b12]) and CD4-IgG2. These results predict the presence of HIV-1 variants with increased CCR5 affinity and reduced dependence on CCR5 and CD4 in the brains of some AIDS patients with central nervous system disease and suggest that R5 variants with increased CCR5 affinity may represent a pathogenic viral phenotype contributing to the neurodegenerative manifestations of AIDS.

MeSH Terms
AIDS Dementia Complex/virology Amino Acid Sequence Brain/virology CD4 Antigens/metabolism Encephalitis, Viral/virology Giant Cells/physiology HIV Envelope Protein gp160/chemistry,genetics HIV-1/isolation & purification,pathogenicity Humans Macrophages/virology Molecular Sequence Data Monocytes/virology Neurons/pathology,virology Organ Culture Techniques Receptors, CCR5/metabolism Virulence
Chemicals
CD4 Antigens HIV Envelope Protein gp160 Receptors, CCR5
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Gorry Paul R
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Taylor Joann
Holm Geoffrey H
Mehle Andrew
Morgan Tom
Cayabyab Mark
Farzan Michael
Wang Hui
Bell Jeanne E
Kunstman Kevin
Moore John P
Wolinsky Steven M
Gabuzda Dana
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/jvi.76.12.6277-6292.2002
Published
2002-06-00
Pages
6277-92
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC136234
Subset
IM
Grants
NINDS NIH HHS · NS35734 · United States
NIAID NIH HHS · P30 AI028691 · United States
NINDS NIH HHS · R01 NS035734 · United States
NIAID NIH HHS · AI41420 · United States
NCI NIH HHS · CA79458 · United States
NINDS NIH HHS · R01 NS037277 · United States
NIDA NIH HHS · DA13127 · United States
NINDS NIH HHS · NS37277 · United States
NIAID NIH HHS · AI28691 · United States
NIAID NIH HHS · R01 AI041420 · United States
NIAID NIH HHS · U01 AI35039 · United States
NIAID NIH HHS · U01 AI035039 · United States
Databases
GENBANK
AF491737, AF491738, AF491739, AF491740, AF491741, AF491742
External Links
PubMed source DOI: 10.1128/jvi.76.12.6277-6292.2002 PMC Full Text View journal details
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