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PMID: 9696841 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Influence of the CCR2-V64I polymorphism on human immunodeficiency virus type 1 coreceptor activity and on chemokine receptor function of CCR2b, CCR3, CCR5, and CXCR4.

Journal of virology ·Vol. 72 ·No. 9 ·1998-09-00 ·Pages 7450-8

Lee B, Doranz BJ, Rana S, Yi Y, Mellado M, Frade JM, Martinez-A C, O'Brien SJ, Dean M, Collman RG, Doms RW

Abstract

The chemokine receptors CCR5 and CXCR4 are used by human immunodeficiency virus type 1 (HIV-1) in conjunction with CD4 to infect cells. In addition, some virus strains can use alternative chemokine receptors, including CCR2b and CCR3, for infection. A polymorphism in CCR2 (CCR2-V64I) is associated with a 2- to 4-year delay in the progression to AIDS. To investigate the mechanism of this protective effect, we studied the expression of CCR2b and CCR2b-V64I, their chemokine and HIV-1 coreceptor activities, and their effects on the expression and receptor activities of the major HIV-1 coreceptors. CCR2b and CCR2b-V64I were expressed at similar levels, and neither molecule affected the expression or coreceptor activity of CCR3, CCR5, or CXCR4 in cotransfected cell lines. Peripheral blood mononuclear cells (PBMCs) from CCR2-V64I heterozygotes had normal levels of CCR2b and CCR5 but slightly reduced levels of CXCR4. CCR2b and CCR2b-V64I functioned equally well as HIV-1 coreceptors, and CCR2-V64I PBMCs were permissive for HIV-1 infection regardless of viral tropism. The MCP-1-induced calcium mobilization mediated by CCR2b signaling was unaffected by the polymorphism, but MCP-1 signaling mediated by either CCR2b- or CCR2-V64I-encoded receptors resulted in heterologous desensitization (i.e., limiting the signal response of other receptors) of both CCR5 and CXCR4. The heterologous desensitization of CCR5 and CXCR4 signaling by both CCR2 allele receptor types provides a mechanistic link that might help explain the in vivo effects of CCR2 gene variants on progression to AIDS as well as the reported antiviral activity of natural CCR2 ligands.

MeSH Terms
Cell Line, Transformed HIV-1/metabolism Humans Isoleucine/metabolism Polymorphism, Genetic Receptors, CCR2 Receptors, CCR3 Receptors, CCR5/biosynthesis,metabolism Receptors, CXCR4/biosynthesis,metabolism Receptors, Chemokine/biosynthesis,metabolism Receptors, Cytokine/biosynthesis,metabolism Receptors, HIV/biosynthesis,metabolism Valine/metabolism
Chemicals
CCR2 protein, human CCR3 protein, human Receptors, CCR2 Receptors, CCR3 Receptors, CCR5 Receptors, CXCR4 Receptors, Chemokine Receptors, Cytokine Receptors, HIV Isoleucine Valine
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Lee B
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Doranz B J
Rana S
Yi Y
Mellado M
Frade J M
Martinez-A C
O'Brien S J
Dean M
Collman R G
Doms R W
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.72.9.7450-7458.1998
Published
1998-09-00
Pages
7450-8
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC109977
Subset
IM
Grants
NIAID NIH HHS · R01 AI035502 · United States
NIAID NIH HHS · R01 AI040880 · United States
PHS HHS · R01-40880 · United States
NIAID NIH HHS · R01-AI-35502 · United States
External Links
PubMed source DOI: 10.1128/JVI.72.9.7450-7458.1998 PMC Full Text View journal details
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