The CC-chemokine RANTES increases the attachment of human immunodeficiency virus type 1 to target cells via glycosaminoglycans and also activates a signal transduction pathway that enhances viral infectivity.
We have studied the mechanisms by which the CC-chemokine RANTES can enhance the infectivities of human immunodeficiency virus type 1 (HIV-1) and other enveloped viruses, when present at concentrations in excess of 500 ng/ml in vitro. Understanding the underlying mechanisms might throw light on fundamental processes of viral infection, in particular for HIV-1. Our principal findings are twofold: firstly, that oligomers of RANTES can cross-link enveloped viruses, including HIV-1, to cells via glycosaminoglycans (GAGs) present on the membranes of both virions and cells; secondly, that oligomers of RANTES interact with cell-surface GAGs to transduce a herbimycin A-sensitive signal which, over a period of several hours, renders the cells more permissive to infection by several viruses, including HIV-1. The enhancement mechanisms require that RANTES oligomerize either in solution or following binding to GAGs, since no viral infectivity enhancement is observed with a mutant form of the RANTES molecule that contains a single-amino-acid change (glutamic acid to serine at position 66) which abrogates oligomerization.
The Aaron Diamond AIDS Research Center, New York University School of Medicine, New York, USA. atrkola@adarc.org
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A
Trkola
C
C
Gordon
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J
Matthews
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Maxwell
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Ketas
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Czaplewski
A E
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Proudfoot
J P
JP
Moore
D000818:Animals; D016466:CHO Cells; D002459:Cell Fusion; D018946:Chemokine CCL5 / Q000378:metabolism*; D006224:Cricetinae; D006025:Glycosaminoglycans / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D015728:Receptors, HIV / Q000378:metabolism*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014771:Virion
D018946:Chemokine CCL5; D006025:Glycosaminoglycans; D015728:Receptors, HIV