The B-Oligomer of Pertussis Toxin Deactivates CC Chemokine Receptor 5 and Blocks Entry of M-tropic HIV-1 Strains

doi:10.1084/jem.190.5.597

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© The Rockefeller University Press, 0022-1007/1999/9/597/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 5, September 6, 1999 597-606

The B-Oligomer of Pertussis Toxin Deactivates CC Chemokine Receptor 5 and Blocks Entry of M-tropic HIV-1 Strains

Massimo Alfano^a, Helena Schmidtmayerova^a,b, Carol-Ann Amella^a, Tatiana Pushkarsky^a, and Michael Bukrinsky^a
^a From The Picower Institute for Medical Research, Manhasset, New York 11030
^b Institute of Virology, Slovak Academy of Sciences, 842 46 Bratislava, Slovakia

Correspondence to: Michael Bukrinsky, The Picower Institute for Medical Research, 350 Community Dr., Manhasset, NY 11030. Tel:516-365-4200 Fax:516-365-5090 E-mail:mbukrinsky{at}picower.edu.

Infection of target cells by HIV-1 requires initial bindinginteractions between the viral envelope glycoprotein gp120,the cell surface protein CD4, and one of the members of theseven-transmembrane G protein–coupled chemokine receptorfamily. Most primary isolates (R5 strains) use chemokine receptorCCR5, but some primary syncytium-inducing, as well as T cellline–adapted, strains (X4 strains) use the CXCR4 receptor.Signaling from both CCR5 and CXCR4 is mediated by pertussistoxin (PTX)-sensitive G_i proteins and is not required for HIV-1entry. Here, we show that the PTX holotoxin as well as its bindingsubunit, B-oligomer, which lacks G_i-inhibitory activity, blockedentry of R5 but not X4 strains into primary T lymphocytes. Interestingly,B-oligomer inhibited virus production by peripheral blood mononuclearcell cultures infected with either R5 or X4 strains, indicatingthat it can affect HIV-1 replication at both entry and post-entrylevels. T cells treated with B-oligomer did not initiate signaltransduction in response to macrophage inflammatory protein(MIP)-1ß or RANTES (regulated upon activation, normalT cell expressed and secreted); however, cell surface expressionof CCR5 and binding of MIP-1ß or HIV-1 to such cells werenot impaired. The inhibitory effect of B-oligomer on signalingfrom CCR5 and on entry of R5 HIV-1 strains was reversed by proteinkinase C (PKC) inhibitors, indicating that B-oligomer activityis mediated by signaling events that involve PKC. B-oligomeralso blocked cocapping of CCR5 and CD4 induced by R5 HIV-1 inprimary T cells, but did not affect cocapping of CXCR4 and CD4after inoculation of the cultures with X4 HIV-1. These resultssuggest that the B-oligomer of PTX cross-deactivates CCR5 toimpair its function as a coreceptor for HIV-1.

Key Words: CCR5, signal transduction, G_i protein, receptor capping, receptordesensitization

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