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Journal of Virology, May 2007, p. 5294-5304, Vol. 81, No. 10
0022-538X/07/$08.00+0     doi:10.1128/JVI.02553-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Sphingomyelinase Restricts the Lateral Diffusion of CD4 and Inhibits Human Immunodeficiency Virus Fusion{triangledown}

Catherine M. Finnegan,1,{dagger} Satinder S. Rawat,1,{ddagger} Edward H. Cho,2 Danielle L. Guiffre,1 Stephen Lockett,2 Alfred H. Merrill Jr.,3 and Robert Blumenthal1*

Center for Cancer Research Nanobiology Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702,1 Image Analysis Laboratory, SAIC-Frederick, National Cancer Institute at Frederick, P.O. Box B, Frederick, Maryland 21702,2 School of Biology and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 303223

Received 20 November 2006/ Accepted 23 February 2007

Previously, we reported that treatment of cells with sphingomyelinase inhibits human immunodeficiency virus type 1 (HIV-1) entry. Here, we determined by measuring fluorescence recovery after photobleaching that the lateral diffusion of CD4 decreased 4-fold following sphingomyelinase treatment, while the effective diffusion rate of CCR5 remained unchanged. Notably, sphingomyelinase treatment of cells did not influence gp120 binding, HIV-1 attachment, or fluid-phase and receptor-mediated endocytosis. Furthermore, sphingomyelinase treatment did not affect the membrane disposition of the HIV receptor proteins CD4, CXCR4, and CCR5, as determined by Triton X-100 extraction. Restriction of CD4 diffusion by antibody cross-linking also inhibited HIV infection. We therefore interpret the decrease in CD4 lateral mobility following sphingomyelinase treatment in terms of clustering of CD4 molecules. Examination of fusion intermediates indicated that sphingomyelinase treatment inhibited HIV at a step in the fusion process after CD4 engagement. Maximal inhibition of fusion was observed following short coculture times and with target cells that express low levels of CD4. As HIV entry into cells requires the sequential engagement of viral envelope protein with CD4 and coreceptor, we propose that sphingomyelinase inhibits HIV infection by inducing CD4 clustering that prevents coreceptor engagement and HIV fusion.

* Corresponding author. Mailing address: P.O. Box B, Bldg. 469, Rm. 151, Miller Drive, Frederick, MD 21702-1201. Phone: (301) 846-5532. Fax: (301) 846-5598. E-mail: blumen{at}helix.nih.gov

{triangledown} Published ahead of print on 7 March 2007.

{dagger} Current address: Panacos Pharmaceuticals, Gaithersburg, MD.

{ddagger} Current address: Program in Gene Function and Expression, UMass Medical School, Worcester, MA 01605.

Journal of Virology, May 2007, p. 5294-5304, Vol. 81, No. 10
0022-538X/07/$08.00+0     doi:10.1128/JVI.02553-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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