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Journal of Virology, December 2008, p. 12126-12144, Vol. 82, No. 24
0022-538X/08/$08.00+0     doi:10.1128/JVI.01146-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus Forms a Multimolecular Complex of Integrins ({alpha}Vβ5, {alpha}Vβ3, and {alpha}3β1) and CD98-xCT during Infection of Human Dermal Microvascular Endothelial Cells, and CD98-xCT Is Essential for the Postentry Stage of Infection{triangledown}

Mohanan Valiya Veettil,1 Sathish Sadagopan,1 Neelam Sharma-Walia,1 Fu-Zhang Wang,2 Hari Raghu,1 Laszlo Varga,1 and Bala Chandran1*

H. M. Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois,1 Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina—Chapel Hill, Chapel Hill, North Carolina2

Received 2 June 2008/ Accepted 23 September 2008

Kaposi's sarcoma-associated herpesvirus (KSHV) interacts with cell surface heparan sulfate (HS) and {alpha}3β1 integrin during the early stages of infection of human dermal microvascular endothelial cells (HMVEC-d) and human foreskin fibroblasts (HFF), and these interactions are followed by virus entry overlapping with the induction of preexisting host cell signal pathways. KSHV also utilizes the amino acid transporter protein xCT for infection of adherent cells, and the xCT molecule is part of the cell surface heterodimeric membrane glycoprotein CD98 (4F2 antigen) complex known to interact with {alpha}3β1 and {alpha}Vβ3 integrins. KSHV gB mediates adhesion of HMVEC-d, CV-1, and HT-1080 cells and HFF via its RGD sequence. Anti-{alpha}V and -β1 integrin antibodies inhibited the cell adhesion mediated by KSHV-gB. Variable levels of neutralization of HMVEC-d and HFF infection were observed with antibodies against {alpha}Vβ3 and {alpha}Vβ5 integrins. Similarly, variable levels of inhibition of virus entry into adherent HMVEC-d, 293 and Vero cells, and HFF was observed by preincubating virus with soluble {alpha}3β1, {alpha}Vβ3, and {alpha}Vβ5 integrins, and cumulative inhibition was observed with a combination of integrins. We were unable to infect HT1080 cells. Virus binding and DNA internalization studies suggest that {alpha}Vβ3 and {alpha}Vβ5 integrins also play roles in KSHV entry. We observed time-dependent temporal KSHV interactions with HMVEC-d integrins and CD98/xCT with three different patterns of association and dissociation. Integrin {alpha}Vβ5 interaction with CD98/xCT predominantly occurred by 1 min postinfection (p.i.) and dissociated at 10 min p.i., whereas {alpha}3β1-CD98/xCT interaction was maximal at 10 min p.i. and dissociated at 30 min p.i., and {alpha}Vβ3-CD98/xCT interaction was maximal at 10 min p.i. and remained at the observed 30 min p.i. Fluorescence microscopy also showed a similar time-dependent interaction of {alpha}Vβ5-CD98. Confocal-microscopy studies confirmed the association of CD98/xCT with {alpha}3β1 and KSHV. Preincubation of KSHV with soluble heparin and {alpha}3β1 significantly inhibited this association, suggesting that the first contact with HS and integrin is an essential element in subsequent CD98-xCT interactions. Anti-CD98 and xCT antibodies did not block virus binding and entry and nuclear delivery of viral DNA; however, viral-gene expression was significantly inhibited, suggesting that CD98-xCT play roles in the post-entry stage of infection, possibly in mediating signal cascades essential for viral-gene expression. Together, these studies suggest that KSHV interacts with functionally related integrins ({alpha}Vβ3, {alpha}3β1, and {alpha}Vβ5) and CD98/xCT molecules in a temporal fashion to form a multimolecular complex during the early stages of endothelial cell infection, probably mediating multiple roles in entry, signal transduction, and viral-gene expression.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064. Phone: (847) 578-8822. Fax: (847) 578-3349. E-mail: bala.chandran{at}rosalindfranklin.edu

{triangledown} Published ahead of print on 1 October 2008.

Journal of Virology, December 2008, p. 12126-12144, Vol. 82, No. 24
0022-538X/08/$08.00+0     doi:10.1128/JVI.01146-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Raghu, H., Sharma-Walia, N., Veettil, M. V., Sadagopan, S., Chandran, B. (2009). Kaposi's Sarcoma-Associated Herpesvirus Utilizes an Actin Polymerization-Dependent Macropinocytic Pathway To Enter Human Dermal Microvascular Endothelial and Human Umbilical Vein Endothelial Cells. J. Virol. 83: 4895-4911 [Abstract] [Full Text]  


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