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Journal of Virology, October 2007, p. 10970-10980, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.00998-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Inhibition of Transfer to Secondary Receptors by Heparan Sulfate-Binding Drug or Antibody Induces Noninfectious Uptake of Human Papillomavirus{triangledown}

Hans-Christoph Selinka,1,{dagger} Luise Florin,1,{dagger} Hetal D. Patel,2,{dagger} Kirsten Freitag,1 Michaela Schmidtke,3 Vadim A. Makarov,4 and Martin Sapp2*

Institute for Medical Microbiology and Hygiene, University of Mainz, Germany,1 Department of Microbiology and Immunology, Feist-Weiller Cancer Center, Center for Molecular Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, Louisiana,2 Institute of Virology and Antiviral Therapy, Friedrich Schiller University of Jena, Jena, Germany,3 State Scientific Center of the Russian Federation, and NIOPIK, Moscow, Russia4

Received 8 May 2007/ Accepted 30 July 2007

Infection with various human papillomaviruses (HPVs) induces cervical cancers. Cell surface heparan sulfates (HS) have been shown to serve as primary attachment receptors, and molecules with structural similarity to cell surface HS, like heparin, function as competitive inhibitors of HPV infection. Here we demonstrate that the N,N'-bisheteryl derivative of dispirotripiperazine, DSTP27, efficiently blocks papillomavirus infection by binding to HS moieties, with 50% inhibitory doses of up to 0.4 µg/ml. In contrast to short-term inhibitory effects of heparin, pretreatment of cells with DSTP27 significantly reduced HPV infection for more than 30 h. Using DSTP27 and heparinase, we furthermore demonstrate that HS moieties, rather than laminin 5, present in the extracellular matrix (ECM) secreted by keratinocytes are essential for infectious transfer of ECM-bound virions to cells. Prior binding to ECM components, especially HS, partially alleviated the requirement for cell surface HS. DSTP27 blocks infection by cell-bound virions by feeding into a noninfectious entry pathway. Under these conditions, virus colocalized with HS moieties in endocytic vesicles. Similarly, postattachment treatment of cells with heparinase, cytochalasin D, or neutralizing antibodies resulted in uptake of virions without infection, indicating that deviation into a noninfectious entry pathway is a major mode of postattachment neutralization. In untreated cells, initial colocalization of virions with HS on the cell surface and in endocytic vesicles was lost with time. Our data suggest that initial attachment of HPV to HS proteoglycans (HSPGs) must be followed by secondary interaction with additional HS side chains and transfer to a non-HSPG receptor for successful infection.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71115. Phone: 318 675 5760. Fax: 318 675 5764. E-mail: msapp1{at}lsuhsc.edu

{triangledown} Published ahead of print on 8 August 2007.

{dagger} H.-C.S., L.F., and H.D.P. contributed equally to the work.

Journal of Virology, October 2007, p. 10970-10980, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.00998-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Johnson, K. M., Kines, R. C., Roberts, J. N., Lowy, D. R., Schiller, J. T., Day, P. M. (2009). Role of Heparan Sulfate in Attachment to and Infection of the Murine Female Genital Tract by Human Papillomavirus. J. Virol. 83: 2067-2074 [Abstract] [Full Text]  
  • Day, P. M., Gambhira, R., Roden, R. B. S., Lowy, D. R., Schiller, J. T. (2008). Mechanisms of Human Papillomavirus Type 16 Neutralization by L2 Cross-Neutralizing and L1 Type-Specific Antibodies. J. Virol. 82: 4638-4646 [Abstract] [Full Text]  


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