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Journal of Virology, May 2004, p. 4720-4729, Vol. 78, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.9.4720-4729.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Herpes Simplex Virus JMP Mutant Enters Receptor-Negative J Cells through a Novel Pathway Independent of the Known Receptors nectin1, HveA, and nectin2

Francesca Cocchi,1 Laura Menotti,1 Valentina Di Ninni,1 Marc Lopez,2 and Gabriella Campadelli-Fiume1*

Department of Experimental Pathology, Section on Microbiology and Virology, University of Bologna, Bologna, Italy,1 Institute of Cancerology, UMR 599, INSERM, Marseille, France2

Received 7 August 2003/ Accepted 24 January 2004

The herpes simplex virus type 1(JMP) [HSV-1(JMP)] mutant was selected for its ability to grow and form plaques in receptor-negative J cells. It enters J cells through a novel gD-dependent pathway, independent of all known HSV receptors, nectin1, nectin2, and HveA. Evidence that the pathway is dependent on a nectin3 binding site on HSV-1(JMP) and requires three mutations in gD rests on the following. We derived monoclonal antibodies to nectin3 and show that J cells express nectin3. HSV-1(JMP) entry and cell-to-cell spread were inhibited by soluble nectin3-Fc, demonstrating that virions carry a binding site for nectin3. The site is either directly involved in HSV-1(JMP) entry, or nectin3 binding to its site affects the gD domains involved in entry (entry site). HSV-1(JMP) entry and cell-to-cell spread in J cells were also inhibited by soluble nectin1-Fc, showing that the nectin1 binding site on gDJMP overlaps with the entry site or that nectin1 binding to gD affects the entry site. gDJMP carries three mutations, S140N, R340H, and Q344R. The latter two lie in the C tail and are present in the parental HSV-1(MP). HSV-1 strain R5000 carrying the S140N substitution was not infectious in J cells, indicating that this substitution was not sufficient. We constructed two recombinants, one carrying the three substitutions and the other carrying the two C-tail substitutions. Only the first recombinant infected J cells with an efficiency similar to that of HSV-1(JMP), indicating that the three mutations are required for the novel entry pathway. The results highlight plasticity in gD which accounts for changes in receptor usage.

* Corresponding author. Mailing address: Department of Experimental Pathology, Section on Microbiology and Virology, University of Bologna, Via San Giacomo, 12-40126 Bologna, Italy. Phone: 39 051 2094733. Fax: 39 051 2094735. E-mail: gabriella.campadelli{at}unibo.it.

Journal of Virology, May 2004, p. 4720-4729, Vol. 78, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.9.4720-4729.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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