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Immunodominant Epitopes in Herpes Simplex Virus Type 2 Glycoprotein D Are Recognized by CD4 Lymphocytes from Both HSV-1 and HSV-2 Seropositive Subjects¹

Min Kim^*, Janette Taylor^*, John Sidney, Zorka Mikloska^*, Neil Bodsworth, Katerina Lagios, Heather Dunckley^¶, Karen Byth-Wilson^||, Martine Denis^#, Robert Finlayson, Rajiv Khanna^**, Alessandro Sette and Anthony L. Cunningham^2,*

^* Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales and University of Sydney, New South Wales, Australia; La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; Taylor Square Private Clinic, Darlinghurst, New South Wales, Australia; Parramatta Sexual Health Clinic, Parramatta, New South Wales, Australia; ^¶ Australian Red Cross Blood Service, Sydney, New South Wales, Australia; ^|| Westmead Hospital, Westmead, New South Wales, Australia; ^# GlaxoSmithKline Biologicals, Rixensart, Belgium; and ^** Queensland Institute of Medical Research, Herston, Queensland, Australia

In human recurrent cutaneous herpes simplex, there is a sequential infiltrate of CD4 and then CD8 lymphocytes into lesions. CD4 lymphocytes are the major producers of the key cytokine IFN- in lesions. They recognize mainly structural proteins and especially glycoproteins D and B (gD and gB) when restimulated in vitro. Recent human vaccine trials using recombinant gD showed partial protection of HSV seronegative women against genital herpes disease and also, in placebo recipients, showed protection by prior HSV1 infection. In this study, we have defined immunodominant peptide epitopes recognized by 8 HSV1⁺ and/or 16 HSV2⁺ patients using ⁵¹Cr-release cytotoxicity and IFN- ELISPOT assays. Using a set of 39 overlapping 20-mer peptides, more than six immunodominant epitopes were defined in gD2 (two to six peptide epitopes were recognized for each subject). Further fine mapping of these responses for 4 of the 20-mers, using a panel of 9 internal 12-mers for each 20-mers, combined with MHC II typing and also direct in vitro binding assay of these peptides to individual DR molecules, showed more than one epitope per 20-mers and promiscuous binding of individual 20-mers and 12-mers to multiple DR types. All four 20-mer peptides were cross-recognized by both HSV1⁺/HSV2^– and HSV1^–/HSV2⁺ subjects, but the sites of recognition differed within the 20-mers where their sequences were divergent. This work provides a basis for CD4 lymphocyte cross-recognition of gD2 and possibly cross-protection observed in previous clinical studies and in vaccine trials.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Health and Medical Research Council of Australia (Project Grant 253684 and Program Grant 358399).

² Address correspondence and reprint request to Prof. Anthony L. Cunningham, Westmead Millennium Institute, Darcy Road, Westmead, New South Wales 2145, Australia. E-mail address: tony_cunningham{at}wmi.usyd.edu.au

³ Abbreviations used in this paper: gD, glycoprotein D; gD1, gD of HSV1; gD2, gD of HSV2; LCL, lymphoblastoid cell line.