We have undertaken a study of Herpes Simplex Virus (HSV) from two perspectives: 1) as a biologicall significant probe of the immune system and specifically the T cell response, and 2) as a target of immune intervention in the infectious process. To this end, we have examined the fine specificity of T cells reactive to the N-terminal f23 amino acids of glycoprotein D (gD) of HSV. We show that the B10.A class II restricted T cell response is highly MHC degenerate, a finding identical to the T cell response to cytochrome c, and give evidence for functional interaction of peptide-Ia- and the cell receptor (TcR). We propose to clone and sequnce both alpha and beta chain TcR genes to examine the hypothesis that beta chain is responsible for recognition of MHC and alpha chain is responsible for recognition of antigen. We have also observed that the N-terminal gD 1-23 peptide when attached to palmitic acid and incorporated into liposomes, confers long term protection to BALB/c mice from a lethal HSV challenge. Adoptive transfer studies initially indicated that Lyt 2+ T cells and not antibody are responsible. However, we have recently identified an L3T4+ T cell population which can also transfer full protection. We are presently examining the fine specificity and functioning of these cells. We are interested in the role of lipid in these studies. The unmodified 1-23 peptide can induce class II restricted proliferative T cells, however it cannot induce protection. The lipid-coupled peptide confers protection and is also able to induce class I restricted Lyt 2+ proliferative and cytotoxic T cells. Thus, we feel that we may have identified a third site, besides the agretope and epitope, for induction of lyt 2+ cells. Further studies are in order. Finally, we are interested in the role of immunodominance in T cell responsiveness and protection from disease. The 1-23 peptide stimulates T cells and induces a protective responsse to HSV. However, this is not an immunodominant determinant. Using recombinant gD to immunize mice and contiguous synthetic peptides (20 mers) along the whole length of the gD molecule to stimulate T cells these animals in vitro, we have edentified determinnts which are dominant. We will assess the role of dominant determinants in terms of protective ability and have had peptides synthesized which are coupled to palmitic acid and of the same sequence as those used for proliferation.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunobiology Study Section (IMB)
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Wistar Institute
United States
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