Human Cytomegalovirus (huCMV) is a beta herpes virus which infects one half of the adult population and is a major cause of birth defects. CMV is also an important opportunistic pathogen which has clinical implications for immunocompromised individuals and transplant recipients. Epstein-Barr Virus (EBV) is a ubiquitous herpes virus that is usually acquired as an asymptomatic infection in all human communities. Whilst most of what is known about EBV biology relates to interaction with cells of the B lymphoid lineage, the virus can also infect epithelial cells. This interaction can result in malignant transformation since the virus is consistently associated with nasopharyngeal carcinoma (NPC) and with a proportion of gastric adenocarcinomas. The persistence and universal prevalence of huCMV and EBV indicates that both of these viruses have developed an evolutionary survival advantage. It is known that huCMV and EBV employ a number of mechanisms to switch off protective immune responses in infected hosts.

This has important implications for most standard immune based vaccine strategies which seek to elicit cell mediated immune responses in vivo. As these viruses have powerful mechanism to avoid such responses, a successful immunological targeting strategy must include ways of avoiding viral evasion mechanisms. The goal of my laboratory is to bypass huCMV and EBV mediated immune evasion by delivering single or groups of viral antigens to dendritic cells (DC) in a way which favors their meaningful presentation on MHC class I. This involves improving our understanding of the basic cell biology of DC and identifying the best vehicles for viral antigen delivery.

We are particularly interested in heat shock proteins (Hsp’s). Hsp’s are pro-inflammatory and remarkable for their ability to both activate the innate immune system and to exert specificity, which is derived from peptide binding. We find that as little as 200pM peptide bound to Mycobacterial HSP70 is sufficient to prime DC to generate cytotoxic T cells. We are currently exploring the receptors used by HSP70 to gain entry to the cell, the compartment where MHC class I is loaded and comparing the efficacy of HSP from different species.

Kemeny DM and MacAry PA (2007) Immunology : making magic bullets. Brit. Med. J. 334

Javid B, MacAry PA and Lehner PJ (2007)  Structure and function : heat shock proteins and adaptive immunity.  J. Immunol. 15:179:2035-2040

Floto AR, MacAry PA, Boname JM, Tan SM, Kampmann B, Hair JR, Oh SH, Houben ENG, Pieters J, Day C, Oehlmann W, Singh M, Smith KGC and Lehner PJ (2006) Dendritic cell stimulation by mycobacterial HSP70 is mediated through CCR5.  Sci. 314:454-458

Floto RA, Clatworthy MR, Heilbronn KR, Rosner DR, MacAry PA, Rankin A, Lehner PJ, Ouwehand WH, Allen JM, Watkins NA and Smith KG (2005) Loss of function of a lupus-associated FcgammaRIIb polymorphism through exclusion from lipid rafts. Nat. Med. 11:1056-1058

Reeves MB, MacAry PA, Lehner PJ, Sissons JGP and Sinclair JH (2005) Latency, Chromatin remodeling and reactivation of human cytomegalovirus in the dendritic cells of healthy carriers. Proc. Natl. Acad. 102:4140-4145

MacAry PA, Javid B, Floto RA, Smith KG, Oehlmann W, Singh M and Lehner PJ (2004) HSP70 peptide binding mutants separate antigen delivery from dendritic cell stimulation. Immunity. 1:95-106

Wang Y, Kelly CG, Karttunen JT, Whittall T, Lehner PJ, Duncan L, MacAry PA, Younson JS, Singh M, Oehlmann W, Cheng G, Bergmeier L and Lehner T (2001) CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of cc-chemokines. Immunity. 15:971-983

MacAry PA, Lindsay M, Scott MA, Craig JI, Luzio JP and Lehner PJ (2001) Mobilization of MHC class I molecules from late endosomes to the cell surface following activation of CD34-derived human Langerhans cells. Proc. Natl. Acad. Sci. 98:3982-3987

Huang TJ, MacAry PA, Eynott P, Moussavi A, Daniel KC, Askenase PW, Kemeny DM and Chung KF (2001) Allergen-specific Th1 cells counteract efferent Th2 cell-dependent bronchial hyperresponsiveness and eosinophilic inflammation partly via IFN-gamma. J. Immunol. 66:207-217