Five leading herpesvirus research laboratories improve and use the reagents and methodologies of SMEs, thus providing the basis for novel product development, validation and marketing in the future, and a foundation for the SMEs in the commercial development of successful treatments and methodologies.

The aim of TargetHerpes is to identify novel targets and develop innovative intervention strategies to control infection of the human herpesviruses, namely HSV, HCMV and HHV-8. Management of disease causing principles, between different persisting pathogens, will enable the successful approaches of TargetHerpes to be adapted for therapy of infections caused by other major pathogens like retroviruses, mycobacteria or other intracellular parasites.

In order to achieve this objective, the following unresolved methodological and experimental aspects of herpesvirus will be addressed.

Rationale

There is a clear and increasing need for improved treatments for herpesvirus (HV) infections in order to improve human health and decrease the economic burden that result from herpesvirus disease. These viruses cause some cancers and many other diseases varying from afflictions of moderate severity that none-the-less can cause extended morbidity, to serious infections that are life-threatening. A main characteristic of herpesvirus infections is that after primary infection (usually in childhood), the viruses establish a latent state that remains for life. Up to 90 percent of the population may be latently infected with one or more herpesviruses, such as herpes simplex virus (HSV) types 1 and 2, varicella zoster virus (VZV), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV) and, to a lesser extent, human herpesvirus-8 (HHV-8). Although latent herpesvirus infections in healthy adults are usually asymptomatic, reactivation of virus from latency can cause severe disease, particularly in immuno-suppressed patients such as transplant recipients, and those with AIDS and other immunodeficiency states. In these cases, the herpesvirus infection can often result in fulminant, life-threatening or debilitating acute diseases as well as tumors that can be very difficult to treat

The social and psychological consequences of severe, frequently reactivating HSV infections should not be underestimated. Genital HSV-2 infection represents a serious problem in pregnant women because of the risk of fatal, serious or long-term debilitating disease in the newborn infant. To prevent neonatal herpes, women in Western Europe are routinely subjected to Ceasarean sections, with consequent personal and social impact, increased risks at delivery, and high health costs. HSV-1 can cause retinitis that results in blindness and the rejection of corneal grafts, and when an infection spreads to the brain the resulting encephalitis is frequently fatal. HCMV is also a major threat to infants because congenital infections cause a serious risk of birth defects: about 1% of newborn babies in Western Europe are infected, and at least 10% of these suffer severe and irreversible damage (hearing loss, microcephaly, intracerebral calcifications, retinitis, liver defects). The number of adversely affected children in western societies is clearly higher than that resulting from better known childhood diseases like fetal alcohol syndrome, Down’s syndrome, Spina bifida, HIV/AIDS or congenital rubella. With one exception, VZV, there are no vaccines available to date that prevent herpesvirus infections.

There is increasing evidence that HCMV can contribute to vascular diseases such as atherosclerosis and restenosis following coronary angioplasty, and the possibility that this virus acts as a co-factor for certain cancers is the subject of much on-going research. EBV and HHV-8 infections are linked to a number of human cancers, (e.g., certain lymphomas and the Kaposi sarcoma, respectively), especially in the immuno-compromised and patients with AIDS.

Current antiherpesvirus treatments utilise inhibitors of viral enzymes, especially the viral DNA polymerases. Although this approach is effective in the case of HSV, it is less so in other herpesvirus infections and completely ineffective against tumors caused by latent infections. Congenital herpesvirus infections, e.g. due to HCMV, lack any therapeutic option since teratogenic side effects of standard antiviral drugs rule out their use during pregnancy. The constant risk of viruses gaining resistance to the drugs that are currently in use necessitates the development of novel strategies to treat virus diseases. TargetHerpes intends to take two approaches to develop novel anti-viral treatments: firstly, the use of siRNAs to identify viral proteins and/or cellular proteins that are required for efficient virus infection; secondly, the use of antagonistic or mimetic peptides to disrupt protein-protein interactions. The ultimate goal of the consortium is the development of novel antiviral compounds that can be further developed into antiviral drugs. The initial work planned for the three years’ duration of this STREP will result in the identification of new targets and lead substances (peptides, siRNAs) that will be tested in cell culture systems and then applied in small animal models, thus providing a new basis for advanced preclinical and clinical drug development and validation in future projects.
The TargetHerpes project encompasses three SMEs whose missions are to research and develop state-of-the-art biotechnology products and services, plus five leading European laboratories in different fields of herpes virology.