Herpesviruses cause ubiquitous infections that usually remain latent, but can be reactivated and progress to life-threatening disease in patients with compromised immune systems, (e.g. transplant patients, AIDS patients, and patients receiving chemotherapy/radiation). In particular, a clinical need exists for effective treatment of human cytomegalovirus (HCMV), a beta- herpesvirus, where currently used anti-viral drugs are limited by toxicity, efficacy, and viral resistance. This project seeks to develop a novel immunotherapeutic treatment for HCMV infection using the recently discovered cytokine LIGHT. Preliminary experiments have demonstrated that LIGHT is structurally related to lymphotoxin alpha and beta and tumor necrosis factor (TNF) and that picomolar amounts of LIGHT can inhibit the spread of clinical isolates of HCMV in cultured dermal fibroblasts by a non- apoptotic mechanism. LIGHT can also potentiate cellular immune responses, but does not display the acute proinflammatory activities typically associated with the interferons and TNF that have limited their clinical usefulness. The goal of this phase I period, is to establish the in vivo efficacy of LIGHT as an antiviral immunotherapeutic using murine CMV infection as a disease model. Distinct mouse strains that mimic immune- compromised conditions will be employed to aid in targeting the most appropriate patient populations for future clinical trials.
The development of an effective anti-viral immunotherapeutic treatment for CMV infection will provide a much needed alternative to currently used anti-viral drugs, the effectiveness of which is limited by toxicity and viral resistance. LIGHT immunotherapy may prove beneficial for several different patient populations including transplant recipients, AIDS patients, and individuals undergoing chemotherapy/radiation.
| Benedict, C A; Banks, T A; Senderowicz, L et al. (2001) Lymphotoxins and cytomegalovirus cooperatively induce interferon-beta, establishing host-virus detente. Immunity 15:617-26 |
