Cytomegalovirus (CMV) infection is widespread and is usually asymptomatic. The virus establishes lifelong latency in the host and becomes a major pathogen when transmitted during pregnancy from mother to fetus, and in immunocompromised hosts. The risk of CMV disease is determined by multiple host and viral factors, but it is unknown whether specific CMV strains are more likely to reactivate and disseminate than others. Currently available antiviral therapies have decreased morbidity and mortality of CMV disease but are limited by toxicities and by variable efficacy in established disease. CMV vaccine is currently not available to prevent congenital infection or disease in immunocompromised hosts. We have been studying human CMV genes located in the UL/b'region of the virus (UL131-UL150). These genes are deleted in laboratory adapted strains but exist in all clinical isolates;therefore, thought to play a pathogenesis role in the host. Some of these genes encode for cytokines and chemokines that may interfere with host immune responses. We sequenced UL144 (TNF1 receptor gene), UL146 and UL147 (1 chemokine genes) from multiple human samples, and defined their polymorphisms. We also showed in two cohort studies that polymorphisms in UL144 correlate with outcome of congenital CMV infection. Recent studies show that the ectodomain of UL144 interacts with the B and T cell lymphocyte attenuator and inhibits T cell proliferation in vitro. UL144 also activates NF-:B, resulting in enhanced expression of the chemokine CCL22, a chemoattractant for Th2 lymphocytes. These studies suggest that UL144 plays a role in interference with host immune surveillance possibly via effects on Th1/Th2 responses, which may help CMV to disseminate. Our hypothesis is that UL144 has a role in allowing CMV to disseminate in the host. Certain UL144 genotypes may elicit less effective host cell mediated immunity than others because of differences in signaling and in activation of Th1 responses, diverting the immune response towards a Th2 response. We propose the following specific aims: 1) to determine some aspects of the molecular mechanisms by which UL144 activates NF-:B. We will determine which domain of UL144 is important in signaling, and identify proteins that interact with UL144. 2) To determine the effects of UL144 on Th1/Th2 responses in vitro. Using co-culture system the effects of UL144 genotypes on Th1/Th2 lymphocyte responses and cytokine production will be determined.
We hope to provide new perspectives and better understanding of the mechanisms by which UL144 activates NF- :B. We will also provide insight into the differences between UL144 genotypes in their signaling and their ability to affect Th1/Th2 responses. Understanding the role of UL144 in allowing viral dissemination and immune evasion, may open a new strategy for drug and vaccine development.
