UL144, a viral orthologue of HVEM.

An interesting connection between the TNF related cytokines and the ß-herpesviruses is the ul144 orf encoded by virulent isolates of human CMV. We originally identified UL144 as an orthologue of the herpesvirus entry mediator (HVEM), a member of the TNF receptor superfamily. Recently, with the identification of HVEM as a ligand for B and T lymphocyte attenuator (BTLA, a negative costimulatory molecule of the Ig-domain containing class of molecules) we have identified UL144 as a BTLA binding partner. Similar to HVEM, the interaction of UL144 with BTLA on the surface of activated CD4 T cells inhibits their proliferation.

We are deciphering how UL144 might function in the context of human CMV infection. Utilizing genetic mutants of human CMV that lack UL144, UL144 expression and functional consequences of UL144-BTLA interaction are being explored in various cell types (dendritic cells, endothelial cells, fibroblasts). The presence of memory CD4 and CD8 T-cells are critical for controlling human CMV disease in immunosuppressed patients. UL144-mediated regulation of memory T-cells specific for human CMV antigens may play an important role in these cases, and we are actively pursuing research in this area.

Regulation of type I interferons during viral infection by the lymphotoxin cytokine system.

Several years ago we demonstrated that cultured cells infected with human cytomegalovirus (CMV) produced significantly higher levels of interferon (IFN)ß when they were treated with either lymphotoxin (LT)a or LTa1ß2, which transmit their signals through either TNFR or LTßR, respectively. The IFNß then reversibly inhibited human CMV replication in the absence of cellular elimination, establishing a state of coexistence between the virus and its host cell. Because CMV (a ß-herpesvirus) is able to maintain a lifelong, persistent infection in its host without overt pathogenicity, this suggested that the LTaß cytokine system was important in regulating the balance between this persistent virus and its host.

Recently we have gone on to show that direct signaling by the LTaß cytokine system is required for resistance of mice to CMV infection, bringing in vivo relevance to our previous observations with human CMV. Mice that are genetically deficient in components of the LTaß system are highly sensitive to infection with mouse CMV, showing severely reduced levels of IFNaß production in vivo. Treatment of LTa or LTß deficient mice at the time of CMV infection with an agonistic antibody recognizing the LTßR restores IFNaß production and extends the survival of the mice. This places the LTaß system at a critical crossroads in regulating antiviral innate immune defense, and possibly for the generation of efficient adaptive immune responses as well.

We have also recently begun to study the requirement of the LTaß system in the regulation of innate defenses to influenza infection. It is known that IFNaß is important for host defense to influenza, and we hypothesize that the LTaß system may contribute to the regulation of IFNaß during flu infection, as it does in the case of CMV. Because influenza replication is largely restricted to the lung epithelium, as opposed to CMV which replicates systemically, this viral system will allow us to assess the contribution of LTaß signaling in the airways.