Cytokine members of the Tumor Necrosis Factor (TNF) Superfamily play key roles in host defense to viral pathogens. In particular, the Lymphotoxin (LT)alpha-beta-LTbeta receptor (LTbetaR) system and other closely related cytokines are required for effective immune defenses against cytomegalovirus (CMV), a beta-herpes virus. Both in vitro studies with human CMV and in vivo studies with murine CMV indicate that the LTbetaR system plays a key role in the establishment and maintenance of immunological balance between the host and this persistent virus. Specifically, in vivo activation of the LTbetaR by an agonist anti-LTbetaR antibody can prevent lymphocyte death, restore IFNbeta levels, reorganize lymphoid tissue and extend the survival of MCMVinfected, LTalpha-deficient mice. These results indicate that modulating the LTbetaR pathway in vivo can restore immune balance during this viral infection. Human CMV infection remains a stubborn clinical problem especially in immune compromised (chemotherapy or AIDS) patients, and emerging evidence suggests chronic inflammation, associated with persistent viruses like HCMV, may also contribute to cardiovascular disease. Clinically, there exists a particular need for effective treatment of this virus since the efficacy of antiviral drugs has been limited by toxicity and viral resistance. Understanding the limitations of currently available anti-viral treatment provides strong impetus to identify novel approaches that will enhance the host's immune responsiveness while at the same time effectively suppressing virus replication. The goal of this proposal is to test the hypothesis that the LTbetaR is a significant factor in host defense to human CMV. To accomplish this 3 specific aims are proposed to investigate the LT cytokine system in a rhesus macaque primate model of CMV infection (RhCMV), a model which most closely resembles human CMV infection.
In specific aim 1, the LTbetaR signaling pathway will be studied in vitro using agonistic and antagonistic reagents to provide mechanistic data for the in vivo studies proposed in specific aims 2 and 3. These in vivo experiments will directly test the efficacy of LT(R agonists and antagonists as modulators of RhCMV infection and in particular the ability of an agonist anti-LTbetaR antibody to ameliorate the infection in both immunocompetent and immunocompromised macaques. The success of this reagent in macaques should validate this novel immunotherapeutic approach as a potential treatment for human CMV infection.
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