Cytheris SA, a clinical stage biopharmaceutical company focused on research and development of new therapies for immune modulation, announced publication of data showing that IL-7 is able to overcome many of the factors that thwart an effective immune response during chronic overwhelming viremia in diseases such as HIV infection and viral hepatitis.
The results of this study also suggest how in the context of the reduced viral load established by current treatments for chronic viral diseases, IL-7 therapy could be used to produce and expand specific T cells and promote a broad and durable immune mediated antiviral response.
“The data generated in this study provide insights into the inhibitory pathways that function to impede immune responses in chronic infections such as HIV, HCV and HBV,” said Marc Pellegrini, PhD, Laboratory Head, Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia, and lead author on the study. “The elucidation of the molecular mechanism whereby IL-7 is able to overcome the immune inhibitory effects of massive viral load and promote extensive expansion of naive and effector T cells has major implications for our understanding of chronic viremia and the potential therapeutic use of IL-7.”
The study utilized the murine model of Lymphocytic Choriomeningitis Virus (LCMV) infection, a well-defined in vivo system for studying protective Cytotoxic T Lymphocyte (CTL) responses involving the variant clone-13. Importantly, the model is characterized by a chronic infection having a high viral turnover in mice, thereby mimicking the massive viral antigen levels associated with the three most common human viral disease infections, HIV, HCV and HBV. Clone-13 infection has served as a powerful tool in characterizing the dysfunctional immune response associated with chronic viremia, and numerous parallels with these three most common infections have been described in the literature. In this context, the study elucidates various molecular mechanisms whereby IL-7 is able to overcome the immune inhibitory effects of massive viral load.
Though in this study, IL-7 alone was used to reduce viral load, the data suggest that IL-7 therapy may become a useful adjuvant to antiviral treatments in chronic HIV, HCV and HBV infection. Antiretroviral therapy is successful in reducing viral load to an undetectable level in HIV infection and the same is true for the new antivirals in late stage development for HCV and those already on the market for treatment of HBV infection.
In this setting of a significantly reduced viral load, T cells become more responsive to IL-7 through restoration of the IL-7 receptor (IL-7R), which then enables their rescue. Following this reduction in viral load, IL-7 therapy can be used to produce and expand specific T cells and promote a broad and durable immune mediated antiviral response.
In addition, the study suggests that the secondary cytoprotective effects of IL-7, mediated by IL-22, have therapeutic implications for the management of hepatitis C virus infections as well.
“Preclinical studies like the one reported here, that combine a well defined animal model with definitive clinical end points together with a precise elucidation of the immune mechanisms supporting the therapeutic effect, have great prospective value,” said Michel Morre, DVM, p resident and CEO of Cytheris. “By choosing the clone-13 chronic LCMV model, reaching viral clearance and detailing the antiviral mechanisms triggered by IL-7, this preclinical study sheds new light on the ways IL-7 activity participates in the effective treatment of chronic viral diseases. In the clinic, we are progressively identifying the full set of these same immune effects supporting IL-7 antiviral activity and are in the process of accumulating definitive clinical proof of this activity against CMV, EBV, the JC virus and, now, against HCV in patients previously resistant to standard of care (PEG-Interferon + Ribavirin).”
Much attention has focused on modulating immune responses in an attempt to promote clearance of chronic viral infections. This is particularly relevant to chronic HCV and HBV hepatitis infections in which the immune system fails to clear the virus and eventually succumbs to uncontrolled viral turnover.
Understanding the mechanisms that circumvent immune responses in cases of overwhelming viral replication and massive antigen expression underlies any rational attempt to augment immunity. However, in the specific case of HIV, it is important to emphasize here that simply enhancing the immune specific response against infected cells, although it might improve viral control, is unlikely to be sufficient to clear the viral reservoir -- a critical element in any attempt to achieve a cure for this complex virus.
Elucidating the factors that impede immune responses to persistent viruses is essential to designing therapies for chronic viral infections. Mice infected with LCMV clone-13 have persistent high-level viremia, which is correlated with a dysfunctional immune response. Interleukin-7, which is critical for immune development and homeostasis, was used in this study to promote immunity toward clone-13, thus enabling a better understanding of the inhibitory pathways underlying impaired antiviral immune response.