UC San Diego

Chronic viral infections present a major health burden worldwide. Using lymphocytic choriomeningitis virus clone 13 (LCMV Cl13), a mouse model of chronic viral infection, I neutralized transforming growth factor beta (TGF-[beta]) and examined the role of gp130 receptor signaling in immune responses. In chronic infection, TGF-[beta] mediates deletion of virus specific CD8⁺ T cells. However, treatment with anti-TGF-[beta] neutralizing antibody, early in LCMV Cl13, did not lead to increased virus specific CD8⁺ T cell numbers and there was no difference in viremia or clearance compared to the PBS treated group. The transmembrane receptor, gp130, is a common signaling protein utilized by the interleukin-6 (IL-6) family of cytokines. Infection of mice with a genetic ablation of gp130 or IL-27 (a IL-6 family cytokine) signaling on T cells led to a complete failure in viral control, with both antibody mediated and cellular immunity being compromised compared to wild type mice. In contrast, gp130 or IL-27 signaling was not found to be important in the control of an acute viral infection. Then I tested the therapeutic potential of this pathway by treating wild type LCMV Cl13 infected mice with IL-6 and HYPER-IL6, a designer cytokine-receptor complex capable of universally activate the gp130 pathway. Mice receiving HYPER-IL6 showed slightly enhanced viral control compared to PBS treated control mice. This study identifies gp130 signaling as a vital component of the immune response during chronic infection, and opens the possibility that therapeutically targeting this pathway directly on CD4⁺ T cells may enhance viral control