Enforced viral replication as a mechanism for immune activation: Relevance for viral persistence and vaccination strategies

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The aim of the project is to determine how enforced viral replication can be modulated to improve the outcome of chronic viral infections. To that end, four important goals were achieved during the last years: 1) We determined how enforced viral replication contributes to immunopathology in various scenarios. We found that during chronic viral infection, enforced viral replication is essential for inducing exhaustion of CD8+ T cells. Therefore, the lack of CD169+ macrophages or Ubp43 (Usp18) leads to massive immunopathology during chronic viral infection. 2) We determined that chronic viral infection modulates the type I interferon (IFN-I) signature and limits enforced viral replication of a secondary infection. 3) We found that Ceacam1 (Ceacam1), B-Myb (Mybl2), and CD103 (Itgae) are important regulators of enforced viral replication. 4) We determined that enforced viral replication is necessary for vaccination with a single-cycle vector. Furthermore, we found that after reinfection with the same virus, enforced viral replication contributes to boosting the immune system. In the new funding period we want to determine how modulation of enforced viral replication can be beneficial during chronic viral infection. Mechanistically we will focus on Ceacam1 (Ceacam1), B-Myb (Mybl2), and CD103 (Itgae). We aim to determine whether 1) inhibition of B-Myb prevents CD8+ T-cell exhaustion during chronic LCMV infection; 2) inhibition of CD103 (Itgae) prevents CD8+ T-cell exhaustion during chronic LCMV infection; 3) treatment with anti-CEACAM1 antibody improves immunity and improves control of HIV in humanized mice; and 4) enforced viral replication determines immune responses after immunization with vesicular stomatitis virus (VSV)-HIV. In conclusion, our project is aimed at understanding how modulation of the important regulators of enforced viral replication, Ceacam1 (Ceacam1), B-Myb (Mybl2), and CD103 (Itgae), can improve the outcome of chronic viral infection.