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

该项目的目的是确定如何调节强制病毒复制以改善慢性病毒感染的结果。为此，在过去几年中实现了四个重要目标：1）我们确定了在各种情况下强制病毒复制如何有助于免疫病理学。我们发现，在慢性病毒感染期间，强制病毒复制对于诱导CD 8 + T细胞耗竭是必不可少的。因此，CD 169+巨噬细胞或Ubp 43（Usp 18）的缺乏导致慢性病毒感染期间的大量免疫病理学。2)我们确定，慢性病毒感染调节I型干扰素（IFN-I）的签名，并限制了继发感染的病毒复制。3)我们发现Ceacam 1（Ceacam 1），B-Myb（Mybl 2）和CD 103（Itgae）是强制病毒复制的重要调节因子。4)我们确定，强制病毒复制是必要的疫苗接种与单循环载体。此外，我们发现，在再次感染同一病毒后，强制病毒复制有助于增强免疫系统。在新的资助期内，我们希望确定在慢性病毒感染期间如何调节强制病毒复制。从机制上讲，我们将重点关注Ceacam 1（Ceacam 1），B-Myb（Mybl 2）和CD 103（Itgae）。我们的目的是确定1）B-Myb的抑制是否防止慢性LCMV感染期间的CD 8 + T细胞耗竭; 2）CD 103（Itgae）的抑制是否防止慢性LCMV感染期间的CD 8 + T细胞耗竭; 3）用抗CEACAM 1抗体治疗是否改善免疫力并改善人源化小鼠中HIV的控制;和4）在用水泡性口炎病毒（VSV）-HIV免疫后，强制病毒复制决定免疫应答。总之，我们的项目旨在了解如何调节强制病毒复制的重要调节因子Ceacam 1（Ceacam 1），B-Myb（Mybl 2）和CD 103（Itgae）可以改善慢性病毒感染的结果。

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.