| The immunology of poxvirus infection is vastly understudied, but has elicited growing interest in recent years as Orthopoxvirus vectors appear to be promising candidate vaccines and weaponized smallpox has emerged as a potential threat. In this work, we extensively investigated the interactions between cells of the human immune system and the Orthopoxviruses vaccinia virus (VV) and the attenuated modified vaccinia virus Ankara (MVA). We focused on the cellular tropism, mechanisms of immunogenicity, and immune evasion strategies of these viruses. By studying primary, hematolymphoid human cells we discovered that Orthopoxviruses exhibit a more limited tropism than has previously been appreciated, with preferential infection of antigen-presenting cells and activated T cells, and that susceptibility to infection is determined by the expression of a virus-binding receptor. We found that the infection of dendritic cells (DCs) with MVA, compared to VV, shows features that are consistent with its increased immunogenicity. Although both viruses abortively infect DCs and inhibit their maturation, only MVA induces the expression of Th1-polarizing cytokines and chemokines in infected DCs. MVA infection of DCs is also associated with earlier apoptosis, suggesting that cross-presentation of viral antigens is essential to the generation of immunity. These data contribute to our knowledge of the mechanisms of poxvirus infection and immunity and provide a rationale for genetic modifications of MVA aimed at further enhancing its desirable immunogenic properties, thereby optimizing the use of this virus as a vaccine vector. |
