The innate and T-cell mediated immune response during acute and chronic gammaherpesvirus infection

Abstract

Immediately after entry into host cells, viruses are sensed by the innate immune system, leading to the activation of innate antiviral effector mechanisms including the type I interferon (IFN) response and natural killer (NK) cells. This innate immune response helps to shape an effective adaptive T cell immune response mediated by cytotoxic T cells and CD4+ T helper cells and is also critical for the maintenance of protective T cells during chronic infection. The human gammaherpesvirus Epstein-Barr virus (EBV) is a highly prevalent lymphotropic oncovirus that establishes chronic lifelong infections in the vast majority of the adult population. Although acute EBV infection is controlled in an immunocompetent host, chronic EBV infection can lead to severe complications in immunosuppressed patients. Given that EBV is strictly host-specific, its murine homolog murid herpesvirus 4 or MHV68 is a widely used model to obtain in vivo insights into the interaction between gammaherpesviruses and their host. Despite the fact that EBV and MHV68 have developed strategies to evade the innate and adaptive immune response, innate antiviral effector mechanisms still play a vital role in not only controlling the acute infection but also shaping an efficient long-lasting adaptive immune response. Here, we summarize the current knowledge about the innate immune response mediated by the type I IFN system and NK cells, and the adaptive T cell-mediated response during EBV and MHV68 infection. Investigating the fine-tuned interplay between the innate immune and T cell response will provide valuable insights which may be exploited to design better therapeutic strategies to vanquish chronic herpesviral infection.

Deciphering the Role of Epstein–Barr Virus Latent Membrane Protein 1 in Immune Modulation: A Multifaced Signalling Perspective

“…The antiviral innate immune response sets in motion all the main components of the adaptive immune response: the cytotoxic CD8+ T cells, CD4+ T helper cells and antibody-producing B cells. While CD8+ cells have the ability to directly attack and get rid of the infected cells, CD4+ cells mediate immune responses through the secretion of specific cytokines [ 64 ]. This response is exemplary in acute IM, which has a characteristically exaggerated expansion of CD8+ T cells that are mostly specific for EBV lytic phase antigens and can account for up to almost 50% of all blood circulating lymphocytes [ 65 , 66 ].…”

Mouse Models for Human Herpesviruses

“…An overview of MHV-68-associated pathogenesis in mice and the interaction with the host was provided previously [ 81 ]. More recently, the features of innate and T cell responses in the context of MHV-68 infection in mice and their relevance for EBV were summarized [ 82 ].…”

“…Skin xenograft models confirmed that infected T cells can release infectious virions in vivo [ 82 , 134 , 135 ]. Notably, VZV infection also induced slow progression of typical skin lesions and was associated with a robust innate immune response of epidermal cells in the skin [ 153 ].…”

Mechanisms of T cell evasion by Epstein-Barr virus and implications for tumor survival

“…EBV has evolved numerous techniques for manipulating the IFN response, thus enhancing its immunoevasive capabilities ( 179 ). One protein that contributes to downregulation of the IFN response is the early protein BFRF1 ( 180 ).…”