Functions of viral glycoproteins in the pathogenesis of Aujeszky's disease virus in pigs

Abstract - At present, eleven viral glycoproteins have been described for Aujeszky's disease virus (ADV): gB, gC, gD, gE, gG, gH, gI, gK, gL, gM and gN, with gE and gI, gH and gL, gM and gN forming structural complexes. All glycoproteins except gG are present in the viral envelope and in the membranes of infected cells and are called envelope glycoproteins. gG is secreted by infected cells and for the moment has no clear function. The envelope glycoproteins are involved in the virus replication cycle at different levels and control virus spread and invasion and immune-evasion in the host. The envelope glycoproteins play an important role during the replication cycle due to their outer position in the virion. The first interaction with the host cell, the attachment, is mediated by gC interacting with a heparansulfate receptor. This low affinity binding is converted into a more stable binding by gD interaction with its cellular counterpart, which has recently been characterised as the "herpes virus entry mediator". gB, gD, gH/gL are essential during the next step, the fusion of the envelope with the cell membrane. gC, gK and gM/gN are non essential but modulate this process. In addition, viral glycoproteins control intracellular transport (gE/gI) and the egress (gC and gE/gI) of newly assembled viruses. The glycoproteins that are expressed in the outer cell membrane also have important functions in intercellular interactions. gB, gC and, to a lesser degree gD, cause binding of infected cells to uninfected cells. gB and gH (essential) and gD and gE/gI (modulatory) are involved in the formation of intercellular bridges by fusing the membrane in which they are embedded with the membrane of a neighbouring cell. By doing this, ADV succeeds in spreading in a strictly cell-associated way. Due to the above-mentioned functions, one may easily understand why viral glycoproteins may affect viral spread and invasion in its host. The pathogenesis of wild type ADV in non immune pigs can be summarised as follows: (i) replication in the epithelial cells of the respiratory tract; (ii) spread over the different layers of the mucosa and submucosa; (iii) invasion by the lymph, blood (infected monocytes), and nerves; (iv) spread in the brain and internal organs, such as the pregnant uterus. The roles of the non essential glycoproteins gC, gE and gI in the pathogenesis of ADV in pigs have already been studied extensively. gE alone is important in the transmission over the different tissue layers in the upper respiratory tract whereas both gE and gI are involved in the invasion and spread in the brains. The gC-deletion mutant acts like the parental strain. The reduction of the neurovirulence by deleting the gE/gI complex may be explained in part by the finding that this complex is active during the anterograde transport of newly produced virus. It was recently found that the intranasal replication of ADV is also affected by deleting gN. The capacity of the phenotypically complemented gD deletion mutant to be transmitted over synapses in between nerves and transplacentally proves that ADV is extremely specialised in spreading in a cell-associated way. ADV is like all other herpesviruses: an artist in evading the host's immunity. Indeed, in spite of the presence of immunity, the virus succeeds in (i) replicating in the upper respiratory tract (though to lower titers than in naïve pigs), (ii) spreading by infected blood monocytes and (iii) crossing the placenta and infecting fetuses. Recent studies have revealed a mechanism by which infected monocytes may evade from both humoral and cellular immunity. After binding of anti-ADV antibodies, viral glycoproteins that are expressed in the outer cell membrane aggregate into patches and become endocytosed. The viral glycoproteins gB and gD are essential during this process while gE/gI has a modulatory function. As a result of the endocytosis event, all viral glycoproteins disappear from the outer cell membrane, leaving a cell which can no longer be eliminated by antibody-mediated cell lysis processes by means of complement and phagocytes. Since MHC1 molecules undergo co-endocytosis, the cell is additionally invisible for cytotoxic T-lymphocytes. In summary, it can be stated that viral glycoproteins have multiple functions in pathogenesis, not only in non immune but also in immune pigs.