Antibody-induced internalization of viral glycoproteins and gE–gI Fc receptor activity protect pseudorabies virus-infected monocytes from efficient complement-mediated lysis

Abstract

Pseudorabies virus (PRV)-infected blood monocytes are able to transport virus throughout the body of vaccination-immune pigs. PRV-infected monocytes express viral glycoproteins in their plasma membrane that can be recognized by virus-specific antibodies. Recently, it has been shown that addition of PRV-specific polyclonal immunoglobulins to PRV-infected monocytes at 37˚C induces internalization of the majority of plasma membrane-expressed viral glycoproteins. This study investigated whether this process may interfere with efficient antibody-dependent complementmediated lysis (ADCML) of infected monocytes. Therefore, an ADCML assay was set up in vitro. A significant decrease in the percentage of cells lysed by ADCML was observed when antibody-induced internalization of PRV glycoproteins occurred (P<0?005). Furthermore, it is shown (i) that the PRV gE-gI complex, which, like certain other alphaherpesvirus orthologues, possesses IgG-binding capacity, aids in avoiding efficient ADCML of PRV-infected monocytes and (ii) that the efficiency of PRV gE-gI-mediated evasion of ADCML can be decreased by the presence of gE-gI-specific antibodies. INTRODUCTIONPseudorabies virus (PRV), a member of the subfamily Alphaherpesvirinae, causes Aujeszky's disease in its natural host, the pig. Clinical signs depend on the age of the pig and are characterized by nervous signs in newborn pigs, respiratory disorders in fattening pigs and reproductive failure in sows. Abortion may be an important consequence of PRV infection in pregnant sows (Pensaert & Kluge, 1989). In the presence of a vaccination-induced immunity, PRV may still replicate in the respiratory tract and draining lymph nodes, resulting in a restricted viraemia (Wittmann et al., 1980). The limited replication in immune animals generally does not cause problems. However, abortion may occur as a result of cell-mediated transplacental spread and intrafoetus replication. It has been shown that blood monocytes are essential to transport the virus to the pregnant uterus in vaccination-immune pigs (Nauwynck & Pensaert, 1992, 1995a but little is known on exactly how these infected monocytes survive in the blood of a vaccination-immune animal.PRV-infected monocytes (and PRV-infected cells in general) express viral envelope proteins on their plasma membrane (Favoreel et al., 1999). Antibodies bind to these viral glycoproteins, which should induce antibody-dependent lysis of infected cells (Sissons & Oldstone, 1980). A major component of the antibody-dependent immune system is the complement cascade (reviewed by Sim & Dodds, 1997). Complement components bind to the Fc region of antibodies, which leads to a cascade of events and results finally in lysis of antibody-covered infected cells (antibodydependent complement-mediated cell lysis or ADCML) (reviewed by Müller-Eberhard, 1984).Recently, we described a process of how PRV-infected monocytes may avoid efficient lysis by ADCML. Addition of PRV-specific antibodies to PRV-infected monocytes in vitro results in aggregation of the majority...

Copatching and Lipid Raft Association of Different Viral Glycoproteins Expressed on the Surfaces of Pseudorabies Virus-Infected Cells

“…Such redistribution may lead to capping, shedding, or internalization of the viral cell surface proteins, processes which have been suggested to be implicated in interference with antibody-dependent cell lysis, enhancement of cell-to-cell spread, and/or suppression of the ongoing intracellular virus replication (11,39,45).…”

“…The exact function of these processes is not fully understood, although there are strong indications that they may be important for alphaherpesviruses to enhance virus survival in the face of an antibody response. First, the internalization of patches of viral cell surface proteins in PRV-infected monocytes has been shown to interfere with efficient antibodydependent lysis of the infected monocytes (45). Further, capping of antibody-antigen patches has been suggested to be related to antibody-dependent enhancement of cell-tocell spread of HSV (39).…”

Antibody-Induced Internalization of the Human Respiratory Syncytial Virus Fusion Protein

“…Also, virus assembly can be affected by the internalization of viral glycoproteins (23). Furthermore, internalization can be important for viral pathogenesis by downregulation of viral antigen surface expression and reduced recognition of infected cells by the immune system (20,(24)(25)(26). Two different types of internalization have been described previously.…”

“…Spontaneous endocytosis was observed for many herpesviruses, and human immunodeficiency virus (HIV) was observed among others. A second type of internalization is induced by the interaction of specific antibodies with viral proteins expressed on the surface of infected cells, followed by internalization of antibody-antigen complexes in the cell (25,27,28). Such viral protein internalization may result from cross-linking or depend on specific endocytic motifs in the cytoplasmic or transmembrane domains of glycoproteins, such as common tyrosine-based sorting motifs and dileucine motifs (20,24,29,30).…”

Cell biological and molecular characteristics of pseudorabies virus infections in cell cultures and in pigs with emphasis on the respiratory tract

“…Such attachment has already been described between PrVinfected monocytes and endothelial cells [67]. PrV-infected monocytes that have been exposed to virus-specific antibodies internalize their viral glycoproteins together with their MHCI molecules, leaving cells that are masked from efficient recognition and elimination by different components of the immune system [11,68]. These immune-masked monocytes have been shown to adhere specifically to endothelial cells by the cellular adhesion molecules wCD11R3 and CD18.…”