Herpes Simplex Virus Type 1 and 2 Glycoprotein C Prevents Complement-Mediated Neutralization Induced by Natural Immunoglobulin M Antibody

Abstract

Glycoprotein C (gC) of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) binds complement component C3b and protects virus from complement-mediated neutralization. Differences in complement interacting domains exist between gC of HSV-1 (gC1) and HSV-2 (gC2), since the amino terminus of gC1 blocks complement C5 from binding to C3b, while gC2 fails to interfere with this activity. We previously reported that neutralization of HSV-1 gC-null virus by HSV antibody-negative human serum requires activation of C5 but not of downstream components of the classical complement pathway. In this report, we evaluated whether activation of C5 is sufficient to neutralize HSV-2 gC-null virus, or whether formation of the membrane attack complex by C6 to C9 is required for neutralization. We found that activation of the classical complement pathway up to C5 was sufficient to neutralize HSV-2 gC-null virus by HSV antibody-negative human serum. We evaluated the mechanisms by which complement activation occurred in seronegative human serum. Interestingly, natural immunoglobulin M antibodies bound to virus, which triggered activation of C1q and the classical complement pathway. HSV antibody-negative sera obtained from four individuals differed over an approximately 10-fold range in their potency for complement-mediated virus neutralization. These findings indicate that humans differ in the ability of their innate immune systems to neutralize HSV-1 or HSV-2 gC-null virus and that a critical function of gC1 and gC2 is to prevent C5 activation.Viruses employ a variety of mechanisms to evade both innate and adaptive immunity. Herpes simplex virus type 1 (HSV-1) establishes latency within the sensory ganglia of the peripheral nervous system, and interferes with the induction of interferon and immunity mediated by antibody and complement (5, 35, 39). HSV-1 also blocks cytotoxic T-lymphocyte activation by preventing antigen presentation by the major histocompatibility complex class I (15, 22, 51). HSV-1 encodes the immediate-early protein ICP47, which prevents the transport of antigenic peptides into the endoplasmic reticulum and subsequent loading onto major histocompatibility complex class I molecules.HSV-1 glycoproteins E (gE) and I (gI) together form a high-affinity Fc receptor (2,4,6,10,25,26). This receptor binds the Fc region of HSV-specific immunoglobulin G (IgG) antibodies in a process called antibody bipolar bridging (10). Antibody bipolar bridging blocks functions mediated by IgG, including antibody-dependent complement neutralization, antibody-dependent cellular cytotoxicity, and phagocytosis (7,10,40,49). In a murine flank model of infection, antibody is significantly more effective at protecting animals against disease caused by an HSV-1 mutant deficient in Fc receptor activity than by wild-type virus (40).HSV-1 glycoprotein C binds complement component C3b and inhibits the interaction of C5 and properdin (P) with C3b, blocking activation of both the classical and alternative complement pathways (11,23,32). HSV-1 gC prevent...

Herpes Simplex Virus 1 ICP22 but Not US1.5 Is Required for Efficient Acute Replication in Mice and VICE Domain Formation

“…Ultimately, this defect in late viral gene expression likely reduces d22 growth in mice. Additionally, a reduction in gC levels could thwart the ability of HSV-1 to counteract complement-mediated neutralization (47)(48)(49)(50), which might further contribute to the defective acute replication phenotype of d22 in vivo. Lastly, the composition of virion proteins in the ICP22 mutant 22/n199 is altered, and this mutant replicates poorly in mice (8).…”

Immunization with a Vaccine Combining Herpes Simplex Virus 2 (HSV-2) Glycoprotein C (gC) and gD Subunits Improves the Protection of Dorsal Root Ganglia in Mice and Reduces the Frequency of Recurrent Vaginal Shedding of HSV-2 DNA in Guinea Pigs Compared to Immunization with gD Alone

“…The classical pathway is activated when C1q binds to the Fc domain of natural antibody or virus-specific antibody (22). The lectin and alternative pathways are antibody independent.…”

Evasión de la respuesta inmune por virus herpes simplex

“…Se ha descrito que, tanto VHS-1 como VHS-2 modulan negativamente la actividad de componentes inmunes innatos a través de sus glicoproteínas C (gC) de superficie, las que poseen capacidad para contrarrestar el efecto del complemento del hospedero en la superficie viral 53 . gC interfiere específicamente con la función de C5 del complemento, un elemento clave para la actividad Patogenia antimicrobiana de este componente inmune 53,110 .…”

“…gC interfiere específicamente con la función de C5 del complemento, un elemento clave para la actividad Patogenia antimicrobiana de este componente inmune 53,110 . Con ello, estos virus impiden que se forme el complejo de ataque a membranas en la envoltura del virión, lo que le permite incrementar su viabilidad cuando se encuentran en el ambiente extracelular.…”

“…Este proceso es denominado sinapsis virológica. Debido a que la distancia entre una célula infectada y una no-infectada es pequeña, la infección celular por esta vía permitirá al virus evadir los efectos de moléculas inmunes solubles, tales como el sistema del complemento y anticuerpos neutralizantes 52,53 . La ventaja de utilizar mecanismos de infección célula-célula es consistente con el hecho de que títulos elevados de anticuerpos contra VHS-2 no se correlacionan necesariamente con una menor gravedad de la enfermedad causada por este virus 54 .…”