Antibodies Elicited in Response to a Single Cycle Glycoprotein D Deletion Viral Vaccine Candidate Bind C1q and Activate Complement Mediated Neutralization and Cytolysis

Herpes simplex virus (HSV) prevention is a global health priority but, despite decades of research, there is no effective vaccine. Prior efforts focused on generating glycoprotein D (gD) neutralizing antibodies, but clinical trial outcomes were disappointing. The deletion of gD yields a single-cycle candidate vaccine (∆gD-2) that elicits high titer polyantigenic non-gD antibodies that exhibit little complement-independent neutralization but mediate antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Active or passive immunization with ΔgD-2 completely protects mice from lethal disease and latency following challenge with clinical isolates of either serotype. The current studies evaluated the role of complement in vaccine-elicited protection. The immune serum from the ΔgD-2 vaccinated mice exhibited significantly greater C1q binding compared to the serum from the gD protein vaccinated mice with infected cell lysates from either serotype as capture antigens. The C1q-binding antibodies recognized glycoprotein B. This resulted in significantly greater antibody-mediated complement-dependent cytolysis and neutralization. Notably, complete protection was preserved when the ΔgD-2 immune serum was passively transferred into C1q knockout mice, suggesting that ADCC and ADCP are sufficient in mice. We speculate that the polyfunctional responses elicited by ΔgD-2 may prove more effective in preventing HSV, compared to the more restrictive responses elicited by adjuvanted gD protein vaccines.

CCL19 and CCL28 Assist Herpes Simplex Virus 2 Glycoprotein D To Induce Protective Systemic Immunity against Genital Viral Challenge

An effective HSV-2 vaccine should induce antigen (Ag)-specific immune responses against viral mucosal infection. This study reveals that chemokine CCL19 or CCL28 enhanced HSV-2 glycoprotein D ectodomain (gD-306aa)-induced immune responses against vaginal virus challenge.

Rigorous anterograde trans-monosynaptic tracing of genetic defined neurons with retargeted HSV1 H129

Neuroanatomical tracing technology is fundamental for unraveling the complex network of brain connectome. Tracing tools that could spread between neurons are urgently needed, especially the rigorous trans-monosynaptic anterograde tracer is still lacking. HSV1 strain H129 was proved to be an anterograde tracer and has been used to trace neuronal networks in several reports. However, H129 has a serious defect that it was demonstrated to infect neurons via axon terminals. Thus, when using H129 to dissect output neural circuit, its terminal take up capacity should be carefully considered. Here, we report a recombinant H129 that carrying the anti-Her2 scFv in glycoprotein D to target genetically defined neurons. With the usage of helper virus complementarily expressing Her2 and gD, we can realize the elucidation of direct projection regions of either a given brain nucleus or a specific neuron type. The retargeted H129 system complements the current neural circuit tracer arsenal, which provides a rigorous and practical anterograde trans-monosynaptic tool.

Restoring Herpesvirus Entry Mediator (HVEM) Immune Function in HVEM−/− Mice Rescues Herpes Simplex Virus 1 Latency and Reactivation Independently of Binding to Glycoprotein D

ABSTRACT The immune modulatory protein herpes virus entry mediator (HVEM) is one of several cellular receptors used by herpes simplex virus 1 (HSV-1) for cell entry. HVEM binds to HSV-1 glycoprotein D (gD) but is not necessary for HSV-1 replication in vitro or in vivo. Previously, we showed that although HSV-1 replication was similar in wild-type (WT) control and HVEM−/− mice, HSV-1 does not establish latency or reactivate effectively in mice lacking HVEM, suggesting that HVEM is important for these functions. It is not known whether HVEM immunomodulatory functions contribute to latency and reactivation or whether its binding to gD is necessary. We used HVEM−/− mice to establish three transgenic mouse lines that express either human WT HVEM or human or mouse HVEM with a point mutation that ablates its ability to bind to gD. Here, we show that HVEM immune function, not its ability to bind gD, is required for WT levels of latency and reactivation. We further show that HVEM binding to gD does not affect expression of the HVEM ligands BTLA, CD160, or LIGHT. Interestingly, our results suggest that binding of HVEM to gD may contribute to efficient upregulation of CD8α but not PD1, TIM-3, CTLA4, or interleukin 2 (IL-2). Together, our results establish that HVEM immune function, not binding to gD, mediates establishment of latency and reactivation. IMPORTANCE HSV-1 is a common cause of ocular infections worldwide and a significant cause of preventable blindness. Corneal scarring and blindness are consequences of the immune response induced by repeated reactivation events. Therefore, HSV-1 therapeutic approaches should focus on preventing latency and reactivation. Our data suggest that the immune function of HVEM plays an important role in the HSV-1 latency and reactivation cycle that is independent of HVEM binding to gD.

Crystal structure of bovine herpesvirus 1 glycoprotein D bound to nectin-1 reveals the basis for its low-affinity binding to the receptor

Bovine herpesvirus 1 (BHV-1) has received increasing attention for its potential oncolytic applications. BHV-1 recognizes nectin-1 for cell entry via viral glycoprotein D (gD) but represents a low-affinity nectin-1 binding virus. The molecular basis underlying this low receptor-binding affinity, however, remains unknown. Here, the crystal structures of BHV-1 gD in the free and nectin-1–bound forms are presented. While showing an overall resembled nectin-1 binding mode to other alphaherpesvirus gDs, BHV-1 gD has a unique G-strand/α2-helix interloop that disturbs gD/nectin-1 interactions. Residue R188 residing in this loop is observed to otherwise cause strong steric hindrance with the bound receptor, making a large conformational change of the loop a prerequisite for nectin-1 engagement. Subsequently, substitution of R188 with glycine markedly enhances the affinity of the BHV-1-gD/nectin-1 interaction (by about fivefold). These structural and functional data delineate the receptor-recognition basis for BHV-1, which might facilitate BHV-1–based oncolytic design in the future.