scholarly journals HVEM signaling promotes protective antibody-dependent cellular cytotoxicity (ADCC) vaccine responses to herpes simplex viruses

2020 ◽  
Vol 5 (50) ◽  
pp. eaax2454
Author(s):  
Clare Burn Aschner ◽  
Lip Nam Loh ◽  
Benjamin Galen ◽  
Isabel Delwel ◽  
Rohit K. Jangra ◽  
...  
Keyword(s):  
Herpes Simplex ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Immune Serum ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Wild Type ◽  
Herpes Simplex Viruses ◽  
Vectored Vaccine

Herpes simplex virus (HSV) glycoprotein D (gD) not only is required for virus entry and cell-to-cell spread but also binds the host immunomodulatory molecule, HVEM, blocking interactions with its ligands. Natural infection primarily elicits neutralizing antibodies targeting gD, but subunit protein vaccines designed to induce this response have failed clinically. In contrast, preclinical studies demonstrate that an HSV-2 single-cycle strain deleted in gD, ΔgD-2, induces primarily non-neutralizing antibodies that activate Fcγ receptors (FcγRs) to mediate antibody-dependent cellular cytotoxicity (ADCC). These studies were designed to test the hypothesis that gD interferes with ADCC through engagement of HVEM. Immunization of Hvem−/− mice with ΔgD-2 resulted in significant reduction in HSV-specific IgG2 antibodies, the subclass associated with FcγR activation and ADCC, compared with wild-type controls. This translated into a parallel reduction in active and passive vaccine protection. A similar decrease in ADCC titers was observed in Hvem−/− mice vaccinated with an alternative HSV vaccine candidate (dl5-29) or an unrelated vesicular stomatitis virus–vectored vaccine. Unexpectedly, not only did passive transfer of immune serum from ΔgD-2–vaccinated Hvem−/− mice fail to protect wild-type mice but transfer of immune serum from ΔgD-2–vaccinated wild-type mice failed to protect Hvem−/− mice. Immune cells isolated from Hvem−/− mice were impaired in FcγR activation, and, conversely, addition of gD protein or anti-HVEM antibodies to in vitro murine or human FcγR activation assays inhibited the response. These findings uncover a previously unrecognized role for HVEM signaling in generating and mediating ADCC and an additional HSV immune evasion strategy.

Antibody-Dependent Cellular Cytotoxicity to Target Cells Infected With Herpes Simplex Viruses: Functional Adequacy in the Neonate

PEDIATRICS ◽  
1977 ◽  
Vol 59 (1) ◽  
pp. 22-28
Author(s):  
Steven L. Shore ◽  
Henry Milgrom ◽  
Phyllis A. Wood ◽  
André J. Nahmias
Keyword(s):  
Herpes Simplex ◽  
Cord Blood ◽  
Mononuclear Cells ◽  
Cell Activity ◽  
Absolute Number ◽  
Target Cells ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Effector Cells ◽  
Herpes Simplex Viruses

The functional adequacy of antibody-dependent cellular cytotoxicity (ADCC) in the human neonate was evaluated in a 51Cr release assay which employs tissue culture cells acutely infected with type 1 or type 2 herpes simplex virus (HSV) as targets. Two aspects of ADCC were assessed: cytotoxic effector activity in cord blood mononuclear cells (MC) and the ability of the antibody mediating ADCC to pass the placenta. Although effector cell activity was readily detected in all 13 cord blood specimens tested, cord blood MC showed moderately reduced cytotoxic activity when compared with blood MC from normal adults at the same effector cell:target cell ratio. This finding suggests that effector cells in cord blood make up a reduced proportion of the total circulating MC population and may be of relevance to the newborns increased susceptibility to HSV infection. On the other hand, the number of MC in cord blood was found to be almost twice that of adult blood, suggesting that the absolute number of ADCC effector cells in cord blood was within the adult range. The antibody mediating ADCC to HSV-infected cells was shown to be transferred (quantitatively across the placenta, providing further evidence that it is an IgG immunoglobulin.

scholarly journals Uninfected Bystander Cells Impact the Measurement of HIV-Specific Antibody-Dependent Cellular Cytotoxicity Responses

mBio ◽  
2018 ◽  
Vol 9 (2) ◽  
Author(s):  
Jonathan Richard ◽  
Jérémie Prévost ◽  
Amy E. Baxter ◽  
Benjamin von Bredow ◽  
Shilei Ding ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Ex Vivo ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Antibody Recognition ◽  
Vaccine Trials ◽  
Infected Cells ◽  
Bystander Cells ◽  
Hiv 1

ABSTRACTThe conformation of the HIV-1 envelope glycoprotein (Env) substantially impacts antibody recognition and antibody-dependent cellular cytotoxicity (ADCC) responses. In the absence of the CD4 receptor at the cell surface, primary Envs sample a “closed” conformation that occludes CD4-induced (CD4i) epitopes. The virus controls CD4 expression through the actions of Nef and Vpu accessory proteins, thus protecting infected cells from ADCC responses. However, gp120 shed from infected cells can bind to CD4 present on uninfected bystander cells, sensitizing them to ADCC mediated by CD4i antibodies (Abs). Therefore, we hypothesized that these bystander cells could impact the interpretation of ADCC measurements. To investigate this, we evaluated the ability of antibodies to CD4i epitopes and broadly neutralizing Abs (bNAbs) to mediate ADCC measured by five ADCC assays commonly used in the field. Our results indicate that the uninfected bystander cells coated with gp120 are efficiently recognized by the CD4i ligands but not the bNabs. Consequently, the uninfected bystander cells substantially affectin vitromeasurements made with ADCC assays that fail to identify responses against infected versus uninfected cells. Moreover, using an mRNA flow technique that detects productively infected cells, we found that the vast majority of HIV-1-infected cells inin vitrocultures orex vivosamples from HIV-1-infected individuals are CD4 negative and therefore do not expose significant levels of CD4i epitopes. Altogether, our results indicate that ADCC assays unable to differentiate responses against infected versus uninfected cells overestimate responses mediated by CD4i ligands.IMPORTANCEEmerging evidence supports a role for antibody-dependent cellular cytotoxicity (ADCC) in protection against HIV-1 transmission and disease progression. However, there are conflicting reports regarding the ability of nonneutralizing antibodies targeting CD4-inducible (CD4i) Env epitopes to mediate ADCC. Here, we performed a side-by-side comparison of different methods currently being used in the field to measure ADCC responses to HIV-1. We found that assays which are unable to differentiate virus-infected from uninfected cells greatly overestimate ADCC responses mediated by antibodies to CD4i epitopes and underestimate responses mediated by broadly neutralizing antibodies (bNAbs). Our results strongly argue for the use of assays that measure ADCC against HIV-1-infected cells expressing physiologically relevant conformations of Env to evaluate correlates of protection in vaccine trials.

scholarly journals Comparison of antibody-dependent cellular cytotoxicity and complement-dependent antibody lysis of herpes simplex virus-infected cells as methods of detecting antiviral antibodies in human sera

1977 ◽  
Vol 5 (6) ◽  
pp. 551-558
Author(s):  
T Subramanian ◽  
W E Rawls
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Effector Cells ◽  
Herpes Simplex Viruses ◽  
Adcc Assay ◽  
Human Sera ◽  
Infected Cells ◽  
Simplex Virus

An antibody-dependent cellular cytotoxicity (ADCC) assay was used to detect antibodies to the herpes simplex viruses in humans sera. The assay utilized the release of 51Cr from BHK-21 cells infected with the viruses, hamster peritoneal exudate cells as effector cells, and antiviral antibodies in human sera. The technique was found to be far more sensitive than complement-dependent antibody lysis of infected cells and virus neutralization. The ADCC assay was useful in detecting antibodies in sera that had low titers or no antibodies detectable by other methods. In a sample of 100 sera from university students, 40 were positive by complement-dependent lysis whereas 73 were positive by ADCC. Of 400 sera from women with cervical cancer, 17 did not have detectable antibodies by microneutralization or complement-dependent lysis; however, all sera were positive by ADCC, suggesting that all of the women had been infected in the past with one or both types of herpes simplex virus.

scholarly journals ON THE ROLE OF RIBONUCLEIC ACID IN ANIMAL VIRUS SYNTHESIS

1960 ◽  
Vol 111 (3) ◽  
pp. 351-368 ◽  
Author(s):  
Igor Tamm ◽  
Rostom Bablanian
Keyword(s):  
Herpes Simplex ◽  
Vaccinia Virus ◽  
Ribonucleic Acid ◽  
Chorioallantoic Membrane ◽  
Host Cells ◽  
Active Inhibitor ◽  
Herpes Simplex Viruses ◽  
Virus Particles ◽  
Highly Active

Ribonuclease is a highly active inhibitor of vaccinia virus multiplication in vitro in the chorioallantoic membrane removed from embryonated chicken eggs. It is also a highly active inhibitor of pock formation by vaccinia and herpes simplex viruses on the chorioallantoic membrane in vivo. Marked inhibitory effects were obtained with 12.5 µg. of RNase. However, complete inhibition was not obtained with several hundred micrograms of the enzyme. RNase caused no inactivation of the infectivity of vaccinia virus particles but it had a marked inhibitory effect on multiplication of this virus when administered many hours after infection of host cells had occurred. RNase also failed to inactivate the infectivity of herpes simplex virus particles. The results obtained indicate that ribonucleic acid is necessary for the multiplication of two DNA-containing viruses; i.e., vaccinia and herpes simplex.

scholarly journals Murine monoclonal antibodies against RBD of SARS-CoV-2 neutralize authentic wild type SARS-CoV-2 as well as B.1.1.7 and B.1.351 viruses and protect in vivo in a mouse model in a neutralization dependent manner

2021 ◽  
Author(s):  
Fatima Amanat ◽  
Shirin Strohmeier ◽  
Wen-Hsin Lee ◽  
Sandhya Bangaru ◽  
Andrew B Ward ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Mouse Model ◽  
Neutralizing Antibodies ◽  
Dependent Manner ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Murine Monoclonal Antibodies

After first emerging in December 2019 in China, severe acute respiratory syndrome 2 (SARS-CoV-2) has since caused a pandemic leading to millions of infections and deaths worldwide. Vaccines have been developed and authorized but supply of these vaccines is currently limited. With new variants of the virus now emerging and spreading globally, it is essential to develop therapeutics that are broadly protective and bind conserved epitopes in the receptor binding domain (RBD) or the whole spike of SARS-CoV-2. In this study, we have generated mouse monoclonal antibodies (mAbs) against different epitopes on the RBD and assessed binding and neutralization against authentic SARS-CoV-2. We have demonstrated that antibodies with neutralizing activity, but not non-neutralizing antibodies, lower viral titers in the lungs when administered in a prophylactic setting in vivo in a mouse challenge model. In addition, most of the mAbs cross-neutralize the B.1.351 as well as the B.1.1.7 variants in vitro.

scholarly journals Vaccination Route as a Determinant of Protective Antibody Responses against Herpes Simplex Virus

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 277
Author(s):  
Clare Burn Aschner ◽  
Carl Pierce ◽  
David M. Knipe ◽  
Betsy C. Herold
Keyword(s):  
Herpes Simplex ◽  
Neutralizing Antibodies ◽  
Lipid A ◽  
Low Dose ◽  
High Titer ◽  
Antibody Responses ◽  
Protein Vaccine ◽  
Herpes Simplex Viruses ◽  
Monophosphoryl Lipid A ◽  
Simplex Virus

Herpes simplex viruses (HSV) are significant global health problems associated with mucosal and neurologic disease. Prior experimental vaccines primarily elicited neutralizing antibodies targeting glycoprotein D (gD), but those that advanced to clinical efficacy trials have failed. Preclinical studies with an HSV-2 strain deleted in gD (ΔgD-2) administered subcutaneously demonstrated that it elicited a high titer, weakly neutralizing antibodies that activated Fcγ receptors to mediate antibody-dependent cellular cytotoxicity (ADCC), and completely protected mice against lethal disease and latency following vaginal or skin challenge with HSV-1 or HSV-2. Vaccine efficacy, however, may be impacted by dose and route of immunization. Thus, the current studies were designed to compare immunogenicity and efficacy following different routes of vaccination with escalating doses of ΔgD-2. We compared ΔgD-2 with two other candidates: recombinant gD protein combined with aluminum hydroxide and monophosphoryl lipid A adjuvants and a replication-defective virus deleted in two proteins involved in viral replication, dl5-29. Compared to the subcutaneous route, intramuscular and/or intradermal immunization resulted in increased total HSV antibody responses for all three vaccines and boosted the ADCC, but not the neutralizing response to ΔgD and dl5-29. The adjuvanted gD protein vaccine provided only partial protection and failed to elicit ADCC independent of route of administration. In contrast, the increased ADCC following intramuscular or intradermal administration of ΔgD-2 or dl5-29 translated into significantly increased protection. The ΔgD-2 vaccine provided 100% protection at doses as low as 5 × 104 pfu when administered intramuscularly or intradermally, but not subcutaneously. However, administration of a combination of low dose subcutaneous ΔgD-2 and adjuvanted gD protein resulted in greater protection than low dose ΔgD-2 alone indicating that gD neutralizing antibodies may contribute to protection. Taken together, these results demonstrate that ADCC provides a more predictive correlate of protection against HSV challenge in mice and support intramuscular or intradermal routes of vaccination.

Sign in / Sign up

Export Citation Format

Share Document