scholarly journals Structure-Based Modeling of Complement C4 Mediated Neutralization of Adenovirus

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 111
Author(s):  
Corey C. Emerson ◽  
Phoebe L. Stewart
Keyword(s):  
Neutralizing Antibodies ◽  
Covalent Binding ◽  
Neutralizing Antibody ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Viral Escape ◽  
Structural Basis ◽  
Penton Base ◽  
Strong Immune Response ◽  
Complement Components

Adenovirus (AdV) infection elicits a strong immune response with the production of neutralizing antibodies and opsonization by complement and coagulation factors. One anti-hexon neutralizing antibody, called 9C12, is known to activate the complement cascade, resulting in the deposition of complement component C4b on the capsid, and the neutralization of the virus. The mechanism of AdV neutralization by C4b is independent of downstream complement proteins and involves the blockage of the release of protein VI, which is required for viral escape from the endosome. To investigate the structural basis underlying how C4b blocks the uncoating of AdV, we built a model for the complex of human adenovirus type-5 (HAdV5) with 9C12, together with complement components C1 and C4b. This model positions C4b near the Arg-Gly-Asp (RGD) loops of the penton base. There are multiple amino acids in the RGD loop that might serve as covalent binding sites for the reactive thioester of C4b. Molecular dynamics simulations with a multimeric penton base and C4b indicated that stabilizing interactions may form between C4b and multiple RGD loops. We propose that C4b deposition on one RGD loop leads to the entanglement of C4b with additional RGD loops on the same penton base multimer and that this entanglement blocks AdV uncoating.

scholarly journals Immunogenicity of an E1-deleted recombinant human adenovirus against rabies by different routes of administration

2001 ◽  
Vol 82 (9) ◽  
pp. 2191-2197 ◽  
Author(s):  
Ad Vos ◽  
Andreas Neubert ◽  
Elke Pommerening ◽  
Thomas Müller ◽  
Leopold Döhner ◽  
...  
Keyword(s):  
Immune Response ◽  
Oral Administration ◽  
Neutralizing Antibodies ◽  
Direct Injection ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Vaccine Virus ◽  
Strong Immune Response ◽  
Routes Of Administration ◽  
Immunogenic Properties

The immunogenic properties of an E1-deleted, human adenovirus type 5 (Ad5) vaccine virus with activity against rabies were examined in mice, foxes and dogs using different routes of administration. NMRI mice received 105·8, 105·3, 104·3, 103·3 and 102·3 TCID50 by peroral or intramuscular (i.m.) administration. Furthermore, six mice received 105·8 TCID50 intracerebrally (i.c.). The construct elicited marked seroconversion in mice after oral administration. Immunoreactivity in mice was even more pronounced i.m. and i.c. After direct oral administration (108·0 TCID50) in foxes, six of eight animals developed rabies virus-neutralizing antibodies (VNA). All foxes immunized by direct injection (107·7 TCID50) in the membrane of the jejunum were shown to seroconvert. Pre-existing immunity against canine adenovirus did not hinder the development of rabies VNA after oral application of the construct (108·0 TCID50). Fox cubs (24–29 days old) born from rabies-immune vixens were shown to develop very high levels of rabies VNA after i.m. administration (108·0 TCID50), indicating that the immunogenicity of the construct could surpass maternally transferred immunity. In dogs, the construct (108·0 TCID50) induced a very strong immune response after i.m. administration. However, no immune response was detectable in dogs after direct oral administration (108·3 TCID50) or after endoscopic deposition in the smaller intestine (108·0 TCID50). Hence, it must be concluded that the construct is not suitable for oral vaccination of dogs against rabies.

The penton base of human adenovirus type 3 has the RGD motif

Gene ◽  
1994 ◽  
Vol 146 (2) ◽  
pp. 257-259 ◽  
Author(s):  
Alain Cuzange ◽  
Jadwiga Chroboczek ◽  
Bernard Jacrot
Keyword(s):  
Human Adenovirus ◽  
Adenovirus Type ◽  
Penton Base ◽  
Rgd Motif ◽  
Type 3

scholarly journals Functional development of a V3/glycan-specific broadly neutralizing antibody isolated from a case of HIV superinfection

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Mackenzie M Shipley ◽  
Vidya Mangala Prasad ◽  
Laura E Doepker ◽  
Adam S Dingens ◽  
Duncan K Ralph ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Viral Escape ◽  
Single Infection ◽  
Structural Studies ◽  
Broadly Neutralizing Antibodies ◽  
Hiv Vaccines ◽  
Functional Development ◽  
Broadly Neutralizing Antibody

Stimulating broadly neutralizing antibodies (bnAbs) directly from germline remains a barrier for HIV vaccines. HIV superinfection elicits bnAbs more frequently than single infection, providing clues of how to elicit such responses. We used longitudinal antibody sequencing and structural studies to characterize bnAb development from a superinfection case. BnAb QA013.2 bound initial and superinfecting viral Env, despite its probable naïve progenitor only recognizing the superinfecting strain, suggesting both viruses influenced this lineage. A 4.15 Å cryo-EM structure of QA013.2 bound to native-like trimer showed recognition of V3 signatures (N301/N332 and GDIR). QA013.2 relies less on CDRH3 and more on framework and CDRH1 for affinity and breadth compared to other V3/glycan-specific bnAbs. Antigenic profiling revealed that viral escape was achieved by changes in the structurally-defined epitope and by mutations in V1. These results highlight shared and novel properties of QA013.2 relative to other V3/glycan-specific bnAbs in the setting of sequential, diverse antigens.

Determination of the nucleotide sequence for the penton-base gene of human adenovirus type 5

Gene ◽  
1988 ◽  
Vol 69 (1) ◽  
pp. 153-157 ◽  
Author(s):  
Rita Neumann ◽  
Jadwiga Chroboczek ◽  
Bernard Jacrot
Keyword(s):  
Nucleotide Sequence ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Penton Base ◽  
Adenovirus Type 5

scholarly journals Seroprevalence of neutralizing antibodies against human adenovirus type 55 in the South Korean military, 2018-2019

PLoS ONE ◽  
2020 ◽  
Vol 15 (7) ◽  
pp. e0236040
Author(s):  
So Yun Park ◽  
Jae-Hoon Ko ◽  
Sezim Monoldorova ◽  
Jonguk Jeong ◽  
Bo-Young Jeon ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
The South ◽  
South Korean

Seroprevalence of Human Adenovirus Type 5 Neutralizing Antibody in Common Marmosets Determined by a New Set of Two Assays

2019 ◽  
Vol 32 (8) ◽  
pp. 348-354 ◽  
Author(s):  
Qi Wang ◽  
Yachun Sun ◽  
Yuxia Xu ◽  
Yilin Wang ◽  
Huafeng Wang ◽  
...  
Keyword(s):  
Neutralizing Antibody ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Common Marmosets ◽  
Adenovirus Type 5

scholarly journals Structural Basis for Accommodation of Emerging B.1.351 and B.1.1.7 Variants by Two Potent SARS-CoV-2 Neutralizing Antibodies

2021 ◽  
Author(s):  
Gabriele Cerutti ◽  
Micah Rapp ◽  
Yicheng Guo ◽  
Fabiana Bahna ◽  
Jude Bimela ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Structural Basis ◽  
Wild Type Virus ◽  
Receptor Binding Domain ◽  
Type Virus ◽  
Wild Type ◽  
Distinct Mechanism ◽  
The Uk

SummaryEmerging SARS-CoV-2 strains, B.1.1.7 and B.1.351, from the UK and South Africa, respectively show decreased neutralization by monoclonal antibodies and convalescent or vaccinee sera raised against the original wild-type virus, and are thus of clinical concern. However, the neutralization potency of two antibodies, 1-57 and 2-7, which target the receptor-binding domain (RBD) of spike, was unaffected by these emerging strains. Here, we report cryo-EM structures of 1-57 and 2-7 in complex with spike, revealing each of these antibodies to utilize a distinct mechanism to bypass or accommodate RBD mutations. Notably, each antibody represented a response with recognition distinct from those of frequent antibody classes. Moreover, many epitope residues recognized by 1-57 and 2-7 were outside hotspots of evolutionary pressure for both ACE2 binding and neutralizing antibody escape. We suggest the therapeutic use of antibodies like 1-57 and 2-7, which target less prevalent epitopes, could ameliorate issues of monoclonal antibody escape.

scholarly journals ADCC-mediating non-neutralizing antibodies can exert immune pressure in early HIV-1 infection

2021 ◽  
Vol 17 (11) ◽  
pp. e1010046
Author(s):  
Dieter Mielke ◽  
Gama Bandawe ◽  
Jie Zheng ◽  
Jennifer Jones ◽  
Melissa-Rose Abrahams ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Viral Evolution ◽  
Neutralizing Antibody ◽  
Protective Role ◽  
Viral Escape ◽  
Immune Pressure ◽  
Control Virus ◽  
Kinetics Of ◽  
Hiv 1

Despite antibody-dependent cellular cytotoxicity (ADCC) responses being implicated in protection from HIV-1 infection, there is limited evidence that they control virus replication. The high mutability of HIV-1 enables the virus to rapidly adapt, and thus evidence of viral escape is a very sensitive approach to demonstrate the importance of this response. To enable us to deconvolute ADCC escape from neutralizing antibody (nAb) escape, we identified individuals soon after infection with detectable ADCC responses, but no nAb responses. We evaluated the kinetics of ADCC and nAb responses, and viral escape, in five recently HIV-1-infected individuals. In one individual we detected viruses that escaped from ADCC responses but were sensitive to nAbs. In the remaining four participants, we did not find evidence of viral evolution exclusively associated with ADCC-mediating non-neutralizing Abs (nnAbs). However, in all individuals escape from nAbs was rapid, occurred at very low titers, and in three of five cases we found evidence of viral escape before detectable nAb responses. These data show that ADCC-mediating nnAbs can drive immune escape in early infection, but that nAbs were far more effective. This suggests that if ADCC responses have a protective role, their impact is limited after systemic virus dissemination.

scholarly journals Structural basis for antibody binding to adenylate cyclase toxin reveals RTX linkers as neutralization-sensitive epitopes

2021 ◽  
Vol 17 (9) ◽  
pp. e1009920
Author(s):  
Jory A. Goldsmith ◽  
Andrea M. DiVenere ◽  
Jennifer A. Maynard ◽  
Jason S. McLellan
Keyword(s):  
Adenylate Cyclase ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Structural Data ◽  
Antibody Binding ◽  
Structural Basis ◽  
Antibody Titers ◽  
Adenylate Cyclase Toxin ◽  
Blocking Antibodies

RTX leukotoxins are a diverse family of prokaryotic virulence factors that are secreted by the type 1 secretion system (T1SS) and target leukocytes to subvert host defenses. T1SS substrates all contain a C-terminal RTX domain that mediates recruitment to the T1SS and drives secretion via a Brownian ratchet mechanism. Neutralizing antibodies against the Bordetella pertussis adenylate cyclase toxin, an RTX leukotoxin essential for B. pertussis colonization, have been shown to target the RTX domain and prevent binding to the αMβ2 integrin receptor. Knowledge of the mechanisms by which antibodies bind and neutralize RTX leukotoxins is required to inform structure-based design of bacterial vaccines, however, no structural data are available for antibody binding to any T1SS substrate. Here, we determine the crystal structure of an engineered RTX domain fragment containing the αMβ2-binding site bound to two neutralizing antibodies. Notably, the receptor-blocking antibodies bind to the linker regions of RTX blocks I–III, suggesting they are key neutralization-sensitive sites within the RTX domain and are likely involved in binding the αMβ2 receptor. As the engineered RTX fragment contained these key epitopes, we assessed its immunogenicity in mice and showed that it elicits similar neutralizing antibody titers to the full RTX domain. The results from these studies will support the development of bacterial vaccines targeting RTX leukotoxins, as well as next-generation B. pertussis vaccines.

Sign in / Sign up

Export Citation Format

Share Document