Insights into neutralization of animal viruses gained from study of influenza virus

It has long been known that the binding of antibodies to viruses can result in a loss of infectivity, or neutralization, but little is understood of the mechanism or mechanisms of this process. This is probably because neutralization is a multifactorial phenomenon depending upon the nature of the virus itself, the particular antigenic site involved, the isotype of immunoglobulin and the ratio of virus to immunoglobulin (see below). Thus not only is it likely that neutralization of one virus will differ from another but that changing the circumstances of neutralization can change the mechanism itself. To give coherence to the topic we are concentrating this review on one virus, influenza type A which is itself well studied and reasonably well understood [1–3]. Reviews of the older literature can be found in references 4 to 7

Not All Children with Cystic Fibrosis Have Abnormal Esophageal Neutralization during Chemical Clearance of Acid Reflux.

PurposeAcid neutralization during chemical clearance is significantly prolonged in children with cystic fibrosis, compared to symptomatic children without cystic fibrosis. The absence of available reference values impeded identification of abnormal findings within individual patients with and without cystic fibrosis. The present study aimed to test the hypothesis that significantly more children with cystic fibrosis have acid neutralization durations during chemical clearance that fall outside the physiological range.MethodsPublished reference value for acid neutralization duration during chemical clearance (determined using combined impedance/pH monitoring) was used to assess esophageal acid neutralization efficiency during chemical clearance in 16 children with cystic fibrosis (3 to <18 years) and 16 age-matched children without cystic fibrosis.ResultsDuration of acid neutralization during chemical clearance exceeded the upper end of the physiological range in 9 of 16 (56.3%) children with and in 3 of 16 (18.8%) children without cystic fibrosis (p=0.0412). The likelihood ratio for duration indicated that children with cystic fibrosis are 2.1-times more likely to have abnormal acid neutralization during chemical clearance, and children with abnormal acid neutralization during chemical clearance are 1.5-times more likely to have cystic fibrosis.ConclusionSignificantly more (but not all) children with cystic fibrosis have abnormally prolonged esophageal clearance of acid. Children with cystic fibrosis are more likely to have abnormal acid neutralization during chemical clearance. Additional studies involving larger sample sizes are needed to address the importance of genotype, esophageal motility, composition and volume of saliva, and gastric acidity on acid neutralization efficiency in cystic fibrosis children

In vivo Neutralization of Pro-inflammatory Cytokines During Secondary Streptococcus pneumoniae Infection Post Influenza A Virus Infection

An overt pro-inflammatory immune response is a key factor contributing to lethal pneumococcal infection in an influenza pre-infected host and represents a potential target for therapeutic intervention. However, there is a paucity of knowledge about the level of contribution of individual cytokines. Based on the predictions of our previous mathematical modeling approach, the potential benefit of IFN-γ- and/or IL-6-specific antibody-mediated cytokine neutralization was explored in C57BL/6 mice infected with the influenza A/PR/8/34 strain, which were subsequently infected with the Streptococcus pneumoniae strain TIGR4 on day 7 post influenza. While single IL-6 neutralization had no effect on respiratory bacterial clearance, single IFN-γ neutralization enhanced local bacterial clearance in the lungs. Concomitant neutralization of IFN-γ and IL-6 significantly reduced the degree of pneumonia as well as bacteremia compared to the control group, indicating a positive effect for the host during secondary bacterial infection. The results of our model-driven experimental study reveal that the predicted therapeutic value of IFN-γ and IL-6 neutralization in secondary pneumococcal infection following influenza infection is tightly dependent on the experimental protocol while at the same time paving the way toward the development of effective immune therapies

Cattle develop neutralizing antibodies to rotavirus serotypes which could not be isolated from faeces of symptomatic calves

Neutralizing antibodies against 10 serotypes of rotavirus were measured in sera from different age groups of German cattle. Only five of 143 sera did not neutralize heterologous serotypes. Sera from 64 of 76 calves younger than 1 year neutralized bovine rotavirus NCDV (serotype 6). From these calves, sera 54, 26, 51, 24, 12, 10 and 37, in neutralized addition, the heterologous serotypes 1, 2, 3, 4, 5, 7 and 9, respectively. Thirty-eight of 46 rotavirus isolates from Bavarian calves with diarrhoea were serotyped by neutralization: 22, 2 and 14 isolates were typed as serotype 6, serotype 10 (B223) and a newly defined subtype of serotype 10 (V1005), respectively. All serotype 6 isolates and none of the serotype 10 or V1005-like viruses tested hybridized to a NCDV-specific cDNA probe. Eight isolates gave equivocal results by neutralization. We failed however to identify serotype 1, 2, 3, 4 or 8 bovine rotavirus isolates by neutralization with hyperimmune sera and dot blot hybridization with serotype-specific cDNA probes. Thus cross-reacting antibodies in cattle might not represent an anamnestic response, but the recognition of a cross-reacting neutralization epitope shared by many rotavirus serotype

Functional stability of HIV-1 envelope trimer affects accessibility to broadly neutralizing antibodies at its apex

ABSTRACT The trimeric envelope glycoprotein spike (Env) of HIV-1 is the target of vaccine development to elicit broadly neutralizing antibodies (bnAbs). Env trimer instability and heterogeneity in principle make subunit interfaces inconsistent targets for the immune response. Here, we investigate how functional stability of Env relates to neutralization sensitivity to V2 bnAbs and V3 crown antibodies that engage subunit interfaces upon binding to unliganded Env. Env heterogeneity was inferred when antibodies neutralized a mutant Env with a plateau of less than 100% neutralization. A statistically significant correlation was found between the stability of mutant Envs and the MPN of V2 bnAb, PG9, as well as an inverse correlation between stability of Env and neutralization by V3 crown antibody, 447-52D. A number of Env-stabilizing mutations and V2 bnAb-enhancing mutations were identified in Env, but they did not always overlap, indicating distinct requirements of functional stabilization versus antibody recognition. Blocking complex glycosylation of Env affected V2 bnAb recognition, as previously described, but also notably increased functional stability of Env. This study shows how instability and heterogeneity affect antibody sensitivity of HIV-1 Env, which is relevant to vaccine design involving its dynamic apex. IMPORTANCE The Env trimer is the only viral protein on the surface of HIV-1 and is the target of neutralizing antibodies that reduce viral infectivity. Quaternary epitopes at the apex of the spike are recognized by some of the most potent and broadly neutralizing antibodies to date. Being that their glycan-protein hybrid epitopes are at subunit interfaces, the resulting heterogeneity can lead to partial neutralization. Here, we screened for mutations in Env that allowed for complete neutralization by the bnAbs. We found that when mutations outside V2 increased V2 bnAb recognition, they often also increased Env stability-of-function and decreased binding by narrowly neutralizing antibodies to the V3 crown. Three mutations together increased neutralization by V2 bnAb and eliminated binding by V3 crown antibodies. These results may aid the design of immunogens that elicit antibodies to the trimer apex. </jats:p

Broad and potent cross clade neutralizing antibodies with multiple specificities in the plasma of HIV-1 subtype C infected individuals.

Broadly Cross clade Neutralizing (BCN) antibodies are recognized as potential therapeutic tools and leads for the design of a vaccine that can protect human beings against various clades of Human Immunodeficiency Virus (HIV). In the present study, we screened plasma of 88 HIV-1 infected ART naïve individuals for their neutralization potential using a standard panel of 18 pseudoviruses belonging to different subtypes and different levels of neutralization. We identified 12 samples with good breadth of neutralization (neutralized &gt;90% of the viruses). Four of these samples neutralized even the difficult-to-neutralize tier-3 pseudoviruses with great potency (GMT &gt; 600). Analysis of neutralization specificities indicated that four samples had antibodies with multiple epitope binding specificities, viz. CD4-binding site (CD4BS), glycans in the V1/V2 and V3 regions and membrane proximal external region (MPER). Our findings indicate the strong possibility of identifying highly potent bNAbs with known or novel specificities from HIV-1 subtype C infected individuals from India that can be exploited as therapeutic tools or lead molecules for the identification of potential epitopes for design of a protective HIV-1 vaccine

Time Evolution of Jets and Perturbative Color Neutralization

In-medium production of leading hadrons in hard reactions, carrying the main fraction of the jet momentum, involves two stages: (i) the parton originated from the hard process propagates through the medium radiating gluons due to the initial hard collision, as well as to multiple interactions in the medium; (ii) perturbative color neutralization, e.g. picking up an anti-colored parton produced perturbatively, followed by evolution and attenuation of the (pre)hadron in the medium. The color neutralization (or production) length for leading hadrons is controlled by coherence, energy conservation and Sudakov suppression. The pT-broadening is a sensitive and model independent probe for the production length. The color neutralization time is expected to shrink with rising hard scale. In particular, we found a very fast energy dissipation by a highly virtual parton: half of the jet energy is radiated during the first Fermi. Energy conservation makes the production of leading hadrons at longer times difficult.Comment: Based on talk given by B.K. at the Fifth International Conference on Perspectives in Hadronic Physics, Trieste, May 200