scholarly journals Neutralization of Virus Infectivity by Antibodies: Old Problems in New Perspectives

2014 ◽  
Vol 2014 ◽  
pp. 1-24 ◽  
Author(s):  
P. J. Klasse
Keyword(s):  
Cellular Immunity ◽  
Neutralizing Antibodies ◽  
Viral Infections ◽  
Viral Proteins ◽  
Virus Neutralization ◽  
Virus Infectivity ◽  
Viral Pathogens ◽  
Enveloped Viruses ◽  
Vaccine Candidates ◽  
Hiv 1

Neutralizing antibodies (NAbs) can be both sufficient and necessary for protection against viral infections, although they sometimes act in concert with cellular immunity. Successful vaccines against viruses induce NAbs but vaccine candidates against some major viral pathogens, including HIV-1, have failed to induce potent and effective such responses. Theories of how antibodies neutralize virus infectivity have been formulated and experimentally tested since the 1930s; and controversies about the mechanistic and quantitative bases for neutralization have continually arisen. Soluble versions of native oligomeric viral proteins that mimic the functional targets of neutralizing antibodies now allow the measurement of the relevant affinities of NAbs. Thereby the neutralizing occupancies on virions can be estimated and related to the potency of the NAbs. Furthermore, the kinetics and stoichiometry of NAb binding can be compared with neutralizing efficacy. Recently, the fundamental discovery that the intracellular factor TRIM21 determines the degree of neutralization of adenovirus has provided new mechanistic and quantitative insights. Since TRIM21 resides in the cytoplasm, it would not affect the neutralization of enveloped viruses, but its range of activity against naked viruses will be important to uncover. These developments bring together the old problems of virus neutralization—mechanism, stoichiometry, kinetics, and efficacy—from surprising new angles.

scholarly journals Comparative Evaluation of HIV-1 Neutralization in External Secretions and Sera of HIV-1-Infected Women

2012 ◽  
Vol 6 (1) ◽  
pp. 293-302 ◽  
Author(s):  
Qing Wei ◽  
Zina Moldoveanu ◽  
Wen-Qiang Huang ◽  
Rashada C Alexander ◽  
Paul A Goepfert ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Specific Binding ◽  
Virus Neutralization ◽  
Virus Infectivity ◽  
Plasma Samples ◽  
Humoral Factors ◽  
Neutralization Activity ◽  
Specific Antibodies ◽  
Low Levels ◽  
Hiv 1

Objectives:Although human immunodeficiency virus type 1 (HIV-1)-specific antibodies are detectable in external secretions by ELISA and western blot (WB), the presence of HIV-1 neutralizing antibodies is difficult to evaluate due to the low levels of immunoglobulins (Ig) and the presence of humoral factors of innate immunity. The objective of this study was to determine virus neutralization activity and the relative contribution of HIV-1-specific antibodies of various isotypes to virus neutralization in serum/plasma samples, cervicovaginal lavages (CVL), and rectal lavages (RL).Design:Serum/plasma, CVL, and RL samples were examined by ELISA, WB and HIV-1 neutralization assays. Selected samples were Ig depleted and analyzed for virus neutralization.Results:IgG specific for three HIV-1 ENV antigens was detected in all serum/plasma samples, while IgA to at least one ENV glycoprotein was found at the low levels in 95% samples. Serum/plasma samples had the ability to neutralize at least one of three clade B and two clade C viruses. The neutralizing titers were reduced significantly or became undetectable after IgG removal. In corresponding CVL and RL, HIV-1 ENV-specific IgG antibodies were readily detected compared to IgA. Furthermore, IgG in CVL had greater ability than IgA to reduce virus infectivity. The difference in HIV-1 neutralization before and after Ig depletion was not observed in RL, implying that innate humoral factors were involved in anti-HIV-1 activity.Conclusions:Results demonstrate that HIV-1-specific neutralizing antibodies are almost exclusively of the IgG isotype in serum/plasma and CVL samples. HIV-1-specific binding antibodies detected in RL are not responsible for neutralization activity, suggesting that the antibody-mediated virus neutralization in external secretions should be verified by means of a selective depletion of Ig.

From Bench Side to Bed-Travelling on a Road to Get a Safe and Effective Vaccine Against COVID-19, Day to Save the Life

2021 ◽  
Vol 15 ◽  
Author(s):  
Suman Kumar Ray ◽  
Sukhes Mukherjee
Keyword(s):  
Neutralizing Antibodies ◽  
Cytotoxic T Cells ◽  
Immunological Response ◽  
Surface Protein ◽  
Viral Proteins ◽  
Effective Vaccine ◽  
Vaccine Candidates ◽  
High Fatality Rate ◽  
Basic Goal ◽  
Epitope Discovery

: Coronavirus Disease 2019 (COVID-19) is caused by a new strain of coronavirus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). It is the most challenging pandemic of this century. The growing COVID-19 pandemic has triggered extraordinary efforts to restrict the virus in numerous ways, owing to the emergence of SARS-CoV-2. Immunotherapy, which includes artificially stimulating the immune system to generate an immunological response, is regarded as an effective strategy for preventing and treating several infectious illnesses and malignancies. Given the pandemic's high fatality rate and quick expansion, an effective vaccination is urgently needed to keep it under control. The basic goal of all COVID-19 vaccine programs is to develop a vaccine that causes the generation of surface protein neutralizing antibodies in subjects. The epitope discovery for the SARS-CoV-2 vaccine candidates is likewise made using an immuno-informatics methodology. It can be used to find the epitopes in viral proteins important for cytotoxic T cells and B cells. A safe and effective COVID-19 vaccine that can elicit the necessary immune response is necessary to end the epidemic. The global search for a safe and effective COVID-19 vaccine is yielding results. More than a dozen vaccines have already been approved around the world, with many more in the clinical trials. Patents can cover the underlying technology used to generate a vaccine, whereas trade secrets can cover manufacturing methods and procedures.

scholarly journals Serum Immune Responses to the Proteins of Porcine Reproductive and Respiratory Syndrome (PRRS) Virus

1994 ◽  
Vol 6 (4) ◽  
pp. 410-415 ◽  
Author(s):  
Eric A. Nelson ◽  
Jane Christopher-Hennings ◽  
David A. Benfield
Keyword(s):  
Immune Responses ◽  
Indirect Immunofluorescence ◽  
Neutralizing Antibodies ◽  
Virus Isolate ◽  
Neutralizing Antibody ◽  
Viral Proteins ◽  
Antibody Responses ◽  
Virus Neutralization ◽  
Respiratory Syndrome Virus ◽  
Prrs Virus

The antibody responses of pigs to porcine reproductive and respiratory syndrome virus (isolate VR-2332) were evaluated by indirect immunofluorescence, virus neutralization, and immunoblotting. All pigs in each group were positive by indirect immunofluorescence 14-21 days postexposure (DPE), and antibodies to specific viral proteins (15, 19 or 26 kD) were initially demonstrated by immunoblotting at 7–21 days DPE. Neutralizing antibodies were detected in only 2 pigs that were inoculated intranasally and given additional parenteral injections with adjuvant. These antibodies appeared much later, 51–70 DPE, than did antibodies detected by indirect immunofluorescence. The titer of the neutralizing antibodies increased until 127 DPE, after which the titers decreased, and 1 animal became seronegative for neutralizing antibody by 262 DPE.

scholarly journals Replicating Rather than Nonreplicating Adenovirus-Human Immunodeficiency Virus Recombinant Vaccines Are Better at Eliciting Potent Cellular Immunity and Priming High-Titer Antibodies

2005 ◽  
Vol 79 (16) ◽  
pp. 10200-10209 ◽  
Author(s):  
Bo Peng ◽  
Liqun Rejean Wang ◽  
Victor Raúl Gómez-Román ◽  
Alberta Davis-Warren ◽  
David C. Montefiori ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Humoral Immunity ◽  
Cellular Immunity ◽  
Neutralizing Antibodies ◽  
High Titer ◽  
Neutralizing Antibody ◽  
Preclinical Trial ◽  
Immunodeficiency Virus ◽  
Hiv Envelope ◽  
Hiv 1

ABSTRACT A major challenge in combating the human immunodeficiency virus (HIV) epidemic is the development of vaccines capable of inducing potent, persistent cellular immunity and broadly reactive neutralizing antibody responses to HIV type 1 (HIV-1). We report here the results of a preclinical trial using the chimpanzee model to investigate a combination vaccine strategy involving sequential priming immunizations with different serotypes of adenovirus (Ad)/HIV-1MN env/rev recombinants and boosting with an HIV envelope subunit protein, oligomeric HIVSF162 gp140ΔV2. The immunogenicities of replicating and nonreplicating Ad/HIV-1MN env/rev recombinants were compared. Replicating Ad/HIV recombinants were better at eliciting HIV-specific cellular immune responses and better at priming humoral immunity against HIV than nonreplicating Ad-HIV recombinants carrying the same gene insert. Enhanced cellular immunity was manifested by a greater frequency of HIV envelope-specific gamma interferon-secreting peripheral blood lymphocytes and better priming of T-cell proliferative responses. Enhanced humoral immunity was seen in higher anti-envelope binding and neutralizing antibody titers and better induction of antibody-dependent cellular cytotoxicity. More animals primed with replicating Ad recombinants mounted neutralizing antibodies against heterologous R5 viruses after one or two booster immunizations with the mismatched oligomeric HIV-1SF162 gp140ΔV2 protein. These results support continued development of the replicating Ad-HIV recombinant vaccine approach and suggest that the use of replicating vectors for other vaccines may prove fruitful.

scholarly journals Activity of and Effect of Subcutaneous Treatment with the Broad-Spectrum Antiviral Lectin Griffithsin in Two Laboratory Rodent Models

2013 ◽  
Vol 58 (1) ◽  
pp. 120-127 ◽  
Author(s):  
Christopher Barton ◽  
J. Calvin Kouokam ◽  
Amanda B. Lasnik ◽  
Oded Foreman ◽  
Alexander Cambon ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Ebola Virus ◽  
Viral Infections ◽  
Antiviral Treatment ◽  
Enveloped Viruses ◽  
Minimal Toxicity ◽  
Human T Cell ◽  
Long Term Treatment ◽  
Hiv 1

ABSTRACTGriffithsin (GRFT) is a red-alga-derived lectin that binds the terminal mannose residues of N-linked glycans found on the surface of human immunodeficiency virus type 1 (HIV-1), HIV-2, and other enveloped viruses, including hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Ebola virus. GRFT displays no human T-cell mitogenic activity and does not induce production of proinflammatory cytokines in treated human cell lines. However, despite the growing evidence showing the broad-spectrum nanomolar or better antiviral activity of GRFT, no study has reported a comprehensive assessment of GRFT safety as a potential systemic antiviral treatment. The results presented in this work show that minimal toxicity was induced by a range of single and repeated daily subcutaneous doses of GRFT in two rodent species, although we noted treatment-associated increases in spleen and liver mass suggestive of an antidrug immune response. The drug is systemically distributed, accumulating to high levels in the serum and plasma after subcutaneous delivery. Further, we showed that serum from GRFT-treated animals retained antiviral activity against HIV-1-enveloped pseudoviruses in a cell-based neutralization assay. Overall, our data presented here show that GRFT accumulates to relevant therapeutic concentrations which are tolerated with minimal toxicity. These studies support further development of GRFT as a systemic antiviral therapeutic agent against enveloped viruses, although deimmunizing the molecule may be necessary if it is to be used in long-term treatment of chronic viral infections.

scholarly journals Impact of glycan positioning on HIV-1 Env glycan shield density, function, and antibody recognition

2020 ◽  
Author(s):  
Qing Wei ◽  
Audra A. Hargett ◽  
Barbora Knoppova ◽  
Alexandra Duverger ◽  
Reda Rawi ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Glycosylation Site ◽  
Cell Entry ◽  
Virus Infectivity ◽  
Ripple Effect ◽  
Dynamic Simulations ◽  
Antibody Recognition ◽  
Cd4 Binding Site ◽  
Env Protein ◽  
Hiv 1

AbstractN-glycans, which represent >50% mass of the HIV-1 envelope (Env) trimer, play important roles for virus-cell entry and immune evasion. How each glycan unit interacts to shape the Env protein-sugar complex and affects Env function is not well understood. Here, high-resolution glycomics analysis of two Env variants from the same donor, with differing functional characteristics and N-glycosylation-site composition, revealed that changes to key N-glycosylation-site not only affected the Env structure at distant locations, but also had a ripple effect on Env-wide glycan processing, virus infectivity, and antibody recognition and virus neutralization. Specifically, the N262 glycan, although not located in the CD4-binding site, controlled Env binding to the CD4 receptor, affected the recognition of Env by several glycan-dependent broadly neutralizing antibodies, and altered heterogeneity of glycosylation at several sites, with N156, N160, and N448 displaying limited glycan processing. Molecular dynamic simulations visualized how specific oligosaccharide positions can move to compensate for loss of a glycan. This study demonstrates how changes in individual glycan units can alter molecular dynamics and processing of the Env-glycan shield and, consequently, Env function.

scholarly journals Establishment of a miRNA profile in paediatric HIV-1 patients and its potential as a biomarker for effectiveness of the combined antiretroviral therapy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Irene Consuegra ◽  
Samanta Gasco ◽  
María Jesús Serramía ◽  
José Luis Jiménez ◽  
Maria Jose Mellado ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Viral Infections ◽  
Mirna Gene ◽  
Mirna Profile ◽  
Control Group ◽  
Virus Infectivity ◽  
Beneficial Effects ◽  
Therapy Effectiveness ◽  
Taqman Array ◽  
Hiv 1

AbstractmiRNAs have been extensively studied in pathological conditions, including viral infections, such as those provoked by HIV-1. Several cellular and circulating miRNAs are altered during HIV-1 infection, with either beneficial effects on host defenses or enhanced virus infectivity. Blood samples were collected in sterile EDTA tubes and plasma was separated and stored, as were PBMCs. RNA was isolated and reverse-transcribed. Finally, the miRNA gene expression profile was assessed using TaqMan Array Human microRNA Card A v2.0. A comprehensive statistical analysis was performed on the results obtained. This is the first study on miRNAs in HIV-1 paediatric patients, and a miRNA profile differentiating patients starting combination antiretroviral therapy (cART) at different times after HIV-1 diagnosis was established. Thirty-four miRNAs were observed to have different expression levels between the control group and the cART group. The data indicates the need to start cART as soon as possible after the establishment of HIV-1 infection to assure the best outcome possible. Finally, the selected 34 miRNAs may be used as biomarkers for prognosis and assessing therapy effectiveness. However, more research must be conducted to establish adequate quantitative correlations.

scholarly journals Structure-Guided Redesign Increases the Propensity of HIV Env To Generate Highly Stable Soluble Trimers

2015 ◽  
Vol 90 (6) ◽  
pp. 2806-2817 ◽  
Author(s):  
Javier Guenaga ◽  
Viktoriya Dubrovskaya ◽  
Natalia de Val ◽  
Shailendra K. Sharma ◽  
Barbara Carrette ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Small Animal ◽  
Subtype C ◽  
Disulfide Linkage ◽  
Vaccine Candidates ◽  
Subtype B ◽  
Subtype A ◽  
Induced Changes ◽  
Hiv 1 ◽  
Hiv Diversity

ABSTRACTDue to high viral diversity, an effective HIV-1 vaccine will likely require Envs derived from multiple subtypes to generate broadly neutralizing antibodies (bNAbs). Soluble Env mimics, like the native flexibly linked (NFL) and SOSIP trimers, derived from the subtype A BG505 Env, form homogeneous, stable native-like trimers. However, other Env sequences, such as JRFL and 16055 from subtypes B and C, do so to a lesser degree. The high-resolution BG505 SOSIP crystal structures permit the identification and redesign of Env elements involved in trimer stability. Here, we identified structure trimer-derived (TD) residues that increased the propensity of the subtype B JRFL and subtype C 16055 Env sequences to form well-ordered, homogenous, and highly stable soluble trimers. The generation of these spike mimics no longer required antibody-based selection, positive or negative. Using the redesigned subtype B and C trimer representatives as respective foundations, we further stabilized the NFL TD trimers by engineering an intraprotomer disulfide linkage in the prebridging sheet, I201C-A433C (CC), that locks the gp120 in the receptor nontriggered state. We demonstrated that this disulfide pair prevented CD4 induced-conformational rearrangements in NFL trimers derived from the prototypic subtype A, B, and C representatives. Coupling the TD-based design with the engineered disulfide linkage, CC, increased the propensity of Env to form soluble highly stable spike mimics that are resistant to CD4-induced changes. These advances will allow testing of the hypothesis that such stabilized immunogens will more efficiently elicit neutralizing antibodies in small-animal models and primates.IMPORTANCEHIV-1 displays unprecedented global diversity circulating in the human population. Since the envelope glycoprotein (Env) is the target of neutralizing antibodies, Env-based vaccine candidates that address such diversity are needed. Soluble well-ordered Env mimics, typified by NFL and SOSIP trimers, are attractive vaccine candidates. However, the current designs do not allow most Envs to form well-ordered trimers. Here, we made design modifications to increase the propensity of representatives from two of the major HIV subtypes to form highly stable trimers. This approach should be applicable to other viral Envs, permitting the generation of a repertoire of homogeneous, highly stable trimers. The availability of such an array will allow us to assess if sequential or cocktail immune strategies can overcome some of the vaccine challenges presented by HIV diversity.

scholarly journals Metagenomic sequencing of stool samples in Bangladeshi infants: virome association with poliovirus shedding after oral poliovirus vaccination

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Susanna K. Tan ◽  
Andrea C. Granados ◽  
Jerome Bouquet ◽  
Yana Emmy Hoy-Schulz ◽  
Lauri Green ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Viral Infections ◽  
Oral Vaccine ◽  
The United States ◽  
Oral Poliovirus Vaccine ◽  
Inverse Association ◽  
Metagenomic Sequencing ◽  
Serum Samples ◽  
Viral Pathogens ◽  
Stool Samples

Abstract The potential role of enteric viral infections and the developing infant virome in affecting immune responses to the oral poliovirus vaccine (OPV) is unknown. Here we performed viral metagenomic sequencing on 3 serially collected stool samples from 30 Bangladeshi infants following OPV vaccination and compared findings to stool samples from 16 age-matched infants in the United States (US). In 14 Bangladeshi infants, available post-vaccination serum samples were tested for polio-neutralizing antibodies. The abundance (p = 0.006) and richness (p = 0.013) of the eukaryotic virome increased with age and were higher than seen in age-matched US infants (p < 0.001). In contrast, phage diversity metrics remained stable and were similar to those in US infants. Non-poliovirus eukaryotic virus abundance (3.68 log10 vs. 2.25 log10, p = 0.002), particularly from potential viral pathogens (2.78log10 vs. 0.83log10, p = 0.002), and richness (p = 0.016) were inversely associated with poliovirus shedding. Following vaccination, 28.6% of 14 infants tested developed neutralizing antibodies to all three Sabin types and also exhibited higher rates of poliovirus shedding (p = 0.020). No vaccine-derived poliovirus variants were detected. These results reveal an inverse association between eukaryotic virome abundance and poliovirus shedding. Overall gut virome ecology and concurrent viral infections may impact oral vaccine responsiveness in Bangladeshi infants.

scholarly journals Antibody response against selected epitopes in the HIV-1 envelope gp41 ectodomain contributes to reduce viral burden in HIV-1 infected patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rute Marcelino ◽  
Filipa Gramacho ◽  
Francisco Martin ◽  
Pedro Brogueira ◽  
Nuno Janeiro ◽  
...  
Keyword(s):  
Viral Load ◽  
T Cell ◽  
Neutralizing Antibodies ◽  
Plasma Viral Load ◽  
Tier 2 ◽  
Vaccine Candidates ◽  
Specific Antibodies ◽  
Cell Counts ◽  
Gp41 Ectodomain ◽  
Hiv 1

AbstractThe ectodomain of gp41 is the target of potent binding and neutralizing antibodies (NAbs) and is being explored in new strategies for antibody-based HIV vaccines. Previous studies have suggested that the W164A-3S (3S) and EC26-2A4 (EC26) peptides located in the gp41 ectodomain may be potential HIV vaccine candidates. We assessed 3S- and EC26-specific binding antibody responses and related neutralizing activity in a large panel of chronic HIV-1-infected Portuguese individuals on ART. A similar proportion of participants had antibodies binding to 3S (9.6%) and EC26 (9.9%) peptides but the level of reactivity against 3S was significantly higher compared to EC26, except in the rare patients with double peptide reactivity. The higher antigenicity of 3S was unrelated with disease stage, as assessed by CD4+ T cell counts, but it was directly related with plasma viral load. Most patients that were tested (89.9%, N = 268) showed tier 1 neutralizing activity, the potency being inversely associated with plasma viral load. In the subset of patients that were tested for neutralization of tier 2 isolates, neutralization breadth was inversely correlated with plasma viral load and directly correlated with CD4+ T cell counts. These results are consistent with a role for neutralizing antibodies in controlling viral replication and preventing the decline of CD4+ T lymphocytes. Importantly, in patients with 3S-specific antibodies, neutralizing titers were inversely correlated with viral RNA levels and proviral DNA levels. Moreover, patients with 3S and/or EC26-specific antibodies showed a 1.9-fold higher tier 2 neutralization score than patients without antibodies suggesting that 3S and/or EC26-specific antibodies contribute to neutralization breadth and potency in HIV-1 infected patients. Overall, these results suggest that antibodies targeting the S3 and EC26 epitopes may contribute to reduce viral burden and provide further support for the inclusion of 3S and EC26 epitopes in HIV-1 vaccine candidates.

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