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Brain microglia (MG) may serve as a human immunodeficiency virus 1 (HIV) reservoir and ignite rebound viremia following cessation of antiretroviral therapy (ART), but they have yet to be proven to harbor replication-competent HIV. Here, we isolated brain myeloid cells (BrMCs) from nonhuman primates and rapid autopsy of people with HIV (PWH) on ART and sought evidence of persistent viral infection. BrMCs predominantly displayed microglial markers, in which up to 99.9% of the BrMCs were [TMEM119.sup.+] MG. Total and integrated SIV or HIV DNA was detectable in the MG, with low levels of cell-associated viral RNA. Provirus in MG was highly sensitive to epigenetic inhibition. Outgrowth virus from parietal cortex MG in an individual with HIV productively infected both MG and PBMCs. This inducible, replication-competent virus and virus from basal ganglia proviral DNA were closely related but highly divergent from variants in peripheral compartments. Phenotyping studies characterized brain-derived virus as macrophage tropic based on the ability of the virus to infect cells expressing low levels of CD4. The lack of genetic diversity in virus from the brain suggests that this macrophage-tropic lineage quickly colonized brain regions. These data demonstrate that MG harbor replication-competent HIV and serve as a persistent reservoir in the brain., Introduction Efforts to clear HIV infection require a careful assessment of all the tissue reservoirs in which the virus persists despite durable antiretroviral therapy (ART). The CNS is a site [...]

Several HIV envelope-targeting (Env-targeting) antibodies with broad and potent neutralizing activity have been Identified and shown to have unusual features. Of these, the PG9 antibody has a long heavy chain complementarity determining region 3 (HCDR3) and possesses unique structural elements that interact with protein and glycan features of the HIV Env glycoprotein. Here, we used the Rosetta software suite to design variants of the PG9 antibody HCDR3 loop with the goal of identifying variants with increased potency and breadth of neutralization for diverse HIV strains. One variant, designated [PG9_N100.sub.F]Y, possessed increased potency and was able to neutralize a diverse set of PG9- resistant HIV strains, including those lacking the Env N160 glycan, which is critical for PG9 binding. An atomic resolution structure of the [PG9_N100.sub.F]Y fragment antigen binding (Fab) confirmed that the mutated residue retains the paratope surface when compared with WT PG9. Differential scanning calorimetry experiments revealed that the mutation caused a modest increase in thermodynamic stability of the Fab, a feature predicted by the computational model. Our findings suggest that thermodynamic stabilization of the long HCDR3 in its active conformation is responsible for the increased potency of [PG9_N100.sub.F]Y, and strategies aimed at stabilizing this region in other HIV antibodies could become an important approach to in silico optimization of antibodies., Introduction Recent studies have described the isolation of a number of human mAbs directed to the HIV envelope (Env) that exhibit broad and potent neutralizing activity, many of which exhibit [...]

Rheumatoid Arthritis (RA) is an autoimmune disease of unknown aetiology involving complex interactions between environmental and genetic factors. Its pathogenesis is suspected to arise from intricate interplays between signalling, gene regulation and metabolism, leading to synovial inflammation, bone erosion and cartilage destruction in the patients' joints. In addition, the resident synoviocytes of macrophage and fibroblast types can interact with innate and adaptive immune cells and contribute to the disease's debilitating symptoms. Therefore, a detailed, mechanistic mapping of the molecular pathways and cellular crosstalks is essential to understand the complex biological processes and different disease manifestations. In this regard, we present the RA-Atlas, an SBGN-standardized, interactive, manually curated representation of existing knowledge related to the onset and progression of RA. This state-of-the-art RA-Atlas includes an updated version of the global RA-map covering relevant metabolic pathways and cell-specific molecular interaction maps for CD4+ Th1 cells, fibroblasts, and M1 and M2 macrophages. The molecular interaction maps were built using information extracted from published literature and pathway databases and enriched using omic data. The RA-Atlas is freely accessible on the webserver MINERVA (https://ramap.uni.lu/minerva/), allowing easy navigation using semantic zoom, cell-specific or experimental data overlay, gene set enrichment analysis, pathway export or drug query. [ABSTRACT FROM AUTHOR]

Background Juvenile-onset recurrent respiratory papillomatosis (JORRP) is a rare and serious disease caused by human papillomavirus (HPV) presumably acquired during vaginal delivery. HPV vaccination of females through age 26 years, recommended in the United States since 2006, can prevent HPV transmission. We assessed trends in JORRP cases before and after HPV vaccine introduction in the United States. Methods Case-patients were identified from 26 pediatric otolaryngology centers in 23 U.S. states. Demographics and clinical history were abstracted from medical records. Case-patients were grouped by year of birth, and birth-cohort incidences were calculated using number of births from either national or state-level natality data from the 23 states. We calculated incidence rate ratios (IRR) and 95% confidence intervals (CI) in 2-year intervals. Results We identified 576 U.S. JORRP case-patients born in 2004–2013. Median age at diagnosis was 3.4 years (interquartile range: 1.9, 5.5). Number of identified JORRP case-patients declined from a baseline of 165 born in 2004–2005 to 36 born in 2012–2013. Incidence of JORRP per 100 000 births using national data declined from 2.0 cases in 2004–2005 to 0.5 cases in 2012–2013 (IRR = 0.2, 95% CI =.1–.4); incidence using state-level data declined from 2.9 cases in 2004–2005 to 0.7 cases in 2012–2013 (IRR = 0.2, 95% CI =.1–.4). Conclusions Over a decade, numbers of JORRP case-patients and incidences declined significantly. Incidences calculated using national denominator data are likely underestimates; those calculated using state-level denominator data could be overestimates. These declines are most likely due to HPV vaccination. Increasing vaccination uptake could lead to elimination of this HPV-related disease. [ABSTRACT FROM AUTHOR]

Background Juvenile-onset recurrent respiratory papillomatosis (JORRP) is a rare disease characterized by the growth of papillomas in the respiratory tract. In the United States, JORRP is not a nationally notifiable condition and current data are limited. Methods Children with JORRP aged <18 years were enrolled from 26 pediatric otolaryngology centers in 23 US states from January 2015 through August 2020. Demographic, birth information, and maternal vaccination history were collected from a parent/guardian. Clinical history was abstracted from medical records. Papilloma biopsies were tested for 28 human papillomavirus (HPV) types. Mothers who delivered in 2006 or later were considered age-eligible for HPV vaccination if aged ≤26 years in 2006. We described characteristics of enrolled children and their birth mothers and analyzed disease severity by diagnosis age and HPV type using multiple logistic regression. Results Among 215 children with JORRP, 88.8% were delivered vaginally; 64.2% were firstborn. Among 190 mothers, the median delivery age was 22 years. Among 114 (60.0%) age-eligible for HPV vaccination, 16 (14.0%) were vaccinated, 1 (0.9%) before delivery. Among 162 specimens tested, 157 (96.9%) had detectable HPV; all 157 had a vaccine-preventable type. Disease severity was associated with younger diagnosis age and HPV 11; adjusted analyses found only younger diagnosis age significant (adjusted odds ratio: 6.1; 95% confidence interval: 2.9, 12.8). Conclusions Children with JORRP were commonly firstborn and delivered vaginally to young mothers; most of the mothers reported no HPV vaccination before delivery. Vaccine-preventable HPV was identified in all specimens with detectable HPV. Increasing preexposure HPV vaccination could substantially reduce or eliminate JORRP in the United States. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a progressive, inflammatory autoimmune disease of unknown aetiology. The complex mechanism of aetiopathogenesis, progress and chronicity of the disease involves genetic, epigenetic and environmental factors. To understand the molecular mechanisms underlying disease phenotypes, one has to place implicated factors in their functional context. However, integration and organization of such data in a systematic manner remains a challenging task. Molecular maps are widely used in biology to provide a useful and intuitive way of depicting a variety of biological processes and disease mechanisms. Recent large-scale collaborative efforts such as the Disease Maps Project demonstrate the utility of such maps as versatile tools to organize and formalize disease-specific knowledge in a comprehensive way, both human and machine-readable. We present a systematic effort to construct a fully annotated, expert validated, state-of-the-art knowledge base for RA in the form of a molecular map. The RA map illustrates molecular and signalling pathways implicated in the disease. Signal transduction is depicted from receptors to the nucleus using the Systems Biology Graphical Notation (SBGN) standard representation. High-quality manual curation, use of only human-specific studies and focus on small-scale experiments aim to limit false positives in the map. The state-of-the-art molecular map for RA, using information from 353 peer-reviewed scientific publications, comprises 506 species, 446 reactions and 8 phenotypes. The species in the map are classified to 303 proteins, 61 complexes, 106 genes, 106 RNA entities, 2 ions and 7 simple molecules. The RA map is available online at ramap.elixir-luxembourg.org as an open-access knowledge base allowing for easy navigation and search of molecular pathways implicated in the disease. Furthermore, the RA map can serve as a template for omics data visualization. [ABSTRACT FROM AUTHOR]

Broadly neutralizing antibodies (bNAbs) are rarely elicited by current human immunodeficiency virus type 1 (HIV-1) vaccine designs, but the presence of bNAbs in naturally infected individuals may be associated with high plasma viral loads, suggesting that the magnitude, duration, and diversity of viral exposure may contribute to the development of bNAbs. Here, we report the isolation and characterization of a panel of human monoclonal antibodies (mAbs) from two subjects who developed broadly neutralizing autologous antibody responses during HIV-1 infection. In both subjects, we identified collections of mAbs that exhibited specificity only to a few autologous envelopes (Envs), with some mAbs exhibiting specificity only to a subset of Envs within the quasispecies of a particular sample at one time point. Neutralizing antibodies (NAbs) isolated from these subjects mapped mostly to epitopes in the Env V3 loop region and the CD4 binding site. None of the individual neutralizing mAbs recovered exhibited the cumulative breadth of neutralization present in the serum of the subjects. Surprisingly, however, the activity of polyclonal mixtures comprising individual mAbs that each possessed limited neutralizing activity, could achieve increased breadth of neutralizing activity against autologous isolates. While a single broadly neutralizing antibody targeting one epitope can mediate neutralization breadth, the findings presented here suggest that a cooperative polyclonal process mediated by diverse antibodies with more limited breadth targeting multiple epitopes also can achieve neutralization breadth against HIV-1. [ABSTRACT FROM AUTHOR]

COVID-19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms GLO:1CEJ/01dec21:msb202110851-toc-0001.jpg PHOTO (COLOR): . gl The authors requested to correct the spelling of Egon Willighagen and Andrea Senff-Ribeiro's names, as well as the following affiliations: Charles Auffray to: "European Institute for Systems Biology and Medicine (EISBM), Vourles, France"; Noriko Hiori to: "Graduate School of Media and Governance, Keio Research Institute at SFC, Keio University, Kanagawa, Japan"; and Leonard Schmeister to: "Center for Mathematics, Chair of Mathematical Modeling of Biological Systems, Technische Universität München, Garching, Germany and Helmholtz Zentrum München - German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg, Germany". [Extracted from the article]

Rheumatoid arthritis (RA) is a multifactorial, complex autoimmune disease that involves various genetic, environmental, and epigenetic factors. Systems biology approaches provide the means to study complex diseases by integrating different layers of biological information. Combining multiple data types can help compensate for missing or conflicting information and limit the possibility of false positives. In this work, we aim to unravel mechanisms governing the regulation of key transcription factors in RA and derive patient-specific models to gain more insights into the disease heterogeneity and the response to treatment. We first use publicly available transcriptomic datasets (peripheral blood) relative to RA and machine learning to create an RA-specific transcription factor (TF) co-regulatory network. The TF cooperativity network is subsequently enriched in signalling cascades and upstream regulators using a state-of-the-art, RA-specific molecular map. Then, the integrative network is used as a template to analyse patients' data regarding their response to anti-TNF treatment and identify master regulators and upstream cascades affected by the treatment. Finally, we use the Boolean formalism to simulate in silico subparts of the integrated network and identify combinations and conditions that can switch on or off the identified TFs, mimicking the effects of single and combined perturbations. [ABSTRACT FROM AUTHOR]

Brain microglia (MG) may serve as a human immunodeficiency virus 1 (HIV) reservoir and ignite rebound viremia following cessation of antiretroviral therapy (ART), but they have yet to be proven to harbor replication-competent HIV. Here, we isolated brain myeloid cells (BrMCs) from nonhuman primates and rapid autopsy of people with HIV (PWH) on ART and sought evidence of persistent viral infection. BrMCs predominantly displayed microglial markers, in which up to 99.9% of the BrMCs were TMEM119+ MG. Total and integrated SIV or HIV DNA was detectable in the MG, with low levels of cell- associated viral RNA. Provirus in MG was highly sensitive to epigenetic inhibition. Outgrowth virus from parietal cortex MG in an individual with HIV productively infected both MG and PBMCs. This inducible, replication-competent virus and virus from basal ganglia proviral DNA were closely related but highly divergent from variants in peripheral compartments. Phenotyping studies characterized brain-derived virus as macrophage tropic based on the ability of the virus to infect cells expressing low levels of CD4. The lack of genetic diversity in virus from the brain suggests that this macrophage-tropic lineage quickly colonized brain regions. These data demonstrate that MG harbor replication-competent HIV and serve as a persistent reservoir in the brain. [ABSTRACT FROM AUTHOR]

Live viral vectors that express heterologous antigens of the target pathogen are being investigated in the development of novel vaccines against serious infectious agents like HIV and Ebola. As some live recombinant vectored vaccines may be replication-competent, a key challenge is defining the length of time for monitoring potential adverse events following immunization (AEFI) in clinical trials and epidemiologic studies. This time period must be chosen with care and based on considerations of pre-clinical and clinical trials data, biological plausibility and practical feasibility. The available options include: (1) adapting from the current relevant regulatory guidelines; (2) convening a panel of experts to review the evidence from a systematic literature search to narrow down a list of likely potential or known AEFI and establish the optimal risk window(s); and (3) conducting "near real-time" prospective monitoring for unknown clustering's of AEFI in validated large linked vaccine safety databases using Rapid Cycle Analysis for pre-specified adverse events of special interest (AESI) and Treescan to identify previously unsuspected outcomes. The risk window established by any of these options could be used along with (4) establishing a registry of clinically validated pre-specified AESI to include in case-control studies. Depending on the infrastructure, human resources and databases available in different countries, the appropriate option or combination of options can be determined by regulatory agencies and investigators. [ABSTRACT FROM AUTHOR]

Introduction: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing., Methods: Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors., Results: Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19., Discussion: The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies., Competing Interests: AN collaborates with SANOFI-AVENTIS R&D via a public–private partnership grant CIFRE contract, n° 2020/0766. DM and AB are employed at Labvantage-Biomax GmbH and will be affected by any effect of this publication on the commercial version of the AILANI software. JB and BG received consulting fees from Two Six Labs, LLC. TH has served as a shareholder and has consulted for Discovery Collective, Inc. RB and RS are founders and shareholders of MEGENO SA and ITTM SA. JS-R reports funding from GSK, Pfizer and Sanofi and fees/honoraria from Travere Therapeutics, Stadapharm, Astex, Owkin, Pfizer and Grunenthal. JP and LF are employees and shareholders of MedBioinformatics Solutions SL. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Niarakis, Ostaszewski, Mazein, Kuperstein, Kutmon, Gillespie, Funahashi, Acencio, Hemedan, Aichem, Klein, Czauderna, Burtscher, Yamada, Hiki, Hiroi, Hu, Pham, Ehrhart, Willighagen, Valdeolivas, Dugourd, Messina, Esteban-Medina, Peña-Chilet, Rian, Soliman, Aghamiri, Puniya, Naldi, Helikar, Singh, Fernández, Bermudez, Tsirvouli, Montagud, Noël, Ponce-de-Leon, Maier, Bauch, Gyori, Bachman, Luna, Piñero, Furlong, Balaur, Rougny, Jarosz, Overall, Phair, Perfetto, Matthews, Rex, Orlic-Milacic, Gomez, De Meulder, Ravel, Jassal, Satagopam, Wu, Golebiewski, Gawron, Calzone, Beckmann, Evelo, D’Eustachio, Schreiber, Saez-Rodriguez, Dopazo, Kuiper, Valencia, Wolkenhauer, Kitano, Barillot, Auffray, Balling, Schneider and the COVID-19 Disease Map Community.)

Why multisystem inflammatory syndrome in children (MIS-C) develops after SARS-CoV-2 infection in a subset of children is unknown. We hypothesized that aberrant virus-specific T cell responses contribute to MIS-C pathogenesis. We quantified SARS-CoV-2-reactive T cells, serologic responses against major viral proteins, and cytokine responses from plasma and peripheral blood mononuclear cells in children with convalescent COVID-19, in children with acute MIS-C, and in healthy controls. Children with MIS-C had significantly lower virus-specific CD4+ and CD8+ T cell responses to major SARS-CoV-2 antigens compared with children convalescing from COVID-19. Furthermore, T cell responses in participants with MIS-C were similar to or lower than those in healthy controls. Serologic responses against spike receptor binding domain (RBD), full-length spike, and nucleocapsid were similar among convalescent COVID-19 and MIS-C, suggesting functional B cell responses. Cytokine profiling demonstrated predominant Th1 polarization of CD4+ T cells from children with convalescent COVID-19 and MIS-C, although cytokine production was reduced in MIS-C. Our findings support a role for constrained induction of anti-SARS-CoV-2-specific T cells in the pathogenesis of MIS-C.

Biomedical research in animal models depends heavily on nonhuman primates (NHP) (Phillips et al., Am J Primatol 76(9):801-827, 2014). In their physiology, neurobiology, and, most importantly, their susceptibility to infectious diseases and subsequent immune responses, NHPs have many parallels with humans (Rhesus Macaque Genome Sequencing and Analysis Consortium et al., Science 316(5822):222-234, 2007). Different species of NHPs have served as important animal models for numerous infectious diseases spanning a wide range of pathogens (Gardner and Luciw, ILAR J 49(2):220-255, 2008). As a result of recognizing their utility in HIV research, NHPs have contributed to groundbreaking studies of disease pathogenesis, vaccination, and curative research (London et al., Lancet 2(8355):869-873, 1983; Henrickson et al., Lancet 1 (8321):388-390, 1983). Many African NHPs are considered natural hosts for SIV in which SIV infection is usually nonprogressive and does not cause acquired immunodeficiency syndrome (AIDS) (Chahroudi et al., Science 335(6073):1188-1193, 2012; Taaffe et al., J Virol 84(11):5476-5484, 2010). However, cross-species transmission of SIV strains to other NHPs or to humans (nonnatural hosts) leads to progressive disease and AIDS (Paiardini et al., Annu Rev Med 60:485-495, 2009). In particular, SIV infection of Asian rhesus macaques recapitulates many features of HIV infection in humans and therefore has become a widely used approach for contemporary HIV research into virus persistence and cure strategies (Gardner and Luciw, FASEB J 3(14):2593-2606, 1989). There are multiple factors that should be considered in HIV/SIV studies using NHPs including the particular monkey species and geographic background, age and sex, certain genetic properties, virus strain, route and dose of infection, interventional treatments, and prespecified study outcomes. Here, we discuss consideration of these factors to address specific questions in HIV cure research., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

There is limited understanding of the viral antibody fingerprint following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children. Herein, SARS-CoV-2 proteome-wide immunoprofiling of children with mild/moderate or severe coronavirus disease 2019 (COVID-19) versus multisystem inflammatory syndrome in children versus hospitalized control patients revealed differential cytokine responses, IgM/IgG/IgA epitope diversity, antibody binding and avidity. Apart from spike and nucleocapsid, IgG/IgA recognized epitopes in nonstructural protein (NSP) 2, NSP3, NSP12-NSP14 and open reading frame (ORF) 3a-ORF9. Peptides representing epitopes in NSP12, ORF3a and ORF8 demonstrated SARS-CoV-2 serodiagnosis. Antibody-binding kinetics with 24 SARS-CoV-2 proteins revealed antibody parameters that distinguish children with mild/moderate versus severe COVID-19 or multisystem inflammatory syndrome in children. Antibody avidity to prefusion spike correlated with decreased illness severity and served as a clinical disease indicator. The fusion peptide and heptad repeat 2 region induced SARS-CoV-2-neutralizing antibodies in rabbits. Thus, we identified SARS-CoV-2 antibody signatures in children associated with disease severity and delineate promising serodiagnostic and virus neutralization targets. These findings might guide the design of serodiagnostic assays, prognostic algorithms, therapeutics and vaccines in this important but understudied population., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Motivation: Molecular interaction maps have emerged as a meaningful way of representing biological mechanisms in a comprehensive and systematic manner. However, their static nature provides limited insights to the emerging behaviour of the described biological system under different conditions. Computational modelling provides the means to study dynamic properties through in silico simulations and perturbations. We aim to bridge the gap between static and dynamic representations of biological systems with CaSQ, a software tool that infers Boolean rules based on the topology and semantics of molecular interaction maps built with CellDesigner., Results: We developed CaSQ by defining conversion rules and logical formulas for inferred Boolean models according to the topology and the annotations of the starting molecular interaction maps. We used CaSQ to produce executable files of existing molecular maps that differ in size, complexity and the use of Systems Biology Graphical Notation (SBGN) standards. We also compared, where possible, the manually built logical models corresponding to a molecular map to the ones inferred by CaSQ. The tool is able to process large and complex maps built with CellDesigner (either following SBGN standards or not) and produce Boolean models in a standard output format, Systems Biology Marked Up Language-qualitative (SBML-qual), that can be further analyzed using popular modelling tools. References, annotations and layout of the CellDesigner molecular map are retained in the obtained model, facilitating interoperability and model reusability., Availability and Implementation: The present tool is available online: https://lifeware.inria.fr/∼soliman/post/casq/ and distributed as a Python package under the GNU GPLv3 license. The code can be accessed here: https://gitlab.inria.fr/soliman/casq., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2020. Published by Oxford University Press.)

In this work we present a systematic effort to summarize current biological pathway knowledge concerning Rheumatoid Arthritis (RA). We are constructing a detailed molecular map based on exhaustive literature scanning, strict curation criteria, re-evaluation of previously published attempts and most importantly experts' advice. The RA map will be web-published in the coming months in the form of an interactive map, using the MINERVA platform, allowing for easy access, navigation and search of all molecular pathways implicated in RA, serving thus, as an on line knowledgebase for the disease. Moreover the map could be used as a template for Omics data visualization offering a first insight about the pathways affected in different experimental datasets. The second goal of the project is a dynamical study focused on synovial fibroblasts' behavior under different initial conditions specific to RA, as recent studies have shown that synovial fibroblasts play a crucial role in driving the persistent, destructive characteristics of the disease. Leaning on the RA knowledgebase and using the web platform Cell Collective, we are currently building a Boolean large scale dynamical model for the study of RA fibroblasts' activation., Competing Interests: CONFLICT OF INTEREST The authors declare no conflict of interest.

Since 2011, over 300 human cases of infection, especially in exposed children, with the influenza A H3N2 variant (H3N2v) virus that circulates in swine in the US have been reported. The structural and genetic basis for the lack of protection against H3N2v induced by vaccines containing seasonal H3N2 antigens is poorly understood. We isolated 17 human monoclonal antibodies (mAbs) that neutralized H3N2v virus from subjects experimentally immunized with an H3N2v candidate vaccine. Six mAbs exhibited very potent neutralizing activity (IC 50 < 200 ng/ml) against the H3N2v virus but not against current human H3N2 circulating strains. Fine epitope mapping and structural characterization of antigen-antibody complexes revealed that H3N2v specificity was attributable to amino acid polymorphisms in the 150-loop and the 190-helix antigenic sites on the hemagglutinin protein. H3N2v-specific antibodies also neutralized human H3N2 influenza strains naturally circulating between 1995 and 2005. These results reveal a high level of antigenic relatedness between the swine H3N2v virus and previously circulating human strains, consistent with the fact that early human H3 seasonal strains entered the porcine population in the 1990s and reentered the human population, where they had not been circulating, as H3N2v about a decade later. The data also explain the increased susceptibility to H3N2v viruses in young children, who lack prior exposure to human seasonal strains from the 1990s.