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Background: Many HIV-1 broadly neutralizing antibodies (bnAbs) isoated from HIV-1 infected donors directly engage, or are dependent upon, N-linked glycans on the HIV-1 envelope-trimer for neutralization. It can take many years for bnAbs to develop following HIV-1 infection making it a challenge to identify immunization strategies that will re-elicit these bnAbs through vaccination. Since other glycosylated pathogens, such as bacteria and parasites, can raise a strong anti-glycan antibody response, the question arises whether the development of glycan-dependent HIV-1 bnAbs could be guided by Abs targeting glycans on other pathogens. We therefore set out to study cross-reactivity of glycan-binding bnAbs with parasite glycans and prevalence of seroreactivity to parasite Schistosoma mansoni in the IAVI Protocol C cohort. Methods: To measure cross-reactivity of known glycan-binding bnAbs with non-self parasite-derived glycans, we used a synthetic parasite glycan microarray and a 'shotgun' parasite glycan microarray The mode of glycan binding was assessed using STD NMR. We further confirmed cross-reactivity with S. mansoni using confocal microscopy and immunohistochemical analysis. To understand the seroprevalence of this parasitic infection in HIV-1 infected individuals in S. mansoni endemic regions we screened plasma from the well-studied IAVI Protocol C cohort for seroreactivity to S. mansoni antigens by ELISA. Results: We observed cross-reactivity of glycan-specific bnAbs to self and non-self S. mansoni glycans and were able to further confirm cross-binding of bnAbs to S. mansoni glycoproteins by confocal microscopy and immunohistochemical analysis. STD NMR analysis demonstrated that bnAb PGT121 contacts both self and non-self components of a representative parasite glycan. We detected an overall 41% seroprevalence against S. mansoni in a subset of IAVI protocol C donors, with a higher occurrence in donors with medium and top plasma neutralization (88% vs. 63%). We further observed cross-reactivity of N332/V3 specific PCDN76 bnAb lineage, including the unmutated common ancestor, with S. mansoni. Conclusions: These findings suggest antibody responses against parasite glycoproteins are readily found in HIV-1 positive donors. The cross-reactivity with parasite glycoproteins, particularly of the unmutated common ancestor of a bnAb suggest a non-self-glycan response could direct the development of glycan reactive HIV-1 bnAbs. These observations will inform and aid HIV-1 immunogen design., OA15.05LB I. Huettner (1); S. Krumm (1,2); E. Landais (3); K. Brzezicka (4); S. Serna (4); A.van Diepen (5); J. Angulo (6); F. Allan (7); A. Emery (7); N. Reichardt [...]

Objectives To report our experience with a case of a child with bilateral testicular micro-lithiasis (TML) who developed bilateral metachronous testicular germ cell tumor (TGCT) and determine the most appropriate follow-up and care management in children with testicular micro calcifications in regards to the theoretical risk of testicular cancer. Case report A 12 year-old boy was diagnosed with TGCT and TML. Ten years after complete remission, he presented with a recurrence on the contralateral testis. Genetic screening was performed on both resected and the patient’s karyotype was analyzed. Results Blood karyotype was normal. Aberrations were found in the tumor karyotype. CGH array showed alterations in chromosome arm 12p. Discussion TML is frequently associated with testicular malignancy in adults: in 16.9% of cases the normal contralateral testicle develops TML in TGCT. Recent works of literature find no relationship between TML and cancer in general, but in patients with additional risks, the relationship becomes stronger. Some authors suggest that environmental components and genetics are determinant factors. This is highly suspected in our reported case. It would seem that TML is not a precancerous lesion per se, but rather a marker of an at-risk situation. Long term evolution is uncertain and regular self-palpation that starts before puberty is the only way to ensure proper screening and monitoring. Conclusion TML have been suspected to be a sign of testicular dysgenesis syndrome, which yields a risk of developing TGCT in case of noxious associations. In patients with a history of TGCT contralateral TML is alarming and aggressive surgical management should be discussed. Therapeutic education of these patients on self-palpation is the best way to ensure proper follow-up. [ABSTRACT FROM AUTHOR]

Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases. [ABSTRACT FROM AUTHOR]

Objective: To assess knowledge of dietary and behaviour-related determinants of non-communicable disease (NCD) of urban Senegalese women.Design: A cross-sectional, population study using an interviewer-administered knowledge questionnaire, developed and validated for this study. The questionnaire consisted of 24 items with six scores measuring knowledge of: (1) diet- and behaviour-related causes of NCD; (2) diet quality-NCD relationship; (3) fruit and vegetable link with NCD; (4) health consequences of obesity; (5) causes of cardiovascular disease (CVD); and (6) causes of certain cancers.Subjects: A random sample of 301 women aged 20-50 years.Results: The knowledge scores developed suggest that the health consequences of obesity (mean score of 65.4%) were best understood followed by causes of CVD (mean score of 60.6%), because obesity, smoking, high blood cholesterol and dietary fat were well recognised as risk factors for CVD. Subjects scored least for their knowledge of the protective effect of fruit and vegetables (mean score of 19.9%). Knowledge of causes of certain cancers (mean score of 36.1%) was also low. Women who worked outside the home had better knowledge for two scores but otherwise no relationship was found between knowledge and literacy, formal education or body mass index.Conclusions: Findings suggest reasonable overall knowledge concerning diet and behaviour with NCD, especially given the relatively new context of the obesity epidemic in Senegal. However, there was poor knowledge of the benefit of eating fruit and vegetables and other preventable causes of certain cancers. Education targeting the benefits of vegetables and fruit may have the greatest impact on NCD prevention. [ABSTRACT FROM AUTHOR]

Abstract Background The increase in the burden of chronic diseases linked to the nutrition transition and associated dietary and lifestyle changes is of growing concern in south and east Mediterranean countries and adolescents are at the forefront of these changes. This study assessed dietary intake and association with socio-economic factors and health outcomes among adolescents in Tunisia. Methods Cross-sectional survey (year 2005); 1019 subjects 15-19 y. from a clustered random sample. Dietary intake was assessed by a validated semi-quantitative frequency questionnaire (134 items) as was physical activity; the Diet Quality Index International measured diet quality; dietary patterns were derived by multiple correspondence analysis from intakes of 43 food groups. Body Mass Index (BMI) ≥85th and 95th percentile defined overweight and obesity. Waist Circumference (WC) assessed abdominal fat. High blood pressure was systolic (SBP) or diastolic blood pressure (DBP) ≥90th of the international reference for 15-17 y., and SBP/DBP ≥120/80 mm Hg for 18-19 y. Results Energy intake levels were quite high, especially for females. The macro-nutrient structure was close to recommendations but only 38% had a satisfactory diet quality. A main traditional to modern dietary gradient, linked to urbanisation and increased economic level, featured an increasing consumption of white bread, dairy products, sugars, added fats and fruits and decreasing consumption of oils, grains, legumes and vegetables; regarding nutrients this modern diet score featured a decreasing relationship with total fat and an increase of calcium intake, but with an increase of energy, sugars and saturated fat, while vitamin C, potassium and fibre decreased. Adjusted for age, energy and physical activity, this modern pattern was associated with increased overweight in males (2nd vs. 1st tertile: Prevalence Odds-Ratio (POR) = 4.0[1.7-9.3], 3rd vs. 1st: POR = 3.3[1.3-8.7]) and a higher WC. Adjusting also for BMI and WC, among females, it was associated with decreased prevalence of high blood pressure (2nd vs. 1st tertile: POR = 0.5[0.3-0.8], 3rd vs. 1st tertile: POR = 0.4[0.2-0.8]). Conclusion The dietary intake contrasts among Tunisian adolescents, linked to socio-economic differentials are characteristic of a nutrition transition situation. The observed gradient of modernisation of dietary intake features associations with several nutrients involving a higher risk of chronic diseases but might have not only negative characteristics regarding health outcomes.

Abstract: The CD8αβ heterodimer interacts with class I pMHC on antigen-presenting cells as a co-receptor for TCR-mediated activation of cytotoxic T cells. To characterize this immunologically important interaction, we used monoclonal antibodies (mAbs) specific to either CD8α or CD8β to probe the mechanism of CD8αβ binding to pMHCI. The YTS156.7 mAb inhibits this interaction and blocks T cell activation. To elucidate the molecular basis for this inhibition, the crystal structure of the CD8αβ immunoglobulin-like ectodomains were determined in complex with mAb YTS156.7 Fab at 2.7 Å resolution. The YTS156.7 epitope on CD8β was identified and implies that residues in the CDR1 and CDR2-equivalent loops of CD8β are occluded upon binding to class I pMHC. To further characterize the pMHCI/CD8αβ interaction, binding of class I tetramers to CD8αβ on the surface of T cells was assessed in the presence of anti-CD8 mAbs. In contrast to YTS156.7, mAb YTS105.18, which is specific for CD8α, does not inhibit binding of CD8αβ to class I tetramers, indicating the YTS105.18 epitope is not occluded in the pMHCI/CD8αβ complex. Together, these data indicate a model for the pMHCI/CD8αβ interaction similar to that observed for CD8αα in the CD8αα/pMHCI complex, but in which CD8α occupies the lower orientation (membrane proximal to the antigen presenting cell), and CD8β occupies the upper position (membrane distal). The implication of this molecular assembly for the function of CD8αβ in T cell activation is discussed. [Copyright &y& Elsevier]

There is considerable interest in the potential of Epstein-Barr virus (EBV) latent antigen-specific CD4+ T cells to act as direct effectors controlling EBV-induced B lymphoproliferations. Such activity would require direct CD4+ T-cell recognition of latently infected cells through epitopes derived from endogenously expressed viral proteins and presented on the target cell surface in association with HLA class II molecules. It is therefore important to know how often these conditions are met. Here we provide CD4+ epitope maps for four EBV nuclear antigens, EBNA1, -2, -3A, and -3C, and establish CD4+ T-cell clones against 12 representative epitopes. For each epitope we identify the relevant HLA class II restricting allele and determine the efficiency with which epitope-specific effectors recognize the autologous EBV-transformed B-lymphoblastoid cell line (LCL). The level of recognition measured by gamma interferon release was consistent among clones to the same epitope but varied between epitopes, with values ranging from 0 to 35% of the maximum seen against the epitope peptide-loaded LCL. These epitope-specific differences, also apparent in short-term cytotoxicity and longer-term outgrowth assays on LCL targets, did not relate to the identity of the source antigen and could not be explained by the different functional avidities of the CD4+ clones; rather, they appeared to reflect different levels of epitope display at the LCL surface. Thus, while CD4+ T-cell responses are detectable against many epitopes in EBV latent proteins, only a minority of these responses are likely to have therapeutic potential as effectors directly recognizing latently infected target cells. [ABSTRACT FROM AUTHOR]

The generation of broadly neutralizing antibodies (bnAbs) to conserved epitopes on HIV Envelope (Env) is one of the cornerstones of HIV vaccine research. The animal models commonly used for HIV do not reliably produce a potent broadly neutralizing serum antibody response, with the exception of cows. Cows have previously produced a CD4 binding site response by homologous prime and boosting with a native-like Env trimer. In small animal models, other engineered immunogens were shown to focus antibody responses to the bnAb V2-apex region of Env. Here, we immunized two groups of cows (n = 4) with two regimens of V2-apex focusing Env immunogens to investigate whether antibody responses could be generated to the V2-apex on Env. Group 1 was immunized with chimpanzee simian immunodeficiency virus (SIV)-Env trimer that shares its V2-apex with HIV, followed by immunization with C108, a V2-apex focusing immunogen, and finally boosted with a cross-clade native-like trimer cocktail. Group 2 was immunized with HIV C108 Env trimer followed by the same HIV trimer cocktail as Group 1. Longitudinal serum analysis showed that one cow in each group developed serum neutralizing antibody responses to the V2-apex. Eight and 11 bnAbs were isolated from Group 1 and Group 2 cows, respectively, and showed moderate breadth and potency. Potent and broad responses in this study developed much later than previous cow immunizations that elicited CD4bs bnAbs responses and required several different immunogens. All isolated bnAbs were derived from the ultralong CDRH3 repertoire. The finding that cow antibodies can target more than one broadly neutralizing epitope on the HIV surface reveals the generality of elongated structures for the recognition of highly glycosylated proteins. The exclusive isolation of ultralong CDRH3 bnAbs, despite only comprising a small percent of the cow repertoire, suggests these antibodies outcompete the long and short CDRH3 antibodies during the bnAb response., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: VVS is a founder and owns equity in Taurus Biosciences LLC, San Diego, CA. The authors declare no other competing interests., (Copyright: © 2024 Altman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Duplications of the 3q29 cytoband are rare chromosomal copy number variations (CNVs) (overlapping or recurrent ~1.6 Mb 3q29 duplications). They have been associated with highly variable neurodevelopmental disorders (NDDs) with various associated features or reported as a susceptibility factor to the development of learning disabilities and neuropsychiatric disorders. The smallest region of overlap and the phenotype of 3q29 duplications remain uncertain. We here report a French cohort of 31 families with a 3q29 duplication identified by chromosomal microarray analysis (CMA), including 14 recurrent 1.6 Mb duplications, eight overlapping duplications (>1 Mb), and nine small duplications (<1 Mb). Additional genetic findings that may be involved in the phenotype were identified in 11 patients. Focusing on apparently isolated 3q29 duplications, patients present mainly mild NDD as suggested by a high rate of learning disabilities in contrast to a low proportion of patients with intellectual disabilities. Although some are de novo, most of the 3q29 duplications are inherited from a parent with a similar mild phenotype. Besides, the study of small 3q29 duplications does not provide evidence for any critical region. Our data suggest that the overlapping and recurrent 3q29 duplications seem to lead to mild NDD and that a severe or syndromic clinical presentation should warrant further genetic analyses., (© 2024 Wiley Periodicals LLC.)

A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features., (© 2024. The Author(s).)

A protective HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). Vaccination with the germline-targeting immunogen eOD-GT8 60mer adjuvanted with AS01 B was found to induce VRC01-class bnAb precursors in 97% of vaccine recipients in the IAVI G001 phase 1 clinical trial; however, heterologous boost immunizations with antigens more similar to the native glycoprotein will be required to induce bnAbs. Therefore, we designed core-g28v2 60mer, a nanoparticle immunogen to be used as a first boost after eOD-GT8 60mer priming. We found, using a humanized mouse model approximating human conditions of VRC01-class precursor B cell diversity, affinity, and frequency, that both protein- and mRNA-based heterologous prime-boost regimens induced VRC01-class antibodies that gained key mutations and bound to near-native HIV envelope trimers lacking the N276 glycan. We further showed that VRC01-class antibodies induced by mRNA-based regimens could neutralize pseudoviruses lacking the N276 glycan. These results demonstrated that heterologous boosting can drive maturation toward VRC01-class bnAb development and supported the initiation of the IAVI G002 phase 1 trial testing mRNA-encoded nanoparticle prime-boost regimens.

Multiple forms of malnutrition coexist in infants and young children (IYC) in Peru. The World Health Organization has proposed double-duty actions (DDAs) to simultaneously address undernutrition and overweight/obesity. We assessed current implementation of- and priority for- government-level actions to tackle multiple forms of malnutrition in IYC in Peru. Mapping of current policy activity was undertaken against 47 indicators of good practice for five DDAs (exclusive breastfeeding, complementary feeding, food marketing, maternal nutrition, preschool nutrition; assessed by 27 indicators) and for the enabling policy environment, i.e., 'infrastructure support' (health in all policies, platforms for interactions, financing, monitoring, governance, leadership; assessed by 20 indicators). Interviews with 16 national experts explored views on the level of and barriers to implementation of DDAs and infrastructure support, as well as their prioritisation based on likely impact and feasibility. The level of implementation of actions was categorised into two groups (agenda setting/formulation vs. implementation/evaluation). Mean scores were generated for prioritisation of DDAs and infrastructure support. Deductive qualitative analysis was undertaken to identify barriers that influence policy implementation. Only 5/27 DDA indicators were reported as fully implemented by all national experts (international code that regulates the marketing of breastmilk substitutes, iron supplementation for IYC, micronutrient powders in IYC, iron/folic acid supplementation in pregnant women, paid maternity leave). Only 1/20 infrastructure support indicator (access to nutrition information) was rated as fully implemented by all experts. Barriers to implementing DDAs and infrastructure support included: legal feasibility or lack of regulations, inadequate monitoring/evaluation to ensure enforcement, commercial influences on policymakers, insufficient resources, shifting public health priorities with the COVID-19 pandemic and political instability. The experts prioritised 12 indicators across all five DDAs and eight infrastructure support indicators. Experts highlighted the need to improve implementation of all DDAs and identified ways to strengthen the enabling policy environment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Huayta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The Minimum Dietary Diversity for Women of Reproductive Age (MDD-W) indicator was validated as a proxy of micronutrient adequacy among nonpregnant women in low- and middle-income countries (LMICs). At that time, indeed, there was insufficient data to validate the indicator among pregnant women, who face higher micronutrient requirements., Objective: This study aimed to validate a minimum food group consumption threshold, out of the 10 food groups used to construct MDD-W, to be used as a population-level indicator of higher micronutrient adequacy among pregnant women aged 15-49 y in LMICs., Methods: We used secondary quantitative 24-h recall data from 6 surveys in 4 LMICs (Bangladesh, Burkina Faso, India, and Nepal, total n  = 4909). We computed the 10-food group Women's Dietary Diversity Score (WDDS-10) and calculated the mean probability of adequacy (MPA) of 11 micronutrients. Linear regression models were fitted to assess the associations between WDDS-10 and MPA. Sensitivity, specificity, and proportion of individuals correctly classified were used to assess the performance of MDD-W in predicting an MPA of >0.60., Results: In the pooled sample, median values (interquartile range) of WDDS-10 and MPA were 3 (1) and 0.20 (0.34), respectively, whereas the proportion of pregnant women with an MPA of >0.60 was 9.6%. The WDDS-10 was significantly positively associated with MPA in each survey. Although the acceptable food group consumption threshold varied between 4 and 6 food groups across surveys, the threshold of 5 showed the highest performance in the pooled sample with good sensitivity (62%), very good specificity (81%), and percentage of correctly classified individuals (79%)., Conclusions: The WDDS-10 is a good predictor of dietary micronutrient adequacy among pregnant women aged 15-49 y in LMICs. Moreover, the threshold of 5 or more food groups for the MDD-W indicator may be extended to all women of reproductive age, regardless of their physiologic status., (© 2023 The Authors.)

Multiple forms of malnutrition coexist in Peru, especially in peri-urban areas and poor households. We investigated the magnitude of, and the contribution of, dietary and socio-demographic factors to the double burden of malnutrition (DBM) at maternal (i.e., maternal overweight/obesity with anaemia) and dyad (i.e., maternal overweight/obesity with child anaemia) levels. A cross-sectional survey was conducted among low-income mother-child (6-23 months) dyads (n = 244) from peri-urban communities in Peru. Dietary clusters and the minimum dietary diversity score (MDD) were generated for mothers and infants, respectively. A composite indicator using the maternal dietary clusters and the MDD was created to relate to dyad level DBM. Two dietary clusters were found: (i) the 'high variety (i.e., animal-source foods, fruit and vegetables), high sugary foods/beverages' (cluster 1) and (ii) the 'high potato, low fruit and vegetables, low red meat' (cluster 2). DBM prevalence among mothers and dyads was 19.9% and 36.3%, respectively. Logistic regression analyses revealed that the only socio-demographic factor positively associated with maternal DBM was maternal age (aOR/5 years: 1.35 [1.07, 1.71]). Mothers belonging to diet cluster 1 were less likely to experience the DBM (aOR = 0.52 [0.26, 1.03]), although CIs straddled the null. Socio-demographic factors positively associated with dyad level DBM included maternal age (aOR/5 years: 1.41 [1.15, 1.73]), and having ≥ two children under 5 years (aOR = 2.44 [1.23, 4.84]). Diet was not associated with dyad-level DBM. Double-duty actions that tackle the DBM are needed given that one-third of dyads and a fifth of mothers had concurrent overweight/obesity and anaemia., (© 2023 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Vaccination strategies aimed at maturing broadly neutralizing antibodies (bnAbs) from naïve precursors are hindered by unusual features that characterize these Abs, including insertions and deletions (indels). Longitudinal studies of natural HIV infection cases shed light on the complex processes underlying bnAb development and have suggested a role for superinfection as a potential enhancer of neutralization breadth. Here we describe the development of a potent bnAb lineage that was elicited by two founder viruses to inform vaccine design. The V3-glycan targeting bnAb lineage (PC39-1) was isolated from subtype C-infected IAVI Protocol C elite neutralizer, donor PC39, and is defined by the presence of multiple independent insertions in CDRH1 that range from 1-11 amino acids in length. Memory B cell members of this lineage are predominantly atypical in phenotype yet also span the class-switched and antibody-secreting cell compartments. Development of neutralization breadth occurred concomitantly with extensive recombination between founder viruses before each virus separated into two distinct population "arms" that evolved independently to escape the PC39-1 lineage. Ab crystal structures show an extended CDRH1 that can help stabilize the CDRH3. Overall, these findings suggest that early exposure of the humoral system to multiple related Env molecules could promote the induction of bnAbs by focusing Ab responses to conserved epitopes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Joyce et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The ability to efficiently isolate antigen-specific B cells in high throughput will greatly accelerate the discovery of therapeutic monoclonal antibodies (mAbs) and catalyze rational vaccine development. Traditional mAb discovery is a costly and labor-intensive process, although recent advances in single-cell genomics using emulsion microfluidics allow simultaneous processing of thousands of individual cells. Here we present a streamlined method for isolation and analysis of large numbers of antigen-specific B cells, including next generation antigen barcoding and an integrated computational framework for B cell multi-omics. We demonstrate the power of this approach by recovering thousands of antigen-specific mAbs, including the efficient isolation of extremely rare precursors of VRC01-class and IOMA-class broadly neutralizing HIV mAbs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hurtado, Flynn, Lee, Salcedo, Cottrell, Skog, Burton, Nemazee, Schief, Landais, Sok and Briney.)

Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype-phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

A small but growing body of scientific literature is emerging about clinical findings in patients with 19p13.3 microdeletion or duplication. Recently, a proximal 19p13.3 microduplication syndrome was described, associated with growth delay, microcephaly, psychomotor delay and dysmorphic features. The aim of our study was to better characterize the syndrome associated with duplications in the proximal 19p13.3 region (prox 19p13.3 dup), and to propose a comprehensive analysis of the underlying genomic mechanism. We report the largest cohort of patients with prox 19p13.3 dup through a collaborative study. We collected 24 new patients with terminal or interstitial 19p13.3 duplication characterized by array-based Comparative Genomic Hybridization (aCGH). We performed mapping, phenotype-genotype correlations analysis, critical region delineation and explored three-dimensional chromatin interactions by analyzing Topologically Associating Domains (TADs). We define a new 377 kb critical region (CR 1) in chr19: 3,116,922-3,494,377, GRCh37, different from the previously described critical region (CR 2). The new 377 kb CR 1 includes a TAD boundary and two enhancers whose common target is PIAS4. We hypothesize that duplications of CR 1 are responsible for tridimensional structural abnormalities by TAD disruption and misregulation of genes essentials for the control of head circumference during development, by breaking down the interactions between enhancers and the corresponding targeted gene., (© 2022 Wiley Periodicals LLC.)

Broadly neutralizing antibodies (bnAbs) to the HIV envelope (Env) V2-apex region are important leads for HIV vaccine design. Most V2-apex bnAbs engage Env with an uncommonly long heavy-chain complementarity-determining region 3 (HCDR3), suggesting that the rarity of bnAb precursors poses a challenge for vaccine priming. We created precursor sequence definitions for V2-apex HCDR3-dependent bnAbs and searched for related precursors in human antibody heavy-chain ultradeep sequencing data from 14 HIV-unexposed donors. We found potential precursors in a majority of donors for only two long-HCDR3 V2-apex bnAbs, PCT64 and PG9, identifying these bnAbs as priority vaccine targets. We then engineered ApexGT Env trimers that bound inferred germlines for PCT64 and PG9 and had higher affinities for bnAbs, determined cryo-EM structures of ApexGT trimers complexed with inferred-germline and bnAb forms of PCT64 and PG9, and developed an mRNA-encoded cell-surface ApexGT trimer. These methods and immunogens have promise to assist HIV vaccine development., Competing Interests: Declaration of interests J.R.W., K.M.M., J.M.S., and W.R.S. are named inventors on patent applications filed by Scripps and IAVI regarding ApexGT immunogens in this manuscript., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The COVID-19 pandemic may impact diet and nutrition through increased household food insecurity, lack of access to health services, and poorer quality diets. The primary aim of this study is to assess the impact of the pandemic on dietary outcomes of mothers and their infants and young children (IYC) in low-income urban areas of Peru. We conducted a panel study, with one survey prepandemic (n = 244) and one survey 9 months after the onset of COVID-19 (n = 254). We assessed breastfeeding and complementary feeding indicators and maternal dietary diversity in both surveys. During COVID-19, we assessed household food insecurity experience and economic impacts of the pandemic on livelihoods; receipt of financial or food assistance, and uptake of health services. Almost all respondents (98.0%) reported adverse economic impacts due to the pandemic and 46.9% of households were at risk of moderate or severe household food insecurity. The proportion of households receiving government food assistance nearly doubled between the two surveys (36.5%-59.5%). Dietary indicators, however, did not worsen in mothers or IYC. Positive changes included an increase in exclusive breastfeeding <6 months (24.2%-39.0%, p < 0.008) and a decrease in sweet food consumption by IYC (33.1%-18.1%, p = 0.001) and mothers (34.0%-14.6%, p < 0.001). The prevalence of sugar-sweetened beverage consumption remained high in both mothers (97%) and IYC (78%). In sum, we found dietary indicators had not significantly worsened 9 months into the COVID-19 pandemic. However, several indicators remain suboptimal and should be targeted in future interventions., (© 2022 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

The HIV-1 Envelope glycoprotein (Env) is the sole target for broadly neutralizing antibodies (bnAbs). Env is heavily glycosylated with host-derived N-glycans, and many bnAbs bind to, or are dependent upon, Env glycans for neutralization. Although glycan-binding bnAbs are frequently detected in HIV-infected individuals, attempts to elicit them have been unsuccessful because of the poor immunogenicity of Env N-glycans. Here, we report cross-reactivity of glycan-binding bnAbs with self- and non-self N-glycans and glycoprotein antigens from different life-stages of Schistosoma mansoni. Using the IAVI Protocol C HIV infection cohort, we examine the relationship between S. mansoni seropositivity and development of bnAbs targeting glycan-dependent epitopes. We show that the unmutated common ancestor of the N332/V3-specific bnAb lineage PCDN76, isolated from an HIV-infected donor with S. mansoni seropositivity, binds to S. mansoni cercariae while lacking reactivity to gp120. Overall, these results present a strategy for elicitation of glycan-reactive bnAbs which could be exploited in HIV-1 vaccine development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Elicitation of HIV broadly neutralizing antibodies (bnAbs) is challenging because unmutated bnAb precursors are rare and seldom bind HIV envelope glycoprotein (Env) trimers. One strategy to initiate bnAb responses is to use germline-targeting (GT) immunogens with high affinity to bnAb-class precursor B cells and then shepherd affinity maturation with booster immunogens that successively look more like native Env. In a mouse model where the frequency of VRC01-precursor (VRC01 gHL ) B cells mimics that of humans, we show that following a GT HIV Env trimer protein prime, VRC01-class B cells in the germinal center (GC) acquire high-affinity VRC01-class B cell somatic hypermutations (SHMs). Many GC-derived VRC01 gHL antibodies robustly bind N276 glycan-deficient Env trimers and neutralize several N276 glycan-deficient tier 2 HIV strains. These results are encouraging for GT Env trimer vaccine designs and demonstrate accumulation of substantial SHMs, including deletions, uncommon point mutations, and functional bnAb features, after a single immunization., Competing Interests: Declaration of interests W.R.S. is an inventor on a patent application concerning the eOD-GT5 60-mer and MD39-GT3.1 Env trimer immunogens., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

During human organogenesis, lung development is a timely and tightly regulated developmental process under the control of a large number of signaling molecules. Understanding how genetic variants can disturb normal lung development causing different lung malformations is a major goal for dissecting molecular mechanisms during embryogenesis. Here, through exome sequencing (ES), array CGH, genome sequencing (GS) and Hi-C, we aimed at elucidating the molecular basis of bilateral isolated lung agenesis in three fetuses born to a non-consanguineous family. We detected a complex genomic rearrangement containing duplicated, triplicated and deleted fragments involving the SHH locus in fetuses presenting complete agenesis of both lungs and near-complete agenesis of the trachea, diagnosed by ultrasound screening and confirmed at autopsy following termination. The rearrangement did not include SHH itself, but several regulatory elements for lung development, such as MACS1, a major SHH lung enhancer, and the neighboring genes MNX1 and NOM1. The rearrangement incorporated parts of two topologically associating domains (TADs) including their boundaries. Hi-C of cells from one of the affected fetuses showed the formation of two novel TADs each containing SHH enhancers and the MNX1 and NOM1 genes. Hi-C together with GS indicate that the new 3D conformation is likely causative for this condition by an inappropriate activation of MNX1 included in the neo-TADs by MACS1 enhancer, further highlighting the importance of the 3D chromatin conformation in human disease., (© 2021. The Author(s).)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike pseudotyped virus (PSV) assays are widely used to measure neutralization titers of sera and of isolated neutralizing Abs (nAbs). PSV neutralization assays are safer than live virus neutralization assays and do not require access to biosafety level 3 laboratories. However, many PSV assays are nevertheless somewhat challenging and require at least 2 d to carry out. In this study, we report a rapid (<30 min), sensitive, cell-free, off-the-shelf, and accurate assay for receptor binding domain nAb detection. Our proximity-based luciferase assay takes advantage of the fact that the most potent SARS-CoV-2 nAbs function by blocking the binding between SARS-CoV-2 and angiotensin-converting enzyme 2. The method was validated using isolated nAbs and sera from spike-immunized animals and patients with coronavirus disease 2019. The method was particularly useful in patients with HIV taking antiretroviral therapies that interfere with the conventional PSV assay. The method provides a cost-effective and point-of-care alternative to evaluate the potency and breadth of the predominant SARS-CoV-2 nAbs elicited by infection or vaccines., (Copyright © 2021 by The American Association of Immunologists, Inc.)

The stochastic development of broadly neutralizing antibodies (bnAbs) to HIV-1 is influenced by complex viral and host interactions. In this issue of Cell Host & Microbe, Townsley et al. reveal that early B cell and virus interactions during acute infection are predictive for developing bnAb responses later in infection., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Despite the urgency regarding increasing rates of obesity and chronic diseases in the Caribbean, few studies described the nutrition transition. We aimed to provide such information by identifying dietary patterns in the French West Indies and their characteristics., Methods: This cross-sectional analysis included 1144 Guadeloupeans and Martinicans from a multistage sampling survey conducted on a representative sample. Dietary patterns were identified using principal component analysis followed by a clustering procedure, and described using multivariable regression models., Results: Four patterns were identified: (i) a "prudent" pattern characterized by high intakes of fruits, vegetables, legumes, seafood and yogurts, low intakes of fatty and sweet products, and a high Diet Quality Index-International (DQI-I); (ii) a "traditional" pattern characterized by high intakes of fruits, vegetables, tubers and fish, low intakes of red and processed meat, snacks, fast foods, and sweetened beverages, with a high DQI-I, mostly shaped by women and older persons; (iii) a "convenient" pattern characterized by high intakes of sweetened beverages, snacks, and fast foods, with the lowest DQI-I, principally shaped by young participants; (iv) a "transitioning" pattern characterized by high consumptions of bread, processed meat, sauces, alcoholic and sweetened beverages, but also high intakes of tubers, legumes, and fish, mainly shaped by men, middle aged, of whom 35% had metabolic syndrome., Conclusion: The co-existing dietary patterns in the French West Indies, marked by a generational contrast, seem to reflect different steps in dietary change as described in the literature, suggesting an ongoing nutrition transition.

Human Immunodeficiency Virus type-1 (HIV-1) establishes a latent viral reservoir soon after infection, which poses a major challenge for drug treatment and curative strategies. Many efforts are therefore focused on blocking infection. To this end, both viral and host factors relevant to the onset of infection need to be considered. Given that HIV-1 is most often transmitted mucosally, strategies designed to protect against infection need to be effective at mucosal portals of entry. These strategies need to contend also with cell-free and cell-associated transmitted/founder (T/F) virus forms; both can initiate and establish infection. This review will discuss how insight from the current model of HIV-1 mucosal transmission and cell entry has highlighted challenges in developing effective strategies to prevent infection. First, we examine key viral and host factors that play a role in transmission and infection. We then discuss preventive strategies based on antibody-mediated protection, with emphasis on targeting T/F viruses and mucosal immunity. Lastly, we review treatment strategies targeting viral entry, with focus on the most clinically advanced entry inhibitors.

HIV broadly neutralizing antibodies (bnAbs) can suppress viremia and protect against HIV infection. However, their elicitation is made difficult by low frequencies of appropriate precursor B cell receptors and the complex maturation pathways required to generate bnAbs from these precursors. Antibody genes can be engineered into B cells for expression as both a functional antigen receptor on cell surfaces and as secreted antibody. Here, we show that HIV bnAb-engineered primary mouse B cells can be adoptively transferred and vaccinated in immunocompetent mice resulting in the expansion of durable bnAb memory and long-lived plasma cells. Somatic hypermutation after immunization indicates that engineered cells have the capacity to respond to an evolving pathogen. These results encourage further exploration of engineered B cell vaccines as a strategy for durable elicitation of HIV bnAbs to protect against infection and as a contributor to a functional HIV cure.

Conventional vaccine design has been based on trial-and-error approaches, which have been generally successful. However, there have been some major failures in vaccine development and we still do not have highly effective licensed vaccines for tuberculosis, HIV, respiratory syncytial virus, and other major infections of global significance. Approaches at rational vaccine design have been limited by our understanding of the immune response to vaccination at the molecular level. Tools now exist to undertake in-depth analysis using systems biology approaches, but to be fully realized, studies are required in humans with intensive blood and tissue sampling. Methods that support this intensive sampling need to be developed and validated as feasible. To this end, we describe here a detailed approach that was applied in a study of 15 healthy adults, who were immunized with hepatitis B vaccine. Sampling included ~350 mL of blood, 12 microbiome samples, and lymph node fine needle aspirates obtained over a ~7-month period, enabling comprehensive analysis of the immune response at the molecular level, including single cell and tissue sample analysis. Samples were collected for analysis of immune phenotyping, whole blood and single cell gene expression, proteomics, lipidomics, epigenetics, whole blood response to key immune stimuli, cytokine responses, in vitro T cell responses, antibody repertoire analysis and the microbiome. Data integration was undertaken using different approaches-NetworkAnalyst and DIABLO. Our results demonstrate that such intensive sampling studies are feasible in healthy adults, and data integration tools exist to analyze the vast amount of data generated from a multi-omics systems biology approach. This will provide the basis for a better understanding of vaccine-induced immunity and accelerate future rational vaccine design., (Copyright © 2020 Ben-Othman, Cai, Liu, Varankovich, He, Blimkie, Lee, Gill, Novotny, Aevermann, Drissler, Shannon, McCann, Marty, Bjornson, Edgar, Lin, Gladish, Maclsaac, Amenyogbe, Chan, Llibre, Collin, Landais, Le, Reiss, Koff, Havenar-Daughton, Heran, Sangha, Walt, Krajden, Crotty, Sok, Briney, Burton, Duffy, Foster, Mohn, Kobor, Tebbutt, Brinkman, Scheuermann, Hancock, Kollmann and Sadarangani.)

An oligomannose patch around the V3 base of HIV-1 envelope glycoprotein (Env) is recognized by multiple classes of broadly neutralizing antibodies (bNAbs). Here, we investigated the bNAb response to the V3 glycan supersite in an HIV-1-infected Chinese donor by Env-specific single B cell sorting, structural and functional studies, and longitudinal analysis of antibody and virus repertoires. Monoclonal antibodies 438-B11 and 438-D5 were isolated that potently neutralize HIV-1 with moderate breadth, are encoded by the V H 1-69 germline gene, and have a disulfide-linked long HCDR3 loop. Crystal structures of Env-bound and unbound antibodies revealed heavy chain-mediated recognition of the glycan supersite with a unique angle of approach and a critical role of the intra-HCDR3 disulfide. The mechanism of viral escape was examined via single-genome amplification/sequencing and glycan mutations around the N332 supersite. Our findings further emphasize the V3 glycan supersite as a prominent target for Env-based vaccine design., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

BG505 SOSIP is a well-characterized near-native recombinant HIV Envelope (Env) trimer that holds promise as part of a sequential HIV immunogen regimen to induce broadly neutralizing antibodies (bnAbs). Rhesus macaques are considered the most appropriate pre-clinical animal model for monitoring antibody (Ab) responses. Accordingly, we report here the isolation of 45 BG505 autologous neutralizing antibodies (nAbs) with multiple specificities from SOSIP-immunized and BG505 SHIV-infected rhesus macaques. We associate the most potent neutralization with two epitopes: the C3/V5 and V1/V3 regions. We show that all of the nAbs bind in close proximity to known bnAb epitopes and might therefore sterically hinder elicitation of bnAbs. We also identify a "public clonotype" that targets the immunodominant C3/V5 nAb epitope, which suggests that common antibody rearrangements might help determine humoral responses to Env immunogens. The results highlight important considerations for vaccine design in anticipation of results of the BG505 SOSIP trimer in clinical trials., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)