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.
View Article and Find Full Text PDFPLoS One
May 2024
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.
View Article and Find Full Text PDFA protective HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). Vaccination with the germline-targeting immunogen eOD-GT8 60mer adjuvanted with AS01 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.
View Article and Find Full Text PDFThe generation of broadly neutralizing antibodies (bnAbs) to specific HIV epitopes of the HIV Envelope (Env) is one of the cornerstones of HIV vaccine research. The current animal models we use have been unable to reliable produce a broadly neutralizing antibody response, with the exception of cows. Cows have rapidly and reliably produced a CD4 binding site response by homologous prime and boosting with a native-like Env trimer.
View Article and Find Full Text PDFMultiple 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.
View Article and Find Full Text PDFVaccination 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.
View Article and Find Full Text PDFFront Cell Infect Microbiol
March 2023
Glycine encephalopathy (MIM #605899) is an autosomal recessive inborn error of metabolism caused by pathogenic variants in three genes , , encoding glycine cleavage enzyme system. We report an 8-year-old boy with late-onset glycine encephalopathy who harbors a novel homozygous likely pathogenic variant c.707G > A p.
View Article and Find Full Text PDFEliciting broadly neutralizing antibodies (bnAbs) is the core of HIV vaccine design. bnAbs specific to the V2-apex region of the HIV envelope acquire breadth and potency with modest somatic hypermutation, making them attractive vaccination targets. To evaluate Apex germline-targeting (ApexGT) vaccine candidates, we engineered knockin (KI) mouse models expressing the germline B cell receptor (BCR) of the bnAb PCT64.
View Article and Find Full Text PDFThe 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).
View Article and Find Full Text PDFElicitation 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) 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).
View Article and Find Full Text PDFDuring 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.
View Article and Find Full Text PDFSevere 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.
View Article and Find Full Text PDFThe 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.
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