A Zika virus-specific IgM elicited in pregnancy exhibits ultrapotent neutralization.

Congenital Zika virus (ZIKV) infection results in neurodevelopmental deficits in up to 14% of infants born to ZIKV-infected mothers. Neutralizing antibodies are a critical component of protective immunity. Here, we demonstrate that plasma IgM contributes to ZIKV immunity in pregnancy, mediating neutralization up to 3 months post-symptoms. From a ZIKV-infected pregnant woman, we isolated a pentameric ZIKV-specific IgM (DH1017.IgM) that exhibited ultrapotent ZIKV neutralization dependent on the IgM isotype. DH1017.IgM targets an envelope dimer epitope within domain II. The epitope arrangement on the virion is compatible with concurrent engagement of all ten antigen-binding sites of DH1017.IgM, a solution not available to IgG. DH1017.IgM protected mice against viremia upon lethal ZIKV challenge more efficiently than when expressed as an IgG. Our findings identify a role for antibodies of the IgM isotype in protection against ZIKV and posit DH1017.IgM as a safe and effective candidate immunotherapeutic, particularly during pregnancy.

Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody.

Antibodies with ontogenies from VH1-2 or VH1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. Here, we define with longitudinal sampling from time-of-infection the development of a VH1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%), and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, and extraordinary level of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the VH1-46 gene, which closely resembled VH1-2. We integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages.

Antibody light-chain-restricted recognition of the site of immune pressure in the RV144 HIV-1 vaccine trial is phylogenetically conserved.

In HIV-1, the ability to mount antibody responses to conserved, neutralizing epitopes is critical for protection. Here we have studied the light chain usage of human and rhesus macaque antibodies targeted to a dominant region of the HIV-1 envelope second variable (V2) region involving lysine (K) 169, the site of immune pressure in the RV144 vaccine efficacy trial. We found that humans and rhesus macaques used orthologous lambda variable gene segments encoding a glutamic acid-aspartic acid (ED) motif for K169 recognition. Structure determination of an unmutated ancestor antibody demonstrated that the V2 binding site was preconfigured for ED motif-mediated recognition prior to maturation. Thus, light chain usage for recognition of the site of immune pressure in the RV144 trial is highly conserved across species. These data indicate that the HIV-1 K169-recognizing ED motif has persisted over the diversification between rhesus macaques and humans, suggesting an evolutionary advantage of this antibody recognition mode.

AisNet: A Universal Interatomic Potential Neural Network with Encoded Local Environment Features.

This paper proposes a new interatomic potential energy neural network, AisNet, which can efficiently predict atomic energies and forces covering different molecular and crystalline materials by encoding universal local environment features, such as elements and atomic positions. Inspired by the framework of SchNet, AisNet consists of an encoding module combining autoencoder with embedding, the triplet loss function and an atomic central symmetry function (ACSF), an interaction module with a periodic boundary condition (PBC), and a prediction module. In molecules, the prediction accuracy of AisNet is comparabel with SchNet on the MD17 dataset, mainly attributed to the effective capture of chemical functional groups through the interaction module. In selected metal and ceramic material datasets, the introduction of ACSF improves the overall accuracy of AisNet by an average of 16.8% for energy and 28.6% for force. Furthermore, a close relationship is found between the feature ratio (i.e., ACSF and embedding) and the force prediction errors, exhibiting similar spoon-shaped curves in the datasets of Cu and HfO2. AisNet produces highly accurate predictions in single-commponent alloys with little data, suggesting the encoding process reduces dependence on the number and richness of datasets. Especially for force prediction, AisNet exceeds SchNet by 19.8% for Al and even 81.2% higher than DeepMD on a ternary FeCrAl alloy. Capable of processing multivariate features, our model is likely to be applied to a wider range of material systems by incorporating more atomic descriptions.

Boosting with AIDSVAX B/E Enhances Env Constant Region 1 and 2 Antibody-Dependent Cellular Cytotoxicity Breadth and Potency.

Induction of protective antibodies is a critical goal of HIV-1 vaccine development. One strategy is to induce nonneutralizing antibodies (NNAbs) that kill virus-infected cells, as these antibody specificities have been implicated in slowing HIV-1 disease progression and in protection. HIV-1 Env constant region 1 and 2 (C1C2) monoclonal antibodies (MAbs) frequently mediate potent antibody-dependent cellular cytotoxicity (ADCC), making them an important vaccine target. Here, we explore the effect of delayed and repetitive boosting of RV144 vaccine recipients with AIDSVAX B/E on the C1C2-specific MAb repertoire. It was found that boosting increased clonal lineage-specific ADCC breadth and potency. A ligand crystal structure of a vaccine-induced broad and potent ADCC-mediating C1C2-specific MAb showed that it bound a highly conserved Env gp120 epitope. Thus, boosting to affinity mature these types of IgG C1C2-specific antibody responses may be one method by which to make an improved HIV vaccine with higher efficacy than that seen in the RV144 trial.IMPORTANCE Over one million people become infected with HIV-1 each year, making the development of an efficacious HIV-1 vaccine an important unmet medical need. The RV144 human HIV-1 vaccine regimen is the only HIV-1 clinical trial to date to demonstrate vaccine efficacy. An area of focus has been on identifying ways by which to improve upon RV144 vaccine efficacy. The RV305 HIV-1 vaccine regimen was a follow-up boost of RV144 vaccine recipients that occurred 6 to 8 years after the conclusion of RV144. Our study focused on the effect of delayed boosting in humans on the vaccine-induced Env constant region 1 and 2 (C1C2)-specific antibody repertoire. It was found that boosting with an HIV-1 Env vaccine increased C1C2-specific antibody-dependent cellular cytotoxicity potency and breadth.

Element Replacement Approach by Reaction with Lewis Acidic Molten Salts to Synthesize Nanolaminated MAX Phases and MXenes.

Nanolaminated materials are important because of their exceptional properties and wide range of applications. Here, we demonstrate a general approach to synthesizing a series of Zn-based MAX phases and Cl-terminated MXenes originating from the replacement reaction between the MAX phase and the late transition-metal halides. The approach is a top-down route that enables the late transitional element atom (Zn in the present case) to occupy the A site in the pre-existing MAX phase structure. Using this replacement reaction between the Zn element from molten ZnCl2 and the Al element in MAX phase precursors (Ti3AlC2, Ti2AlC, Ti2AlN, and V2AlC), novel MAX phases Ti3ZnC2, Ti2ZnC, Ti2ZnN, and V2ZnC were synthesized. When employing excess ZnCl2, Cl-terminated MXenes (such as Ti3C2Cl2 and Ti2CCl2) were derived by a subsequent exfoliation of Ti3ZnC2 and Ti2ZnC due to the strong Lewis acidity of molten ZnCl2. These results indicate that A-site element replacement in traditional MAX phases by late transition-metal halides opens the door to explore MAX phases that are not thermodynamically stable at high temperature and would be difficult to synthesize through the commonly employed powder metallurgy approach. In addition, this is the first time that exclusively Cl-terminated MXenes were obtained, and the etching effect of Lewis acid in molten salts provides a green and viable route to preparing MXenes through an HF-free chemical approach.

Hybrid Fiber Optic Sensor, Based on the Fabry⁻Perot Interference, Assisted with Fluorescent Material for the Simultaneous Measurement of Temperature and Pressure.

Herein we design a fiber sensor able to simultaneously measure the temperature and the pressure under harsh conditions, such as strong electromagnetic interference and high pressure. It is built on the basis of the fiber-optic Fabry⁻Perot (F⁻P) interference and the temperature sensitive mechanism of fluorescent materials. Both halogen lamps and light-emitting diodes (LED) are employed as the excitation light source. The reflected light from the sensor contains the low coherent information of interference cavity and the fluorescent lifetime. This information is independent due to the separate optical path and the different demodulation device. It delivers the messages of pressure and temperature, respectively. It is demonstrated that the sensor achieved pressure measurement at the range of 120⁻400 KPa at room temperature with a sensitivity of 1.5 nm/KPa. Moreover, the linearity of pressure against the cavity length variation was over 99.9%. In the meantime, a temperature measurement in the range of 25⁻80 °C, with a sensitivity of 0.0048 ms/°C, was obtained. These experimental results evince that this kind of sensor has a simple configuration, low-cost, and easy fabrication. As such, it can be particularly applied to many fields.

HIV DNA-Adenovirus Multiclade Envelope Vaccine Induces gp41 Antibody Immunodominance in Rhesus Macaques.

Dominant antibody responses in vaccinees who received the HIV-1 multiclade (A, B, and C) envelope (Env) DNA/recombinant adenovirus virus type 5 (rAd5) vaccine studied in HIV-1 Vaccine Trials Network (HVTN) efficacy trial 505 (HVTN 505) targeted Env gp41 and cross-reacted with microbial antigens. In this study, we asked if the DNA/rAd5 vaccine induced a similar antibody response in rhesus macaques (RMs), which are commonly used as an animal model for human HIV-1 infections and for testing candidate HIV-1 vaccines. We also asked if gp41 immunodominance could be avoided by immunization of neonatal RMs during the early stages of microbial colonization. We found that the DNA/rAd5 vaccine elicited a higher frequency of gp41-reactive memory B cells than gp120-memory B cells in adult and neonatal RMs. Analysis of the vaccine-induced Env-reactive B cell repertoire revealed that the majority of HIV-1 Env-reactive antibodies in both adult and neonatal RMs were targeted to gp41. Interestingly, a subset of gp41-reactive antibodies isolated from RMs cross-reacted with host antigens, including autologous intestinal microbiota. Thus, gp41-containing DNA/rAd5 vaccine induced dominant gp41-microbiota cross-reactive antibodies derived from blood memory B cells in RMs as observed in the HVTN 505 vaccine efficacy trial. These data demonstrated that RMs can be used to investigate gp41 immunodominance in candidate HIV-1 vaccines. Moreover, colonization of neonatal RMs occurred within the first week of life, and immunization of neonatal RMs during this time also induced a dominant gp41-reactive antibody response.IMPORTANCE Our results are critical to current work in the HIV-1 vaccine field evaluating the phenomenon of gp41 immunodominance induced by HIV-1 Env gp140 in RMs and humans. Our data demonstrate that RMs are an appropriate animal model to study this phenomenon and to determine the immunogenicity in new HIV-1 Env trimer vaccine designs. The demonstration of gp41 immunodominance in memory B cells of both adult and neonatal RMs indicated that early vaccination could not overcome gp41 dominant responses.

High-Speed Device-Independent Quantum Random Number Generation without a Detection Loophole.

Quantum mechanics provides the means of generating genuine randomness that is impossible with deterministic classical processes. Remarkably, the unpredictability of randomness can be certified in a manner that is independent of implementation devices. Here, we present an experimental study of device-independent quantum random number generation based on a detection-loophole-free Bell test with entangled photons. In the randomness analysis, without the independent identical distribution assumption, we consider the worst case scenario that the adversary launches the most powerful attacks against the quantum adversary. After considering statistical fluctuations and applying an 80 Gb×45.6 Mb Toeplitz matrix hashing, we achieve a final random bit rate of 114 bits/s, with a failure probability less than 10^{-5}. This marks a critical step towards realistic applications in cryptography and fundamental physics tests.

Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds.

UNLABELLED: The human immunodeficiency virus (HIV-1) envelope glycoproteins (Env) mediate virus entry through a series of complex conformational changes triggered by binding to the receptors CD4 and CCR5/CXCR4. Broadly neutralizing antibodies that recognize conserved Env epitopes are thought to be an important component of a protective immune response. However, to date, HIV-1 Env immunogens that elicit broadly neutralizing antibodies have not been identified, creating hurdles for vaccine development. Small-molecule CD4-mimetic compounds engage the CD4-binding pocket on the gp120 exterior Env and induce Env conformations that are highly sensitive to neutralization by antibodies, including antibodies directed against the conserved Env region that interacts with CCR5/CXCR4. Here, we show that CD4-mimetic compounds sensitize primary HIV-1 to neutralization by antibodies that can be elicited in monkeys and humans within 6 months by several Env vaccine candidates, including gp120 monomers. Monoclonal antibodies directed against the gp120 V2 and V3 variable regions were isolated from the immunized monkeys and humans; these monoclonal antibodies neutralized a primary HIV-1 only when the virus was sensitized by a CD4-mimetic compound. Thus, in addition to their direct antiviral effect, CD4-mimetic compounds dramatically enhance the HIV-1-neutralizing activity of antibodies that can be elicited with currently available immunogens. Used as components of microbicides, the CD4-mimetic compounds might increase the protective efficacy of HIV-1 vaccines. IMPORTANCE: Preventing HIV-1 transmission is a high priority for global health. Eliciting antibodies that can neutralize transmitted strains of HIV-1 is difficult, creating problems for the development of an effective vaccine. We found that small-molecule CD4-mimetic compounds sensitize HIV-1 to antibodies that can be elicited in vaccinated humans and monkeys. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine.