The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp120 glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization. Despite this complexity, the HIV-1 Env must retain conserved determinants that mediate CD4 binding. To evaluate how these determinants might provide opportunities for antibody recognition, we created variants of gp120 stabilized in the CD4-bound state, assessed binding of CD4 and of receptor-binding-site antibodies, and determined the structure at 2.3 Å resolution of the broadly neutralizing antibody b12 in complex with gp120. b12 binds to a conformationally invariant surface that overlaps a distinct subset of the CD4-binding site. This surface is involved in the metastable attachment of CD4, before the gp120 rearrangement required for stable engagement. A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1.The human immunodeficiency virus type 1 (HIV-1) crossed from chimpanzees to humans early in the twentieth century and has since infected ~1% of the world's adult population 1,2 . ThisCorrespondence and requests for materials should be addressed to P.D.K. (pdkwong@nih.gov). Author Contributions T.Z. and P.D.K. carried out structure-based stabilization, SPR analyses and structural determinations; L.X. and G.J.N. constructed gp120 substitutions and developed and implemented a high-throughput gp120-production system suitable for crystallization; B.D. and R.W. carried out ITC characterizations; A.J.H., M.B.Z. and D.R.B. provided b12, b3, b6, b11 and b13, and mutant b12 binding; D.V.R. and J.A. provided D1D2-Igαtp and associated SPR analyses; S.-H.X., X.Y. and J.S. provided OD1 and preliminary design and antigenic analyses; and M.-Y.Z. and D.S.D. provided m6, m14 and m18. All authors contributed to the manuscript preparation.Author Information Coordinates and structure factors have been deposited in the Protein Data Bank and may be obtained from the authors (accession codes 2nxy-2ny6 for the nine variant gp120 molecules with CD4 and 17b; accession code 2ny7 for the b12-gp120 complex). Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests. spread and the absence of an effective vaccine are to a large degree a consequence of the ability of HIV-1 to evade antibody-mediated neutralization 3-5 . On HIV-1, the only viral target available for neutralizing antibodies is the envelope spike, which is composed of three copies of the gp120 exterior envelope glycoprotein and three gp41 transmembrane glyco-protein molecules 6,7 . Genetic, immunological and structural studies of the HIV-1 envelope glycoproteins have revealed extraordinary diversity, manifest in a variety of immunodominant loops, as well as multiple overlapping mechanisms of humoral evasion, including se...

The third variable region (V3) of the HIV-1 gp120 envelope glycoprotein is immunodominant and contains features essential for coreceptor binding. We determined the structure of V3 in the context of an HIV-1 gp120 core complexed to the CD4 receptor and to the X5 antibody at 3.5 angstrom resolution. Binding of gp120 to cell-surface CD4 would position V3 so that its coreceptor-binding tip protrudes 30 angstroms from the core toward the target cell membrane. The extended nature and antibody accessibility of V3 explain its immunodominance. Together, the results provide a structural rationale for the role of V3 in HIV entry and neutralization.

The site on HIV-1 gp120 that binds to the CD4 receptor is vulnerable to antibodies. However, most antibodies that interact with this site cannot neutralize HIV-1. To understand the basis of this resistance, we determined co-crystal structures for two poorly neutralizing, CD4–binding site (CD4BS) antibodies, F105 and b13, in complexes with gp120. Both antibodies exhibited approach angles to gp120 similar to those of CD4 and a rare, broadly neutralizing CD4BS antibody, b12. Slight differences in recognition, however, resulted in substantial differences in F105- and b13-bound conformations relative to b12-bound gp120. Modeling and binding experiments revealed these conformations to be poorly compatible with the viral spike. This incompatibility, the consequence of slight differences in CD4BS recognition, renders HIV-1 resistant to all but the most accurately targeted antibodies.

The conserved surface of the HIV-1 gp120 envelope glycoprotein that binds to the HIV-1 coreceptor is protected from humoral recognition by multiple layers of camouflage. Here we present sequence and genomic analyses for 12 antibodies that pierce these defenses and determine the crystal structures of 5. The data reveal mechanisms and atomic-level details for three unusual immune features: posttranslational mimicry of coreceptor by tyrosine sulfation of antibody, an alternative molecular mechanism controlling such sulfation, and highly selective VH-gene usage. When confronted by extraordinary viral defenses, the immune system unveils novel adaptive capabilities, with tyrosine sulfation enhancing the vocabulary of antigen recognition.

Several human monoclonal antibodies (hmAbs) including b12, 2G12 and 2F5 exhibit relatively potent and broad HIV-1 neutralizing activity. However, their elicitation in vivo by vaccine immunogens based on the HIV-1 envelope glycoprotein (Env) has not been successful. We have hypothesized that HIV-1 has evolved a strategy to reduce or eliminate the immunogenicity of the highly conserved epitopes of such antibodies by using “holes” (absence or very weak binding to these epitopes of germline antibodies that is not sufficient to initiate and/or maintain an efficient immune response) in the human germline B cell receptor (BCR) repertoire. To begin to test this hypothesis we have designed germline-like antibodies corresponding most closely to b12, 2G12 and 2F5 as well as to X5, m44 and m46 which are cross-reactive but with relatively weak neutralizing activity as natively occurring antibodies due to size and/or other effects. The germline-like X5, m44 and m46 bound with relatively high affinity to all tested Envs. In contrast, germline-like b12, 2G12 and 2F5 lacked measurable binding to Envs in an ELISA assay although the corresponding mature antibodies did. These results provide initial evidence that Env structures containing conserved vulnerable epitopes may not initiate humoral responses by binding to germline antibodies. Even if such responses are initiated by very weak binding undetectable in our assay it is likely that they will be outcompeted by responses to structures containing the epitopes of X5, m44, m46, and other antibodies that bind germline BCRs with much higher affinity/avidity. This hypothesis, if further supported by data, could contribute to our understanding of how HIV-1 evades immune responses and offer new concepts for design of effective vaccine immunogens.

Various wearable aerogel sensors are emerging for their light weight, fairly wide sensing range, and sensitive sensing ability. Aramid nanofibers (ANFs) as a kind of burgeoning building blocks realize multifunctional applications in diversified fields for their innate extinguished mechanical property and thermal stability. Limited by their high insulating property, in this work ANFs were designed to integrate with a 2D emerging MXene sheet with a distinct conductive property. Herein, we report an MXene/ANFs composite aerogel through a feasible controllable vacuum filtration followed by a freeze-drying process. Benefiting from the inerratic 3D hierarchical and "mortar− brick" porous structure with an ultralow density of 25 mg/cm 3 , MXene/ANFs aerogels are proved to possess high compressible resilience and appealing sensing performance up to 1000 times. Importantly, verified by a series of simulation experiments, the MXene/ANFs aerogel sensor shows a wide detection range (2.0−80.0% compression strain), sensitive sensing property (128 kPa −1 ), and ultralow detection limit (100 Pa), which still play a flexible role in detecting human light movement and even vigorous sports after undergoing ultrahigh devastating pressures (∼623 kPa). In addition, the MXene/ANFs aerogel sensor can withstand a harsh high temperature of 200 °C and shows excellent flame resistance. The MXene/ANFs aerogel with excellent integrated property, especially the highly sensitive sensing property and excellent thermal stability, presents great potential for a human behavior monitoring sensor and sensing under certain extreme conditions.

Aramid nanofibers (ANFs) are of great interest in various applications due to its 1D nanoscale, high aspect ratio, high specific surface area, excellent strength, and modulus as well as impressive chemical and thermal stabilities. It is considered as one of the most promising nano-sized building blocks with excellent properties and has therefore drawn increasing attention since 2011. However, no review has summarized the research progress and the prospective challenges of ANF. Herein, the methods of ANF fabrication and their relative merits are comprehensively discussed together with the challenges and progress in the deprotonation method for preparing ANF. The fabrication methods and development of ANF-based advanced materials with different macroscopic morphologies, including the 1D ANF aerogel fiber, 2D ANF film/nanopaper/coating, and 3D ANF gel and particle are also described. Furthermore, the applications of ANF in nanocomposite reinforcement, battery separators, electrical insulation nanopaper, flexible electronics, and adsorption and filtration media are presented. Additionally, the possible challenges and outlooks toward the future development of ANF are highlighted. This review indicates that the ANF and ANF-based materials mentioned herein will boost the development of next-generation advanced functional materials.

HIV-1 entry into cells involves formation of a complex between gp120of the viral envelope glycoprotein (Env), a receptor (CD4), and a coreceptor, typically CCR5. Here we provide evidence that purified gp120JR-FL-CD4 -CCR5 complexes exhibit an epitope recognized by a