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Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7
The COVID-19 pandemic has had widespread effects across the globe, and its causative agent, SARS-CoV-2, continues to spread. Effective interventions need to be developed to end this pandemic. Single and combination therapies with monoclonal antibodies have received emergency use authorization
1
–
3
, and more treatments are under development
4
–
7
. Furthermore, multiple vaccine constructs have shown promise
8
, including two that have an approximately 95% protective efficacy against COVID-19
9
,
10
. However, these interventions were directed against the initial SARS-CoV-2 virus that emerged in 2019. The recent detection of SARS-CoV-2 variants B.1.1.7 in the UK
11
and B.1.351 in South Africa
12
is of concern because of their purported ease of transmission and extensive mutations in the spike protein. Here we show that B.1.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclonal antibodies against the receptor-binding domain. It is not more resistant to plasma from individuals who have recovered from COVID-19 or sera from individuals who have been vaccinated against SARS-CoV-2. The B.1.351 variant is not only refractory to neutralization by most monoclonal antibodies against the N-terminal domain but also by multiple individual monoclonal antibodies against the receptor-binding motif of the receptor-binding domain, which is mostly due to a mutation causing an E484K substitution. Moreover, compared to wild-type SARS-CoV-2, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4-fold) and sera from individuals who have been vaccinated (10.3–12.4-fold). B.1.351 and emergent variants
13
,
14
with similar mutations in the spike protein present new challenges for monoclonal antibody therapies and threaten the protective efficacy of current vaccines.
The SARS-CoV-2 variant B.1.1.7 can be neutralized by convalescent sera or sera from vaccinated individuals, whereas the B.1.351 variant is resistant to neutralization by these sera and by several monoclonal antibodies that are in clinical use.
Journal Article
Structural basis of adhesive binding by desmocollins and desmogleins
Desmosomes are intercellular adhesive junctions that impart strength to vertebrate tissues. Their dense, ordered intercellular attachments are formed by desmogleins (Dsgs) and desmocollins (Dscs), but the nature of trans-cellular interactions between these specialized cadherins is unclear. Here, using solution biophysics and coated-bead aggregation experiments, we demonstrate family-wise heterophilic specificity: All Dsgs form adhesive dimers with all Dscs, with affinities characteristic of each Dsg:Dsc pair. Crystal structures of ectodomains from Dsg2 and Dsg3 and from Dsc1 and Dsc2 show binding through a strand-swap mechanism similar to that of homophilic classical cadherins. However, conserved charged amino acids inhibit Dsg:Dsg and Dsc:Dsc interactions by same-charge repulsion and promote heterophilic Dsg:Dsc interactions through opposite-charge attraction. These findings show that Dsg:Dsc heterodimers represent the fundamental adhesive unit of desmosomes and provide a structural framework for understanding desmosome assembly.
Journal Article
cAb-Rep: A Database of Curated Antibody Repertoires for Exploring Antibody Diversity and Predicting Antibody Prevalence
The diversity of B cell receptors provides a basis for recognizing numerous pathogens. Antibody repertoire sequencing has revealed relationships between B cell receptor sequences, their diversity, and their function in infection, vaccination, and disease. However, many repertoire datasets have been deposited without annotation or quality control, limiting their utility. To accelerate investigations of B cell immunoglobulin sequence repertoires and to facilitate development of algorithms for their analysis, we constructed a comprehensive public database of curated human B cell immunoglobulin sequence repertoires, cAb-Rep (https://cab-rep.c2b2.columbia.edu), which currently includes 306 immunoglobulin repertoires from 121 human donors, who were healthy, vaccinated, or had autoimmune disease. The database contains a total of 267.9 million V(D)J heavy chain and 72.9 million VJ light chain transcripts. These transcripts are full-length or near full-length, have been annotated with gene origin, antibody isotype, somatic hypermutations, and other biological characteristics, and are stored in FASTA format to facilitate their direct use by most current repertoire-analysis programs. We describe a website to search cAb-Rep for similar antibodies along with methods for analysis of the prevalence of antibodies with specific genetic signatures, for estimation of reproducibility of somatic hypermutation patterns of interest, and for delineating frequencies of somatically introduced
-glycosylation. cAb-Rep should be useful for investigating attributes of B cell sequence repertoires, for understanding characteristics of affinity maturation, and for identifying potential barriers to the elicitation of effective neutralizing antibodies in infection or by vaccination.
Journal Article
Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus
Current human immunodeficiency virus-1 (HIV-1) vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in approximately 20% of HIV-1-infected individuals, and details of their generation could provide a blueprint for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection. The mature antibody, CH103, neutralized approximately 55% of HIV-1 isolates, and its co-crystal structure with the HIV-1 envelope protein gp120 revealed a new loop-based mechanism of CD4-binding-site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the unmutated common ancestor of the CH103 lineage avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data determine the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies, and provide insights into strategies to elicit similar antibodies by vaccination.
Longitudinal sampling is used to map the evolution of an HIV-1 virus from the time of infection, and the co-evolution of a broadly neutralizing antibody in the same infected patient; the findings have important implications for HIV vaccine development.
Pattern of HIV growth and antibody formation
Hua-Xin Liao
et al
. followed the evolution of an HIV-1 virus, and the concurrent co-evolution of a CD4-binding-site broadly neutralizing antibody (BnAb), from the time of infection of a single African patient for a period of more than 3 years. The neutralizing antibody, of CH103 lineage, is a new type of BnAb that binds in a completely loop-based manner that differs from that of VRC01 class monoclonal antibodies — the CH103 lineage is less mutated, with fewer unusual macromutations and may be easier to induce. This work has implications for HIV vaccine development, suggesting viral strains that might generate broadly neutralizing antibodies within the host.
Journal Article
Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env
The structure of the ligand-free HIV-1–Env trimer allows conformational fixation of Env and generation of an antigen that binds CD4 with high affinity and is recognized by broadly neutralizing antibodies but not poorly neutralizing ones.
As the sole viral antigen on the HIV-1–virion surface, trimeric Env is a focus of vaccine efforts. Here we present the structure of the ligand-free HIV-1–Env trimer, fix its conformation and determine its receptor interactions. Epitope analyses revealed trimeric ligand-free Env to be structurally compatible with broadly neutralizing antibodies but not poorly neutralizing ones. We coupled these compatibility considerations with binding antigenicity to engineer conformationally fixed Envs, including a 201C 433C (DS) variant specifically recognized by broadly neutralizing antibodies. DS-Env retained nanomolar affinity for the CD4 receptor, with which it formed an asymmetric intermediate: a closed trimer bound by a single CD4 without the typical antigenic hallmarks of CD4 induction. Antigenicity-guided structural design can thus be used both to delineate mechanism and to fix conformation, with DS-Env trimers in virus-like-particle and soluble formats providing a new generation of vaccine antigens.
Journal Article
Visualization of clustered protocadherin neuronal self-recognition complexes
Neurite self-recognition and avoidance are fundamental properties of all nervous systems
1
. These processes facilitate dendritic arborization
2
,
3
, prevent formation of autapses
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and allow free interaction among non-self neurons
1
,
2
,
4
,
5
. Avoidance among self neurites is mediated by stochastic cell-surface expression of combinations of about 60 isoforms of α-, β- and γ-clustered protocadherin that provide mammalian neurons with single-cell identities
1
,
2
,
4
–
13
. Avoidance is observed between neurons that express identical protocadherin repertoires
2
,
5
, and single-isoform differences are sufficient to prevent self-recognition
10
. Protocadherins form isoform-promiscuous
cis
dimers and isoform-specific homophilic
trans
dimers
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,
14
–
20
. Although these interactions have previously been characterized in isolation
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,
17
–
20
, structures of full-length protocadherin ectodomains have not been determined, and how these two interfaces engage in self-recognition between neuronal surfaces remains unknown. Here we determine the molecular arrangement of full-length clustered protocadherin ectodomains in single-isoform self-recognition complexes, using X-ray crystallography and cryo-electron tomography. We determine the crystal structure of the clustered protocadherin γB4 ectodomain, which reveals a zipper-like lattice that is formed by alternating
cis
and
trans
interactions. Using cryo-electron tomography, we show that clustered protocadherin γB6 ectodomains tethered to liposomes spontaneously assemble into linear arrays at membrane contact sites, in a configuration that is consistent with the assembly observed in the crystal structure. These linear assemblies pack against each other as parallel arrays to form larger two-dimensional structures between membranes. Our results suggest that the formation of ordered linear assemblies by clustered protocadherins represents the initial self-recognition step in neuronal avoidance, and thus provide support for the isoform-mismatch chain-termination model of protocadherin-mediated self-recognition, which depends on these linear chains
11
.
Clustered protocadherin ectodomains spontaneously assemble to form a zipper-like lattice of alternating
cis
and
trans
interactions at membrane contact sites, which probably represents their mode of function in neuronal self-recognition.
Journal Article
Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies
Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01–12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30–38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development.
A longitudinal study of an individual patient developing neutralizing antibodies against HIV-1 (targeting the V1V2 region of gp120) reveals how such neutralizing antibodies develop and evolve over time, providing important insights relevant to vaccine development.
HIV-neutralizing antibody formation examined
A better understanding of how HIV-1-neutralizing antibodies are generated could be a useful contribution to the design of improved AIDS vaccines. John Mascola and colleagues have now elucidated the immunological pathway of an important category of HIV-1-neutralizing antibody — those that target the variable V1V2 region of the viral envelope. These antibodies are more frequently elicited than CD4-binding site antibodies in the early stages of HIV infection and feature modest affinity maturation, a process that favours mutations in antibody variable domains that enhance antigen binding.
Journal Article
FGF5 is a crucial regulator of hair length in humans
Mechanisms that regulate the growth of eyelashes have remained obscure. We ascertained two families from Pakistan who presented with familial trichomegaly, or extreme eyelash growth. Using a combination of whole exome sequencing and homozygosity mapping, we identified distinct pathogenic mutations within fibroblast growth factor 5 (FGF5) that underlie the disorder. Subsequent sequencing of this gene in several additional trichomegaly families identified an additional mutation in FGF5 . We further demonstrated that hair fibers from forearms of these patients were significantly longer than hairs from control individuals, with an increased proportion in the growth phase, anagen. Using hair follicle organ cultures, we show that FGF5 induces regression of the human hair follicle. We have identified FGF5 as a crucial regulator of hair growth in humans for the first time, to our knowledge, and uncovered a therapeutic target to selectively regulate eyelash growth.
Journal Article
Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01
During HIV-1 infection, antibodies are generated against the region of the viral gp120 envelope glycoprotein that binds CD4, the primary receptor for HIV-1. Among these antibodies, VRC01 achieves broad neutralization of diverse viral strains. We determined the crystal structure of VRC01 in complex with a human immunodeficiency virus HIV-1 gp120 core. VRC01 partially mimics CD4 interaction with gp120. A shift from the CD4-defined orientation, however, focuses VRC01 onto the vulnerable site of initial CD4 attachment, allowing it to overcome the glycan and conformational masking that diminishes the neutralization potency of most CD4-binding-site antibodies. To achieve this recognition, VRC01 contacts gp120 mainly through immunoglobulin V-gene regions substantially altered from their genomic precursors. Partial receptor mimicry and extensive affinity maturation thus facilitate neutralization of HIV-1 by natural human antibodies.
Journal Article