scholarly journals Recapitulation of HIV-1 Env-antibody coevolution in macaques leading to neutralization breadth

Science ◽  
2020 ◽  
Vol 371 (6525) ◽  
pp. eabd2638
Author(s):  
Ryan S. Roark ◽  
Hui Li ◽  
Wilton B. Williams ◽  
Hema Chug ◽  
Rosemarie D. Mason ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Envelope Proteins ◽  
Viral Envelope ◽  
Immunogen Design ◽  
Cd4 Binding Site ◽  
Human Immunodeficiency Viruses ◽  
Chemical Solutions ◽  
Developmental Features ◽  
Hiv 1

Neutralizing antibodies elicited by HIV-1 coevolve with viral envelope proteins (Env) in distinctive patterns, in some cases acquiring substantial breadth. We report that primary HIV-1 envelope proteins—when expressed by simian-human immunodeficiency viruses in rhesus macaques—elicited patterns of Env-antibody coevolution very similar to those in humans, including conserved immunogenetic, structural, and chemical solutions to epitope recognition and precise Env–amino acid substitutions, insertions, and deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a 208-strain panel, revealed a V2 apex mode of recognition like that of human broadly neutralizing antibodies (bNAbs) PGT145 and PCT64-35S. Another rhesus antibody bound the CD4 binding site by CD4 mimicry, mirroring human bNAbs 8ANC131, CH235, and VRC01. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design.

scholarly journals Recapitulation of HIV-1 Env-Antibody Coevolution in Macaques Leading to Neutralization Breadth

2020 ◽  
Author(s):  
Ryan S. Roark ◽  
Hui Li ◽  
Wilton B. Williams ◽  
Hema Chug ◽  
Rosemarie D. Mason ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Virus Antibody ◽  
Human Antibodies ◽  
Immunogen Design ◽  
Cd4 Binding Site ◽  
Human Immunodeficiency Viruses ◽  
Chemical Solutions ◽  
Developmental Features ◽  
Hiv 1

ABSTRACTNeutralizing antibodies elicited by HIV-1 coevolve with viral Envs in distinctive patterns, in some cases acquiring substantial breadth. Here we show that primary HIV-1 Envs, when expressed by simian-human immunodeficiency viruses in rhesus macaques, elicited patterns of Env-antibody coevolution strikingly similar to those in humans. This included conserved immunogenetic, structural and chemical solutions to epitope recognition and precise Env-amino acid substitutions, insertions and deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a 208-strain panel, revealed a V2-apex mode of recognition like that of human bNAbs PGT145/PCT64-35M. Another rhesus antibody bound the CD4-binding site by CD4 mimicry mirroring human bNAbs 8ANC131/CH235/VRC01. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design.One sentence summaryVirus-antibody coevolution in rhesus macaques recapitulates developmental features of human antibodies.

scholarly journals Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques

Science ◽  
2017 ◽  
Vol 358 (6359) ◽  
pp. 85-90 ◽  
Author(s):  
Ling Xu ◽  
Amarendra Pegu ◽  
Ercole Rao ◽  
Nicole Doria-Rose ◽  
Jochen Beninga ◽  
...  
Keyword(s):  
Single Molecule ◽  
Neutralizing Antibodies ◽  
Broadly Neutralizing Antibodies ◽  
Aids Vaccine ◽  
Single Protein ◽  
Hiv Antibodies ◽  
Cd4 Binding Site ◽  
Human Immunodeficiency Viruses ◽  
Glycan Site ◽  
Hiv 1

The development of an effective AIDS vaccine has been challenging because of viral genetic diversity and the difficulty of generating broadly neutralizing antibodies (bnAbs). We engineered trispecific antibodies (Abs) that allow a single molecule to interact with three independent HIV-1 envelope determinants: the CD4 binding site, the membrane-proximal external region (MPER), and the V1V2 glycan site. Trispecific Abs exhibited higher potency and breadth than any previously described single bnAb, showed pharmacokinetics similar to those of human bnAbs, and conferred complete immunity against a mixture of simian-human immunodeficiency viruses (SHIVs) in nonhuman primates, in contrast to single bnAbs. Trispecific Abs thus constitute a platform to engage multiple therapeutic targets through a single protein, and they may be applicable for treatment of diverse diseases, including infections, cancer, and autoimmunity.

scholarly journals Neutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer

2021 ◽  
Author(s):  
Zhi Yang ◽  
Kim-Marie A. Dam ◽  
Michael D. Bridges ◽  
Magnus A.G. Hoffmann ◽  
Andrew T. DeLaitsch ◽  
...  
Keyword(s):  
Binding Site ◽  
Neutralizing Antibodies ◽  
Resonance Spectroscopy ◽  
Broadly Neutralizing Antibodies ◽  
Receptor Binding Site ◽  
Double Electron ◽  
Immunogen Design ◽  
Cd4 Binding Site ◽  
Double Electron Electron Resonance ◽  
Hiv 1

Broadly-neutralizing antibodies (bNAbs) against HIV-1 Env can protect from infection. We characterized Ab1303 and Ab1573, neutralizing CD4-binding site (CD4bs) antibodies, isolated from sequentially-immunized macaques. Ab1303/Ab1573 binding was observed only when Env trimers were not constrained in the closed, prefusion conformation. Fab-Env cryo-EM structures showed that both antibodies recognized the CD4bs on Env trimer with an occluded-open conformation between closed, as targeted by bNAbs, and fully-open, as recognized by CD4. The occluded-open Env trimer conformation included outwardly-rotated gp120 subunits, but unlike CD4-bound Envs, did not exhibit V1V2 displacement, co-receptor binding site exposure, or a 4-stranded gp120 bridging sheet. Inter-protomer distances within trimers measured by double electron-electron resonance spectroscopy suggested an equilibrium between occluded-open and closed Env conformations, consistent with Ab1303/Ab1573 binding stabilizing an existing conformation. Studies of Ab1303/Ab1573 demonstrate that CD4bs neutralizing antibodies that bind open Env trimers can be raised by immunization, thereby informing immunogen design and antibody therapeutic efforts.

scholarly journals Conformational Epitope-Specific Broadly Neutralizing Plasma Antibodies Obtained from an HIV-1 Clade C-Infected Elite Neutralizer Mediate Autologous Virus Escape through Mutations in the V1 Loop

2016 ◽  
Vol 90 (7) ◽  
pp. 3446-3457 ◽  
Author(s):  
Shilpa Patil ◽  
Rajesh Kumar ◽  
Suprit Deshpande ◽  
Sweety Samal ◽  
Tripti Shrivastava ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Core Protein ◽  
Natural Infection ◽  
Viral Envelope ◽  
External Region ◽  
Membrane Proximal External Region ◽  
Virus Escape ◽  
Clade C ◽  
Immunogen Design ◽  
Hiv 1

ABSTRACTBroadly neutralizing antibodies isolated from infected patients who are elite neutralizers have identified targets on HIV-1 envelope (Env) glycoprotein that are vulnerable to antibody neutralization; however, it is not known whether infection established by the majority of the circulating clade C strains in Indian patients elicit neutralizing antibody responses against any of the known targets. In the present study, we examined the specificity of a broad and potent cross-neutralizing plasma obtained from an Indian elite neutralizer infected with HIV-1 clade C. This plasma neutralized 53/57 (93%) HIV pseudoviruses prepared with Env from distinct HIV clades of different geographical origins. Mapping studies using gp120 core protein, single-residue knockout mutants, and chimeric viruses revealed that G37080 broadly cross-neutralizing (BCN) plasma lacks specificities to the CD4 binding site, gp41 membrane-proximal external region, N160 and N332 glycans, and R166 and K169 in the V1-V3 region and are known predominant targets for BCN antibodies. Depletion of G37080 plasma with soluble trimeric BG505-SOSIP.664 Env (but with neither monomeric gp120 nor clade C membrane-proximal external region peptides) resulted in significant reduction of virus neutralization, suggesting that G37080 BCN antibodies mainly target epitopes on cleaved trimeric Env. Further examination of autologous circulating Envs revealed the association of mutation of residues in the V1 loop that contributed to neutralization resistance. In summary, we report the identification of plasma antibodies from a clade C-infected elite neutralizer that mediate neutralization breadth via epitopes on trimeric gp120 not yet reported and confer autologous neutralization escape via mutation of residues in the V1 loop.IMPORTANCEA preventive vaccine to protect against HIV-1 is urgently needed. HIV-1 envelope glycoproteins are targets of neutralizing antibodies and represent a key component for immunogen design. The mapping of epitopes on viral envelopes vulnerable to immune evasion will aid in defining targets of vaccine immunogens. We identified novel conformational epitopes on the viral envelope targeted by broadly cross-neutralizing antibodies elicited in natural infection in an elite neutralizer infected with HIV-1 clade C. Our data extend our knowledge on neutralizing epitopes associated with virus escape and potentially contribute to immunogen design and antibody-based prophylactic therapy.

scholarly journals AAV-delivered eCD4-Ig protects rhesus macaques from high-dose SIVmac239 challenges

2019 ◽  
Vol 11 (502) ◽  
pp. eaau5409 ◽  
Author(s):  
Matthew R. Gardner ◽  
Christoph H. Fellinger ◽  
Lisa M. Kattenhorn ◽  
Meredith E. Davis-Gardner ◽  
Jesse A. Weber ◽  
...  
Keyword(s):  
Rhesus Macaques ◽  
Control Group ◽  
High Dose ◽  
Adeno Associated Virus ◽  
Viral Loads ◽  
Immune Pressure ◽  
Cd4 Binding Site ◽  
Human Immunodeficiency Viruses ◽  
Tier 3 ◽  
Hiv 1

A number of simian and simian human immunodeficiency viruses (SIV and SHIV, respectively) have been used to assess the efficacy of HIV-1 vaccine strategies. Among these, SIVmac239 is considered among the most stringent because, unlike SHIV models, its full genome has coevolved in its macaque host and its tier 3 envelope glycoprotein (Env) is exceptionally hard to neutralize. Here, we investigated the ability of eCD4-Ig, an antibody-like entry inhibitor that emulates the HIV-1 and SIV receptor and coreceptor, to prevent SIVmac239 infection. We show that rh-eCD4-IgI39N expressed by recombinant adeno-associated virus (AAV) vectors afforded four rhesus macaques complete protection from high-dose SIVmac239 challenges that infected all eight control macaques. However, rh-eCD4-IgI39N–expressing macaques eventually succumbed to serial escalating challenge doses that were 2, 8, 16, and 32 times the challenge doses that infected the control animals. Despite receiving greater challenge doses, these macaques had significantly lower peak and postpeak viral loads than the control group. Virus isolated from three of four macaques showed evidence of strong immune pressure from rh-eCD4-IgI39N, with mutations located in the CD4-binding site, which, in one case, exploited a point-mutation difference between rh-eCD4-IgI39N and rhesus CD4. Other escape pathways associated with clear fitness costs to the virus. Our data report effective protection of rhesus macaques from SIVmac239.

scholarly journals Envelope residue 375 substitutions in simian–human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques

2016 ◽  
Vol 113 (24) ◽  
pp. E3413-E3422 ◽  
Author(s):  
Hui Li ◽  
Shuyi Wang ◽  
Rui Kong ◽  
Wenge Ding ◽  
Fang-Hua Lee ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Germ Line ◽  
Virus Entry ◽  
Rhesus Macaques ◽  
Critical Determinant ◽  
Human Immunodeficiency Viruses ◽  
Subtype A ◽  
Hiv 1

Most simian–human immunodeficiency viruses (SHIVs) bearing envelope (Env) glycoproteins from primary HIV-1 strains fail to infect rhesus macaques (RMs). We hypothesized that inefficient Env binding to rhesus CD4 (rhCD4) limits virus entry and replication and could be enhanced by substituting naturally occurring simian immunodeficiency virus Env residues at position 375, which resides at a critical location in the CD4-binding pocket and is under strong positive evolutionary pressure across the broad spectrum of primate lentiviruses. SHIVs containing primary or transmitted/founder HIV-1 subtype A, B, C, or D Envs with genotypic variants at residue 375 were constructed and analyzed in vitro and in vivo. Bulky hydrophobic or basic amino acids substituted for serine-375 enhanced Env affinity for rhCD4, virus entry into cells bearing rhCD4, and virus replication in primary rhCD4 T cells without appreciably affecting antigenicity or antibody-mediated neutralization sensitivity. Twenty-four RMs inoculated with subtype A, B, C, or D SHIVs all became productively infected with different Env375 variants—S, M, Y, H, W, or F—that were differentially selected in different Env backbones. Notably, SHIVs replicated persistently at titers comparable to HIV-1 in humans and elicited autologous neutralizing antibody responses typical of HIV-1. Seven animals succumbed to AIDS. These findings identify Env–rhCD4 binding as a critical determinant for productive SHIV infection in RMs and validate a novel and generalizable strategy for constructing SHIVs with Env glycoproteins of interest, including those that in humans elicit broadly neutralizing antibodies or bind particular Ig germ-line B-cell receptors.

scholarly journals Mechanism of Human Immunodeficiency Virus Type 1 Resistance to Monoclonal Antibody b12 That Effectively Targets the Site of CD4 Attachment

2009 ◽  
Vol 83 (21) ◽  
pp. 10892-10907 ◽  
Author(s):  
Xueling Wu ◽  
Tongqing Zhou ◽  
Sijy O'Dell ◽  
Richard T. Wyatt ◽  
Peter D. Kwong ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Binding Site ◽  
Contact Surface ◽  
Neutralizing Antibodies ◽  
Viral Envelope ◽  
Contact Sites ◽  
Immunodeficiency Virus ◽  
Cd4 Binding Site ◽  
Hiv 1

ABSTRACT The region of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 that engages its primary cellular receptor CD4 forms a site of vulnerability to neutralizing antibodies. The monoclonal antibody b12 exploits the conservation and accessibility of the CD4-binding site to neutralize many, though not all, HIV-1 isolates. To understand the basis of viral resistance to b12, we used the atomic-level definition of b12-gp120 contact sites to study a panel of diverse circulating viruses. A combination of sequence analysis, computational modeling, and site-directed mutagenesis was used to determine the influence of amino acid variants on binding and neutralization by b12. We found that several substitutions within the dominant b12 contact surface, called the CD4-binding loop, mediated b12 resistance, and that these substitutions resided just proximal to the known CD4 contact surface. Hence, viruses varied in key b12 contact residues that are proximal to, but not part of, the CD4 contact surface. This explained how viral isolates were able to evade b12 neutralization while maintaining functional binding to CD4. In addition, some viruses were resistant to b12 despite minimal sequence variation at b12 contact sites. Such neutralization resistance usually could be reversed by alterations at residues thought to influence the quaternary configuration of the viral envelope spike. To design immunogens that elicit neutralizing antibodies directed to the CD4-binding site, researchers need to address the antigenic variation within this region of gp120 and the restricted access to the CD4-binding site imposed by the native configuration of the trimeric viral envelope spike.

scholarly journals Germline VRC01 antibody recognition of a modified clade C HIV-1 envelope trimer and a glycosylated HIV-1 gp120 core

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Andrew J Borst ◽  
Connor E Weidle ◽  
Matthew D Gray ◽  
Brandon Frenz ◽  
Joost Snijder ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
X Ray Crystallography ◽  
Antibody Recognition ◽  
Immunodeficiency Virus ◽  
Gp120 Core ◽  
Clade C ◽  
Immunogen Design ◽  
Cd4 Binding Site ◽  
Variable Loops ◽  
Hiv 1

VRC01 broadly neutralizing antibodies (bnAbs) target the CD4-binding site (CD4BS) of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein (Env). Unlike mature antibodies, corresponding VRC01 germline precursors poorly bind to Env. Immunogen design has mostly relied on glycan removal from trimeric Env constructs and has had limited success in eliciting mature VRC01 bnAbs. To better understand elicitation of such bnAbs, we characterized the inferred germline precursor of VRC01 in complex with a modified trimeric 426c Env by cryo-electron microscopy and a 426c gp120 core by X-ray crystallography, biolayer interferometry, immunoprecipitation, and glycoproteomics. Our results show VRC01 germline antibodies interacted with a wild-type 426c core lacking variable loops 1–3 in the presence and absence of a glycan at position Asn276, with the latter form binding with higher affinity than the former. Interactions in the presence of an Asn276 oligosaccharide could be enhanced upon carbohydrate shortening, which should be considered for immunogen design.

scholarly journals Quaternary Interaction of the HIV-1 Envelope Trimer with CD4 and Neutralizing Antibodies

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1405
Author(s):  
Qingbo Liu ◽  
Peng Zhang ◽  
Paolo Lusso
Keyword(s):  
Binding Site ◽  
Conformational Changes ◽  
Neutralizing Antibodies ◽  
Current Knowledge ◽  
Viral Envelope ◽  
Host Cells ◽  
Initial Contact ◽  
Cd4 Receptor ◽  
Cd4 Binding Site ◽  
Hiv 1

The entry of HIV-1 into host cells is initiated by the interaction of the viral envelope (Env) spike with the CD4 receptor. During this process, the spike undergoes a series of conformational changes that eventually lead to the exposure of the fusion peptide located at the N-terminus of the transmembrane glycoprotein, gp41. Recent structural and functional studies have provided important insights into the interaction of Env with CD4 at various stages. However, a fine elucidation of the earliest events of CD4 contact and its immediate effect on the Env conformation remains a challenge for investigation. Here, we summarize the discovery of the quaternary nature of the CD4-binding site in the HIV-1 Env and the role of quaternary contact in the functional interaction with the CD4 receptor. We propose two models for this initial contact based on the current knowledge and discuss how a better understanding of the quaternary interaction may lead to improved immunogens and antibodies targeting the CD4-binding site.

scholarly journals Structural basis for germline antibody recognition of HIV-1 immunogens

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Louise Scharf ◽  
Anthony P West ◽  
Stuart A Sievers ◽  
Courtney Chen ◽  
Siduo Jiang ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Affinity Maturation ◽  
Structural Basis ◽  
Binding Modes ◽  
Broadly Neutralizing Antibodies ◽  
Antibody Recognition ◽  
Immunogen Design ◽  
Cd4 Binding Site ◽  
Modified Forms ◽  
Hiv 1

Efforts to elicit broadly neutralizing antibodies (bNAbs) against HIV-1 require understanding germline bNAb recognition of HIV-1 envelope glycoprotein (Env). The VRC01-class bNAb family derived from the VH1-2*02 germline allele arose in multiple HIV-1–infected donors, yet targets the CD4-binding site on Env with common interactions. Modified forms of the 426c Env that activate germline-reverted B cell receptors are candidate immunogens for eliciting VRC01-class bNAbs. We present structures of germline-reverted VRC01-class bNAbs alone and complexed with 426c-based gp120 immunogens. Germline bNAb–426c gp120 complexes showed preservation of VRC01-class signature residues and gp120 contacts, but detectably different binding modes compared to mature bNAb-gp120 complexes. Unlike typical antibody-antigen interactions, VRC01–class germline antibodies exhibited preformed antigen-binding conformations for recognizing immunogens. Affinity maturation introduced substitutions increasing induced-fit recognition and electropositivity, potentially to accommodate negatively-charged complex-type N-glycans on gp120. These results provide general principles relevant to the unusual evolution of VRC01–class bNAbs and guidelines for structure-based immunogen design.

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