scholarly journals Identification of HIV-1 Envelope Mutations that Enhance Entry Using Macaque CD4 and CCR5

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 241
Author(s):  
Jeremy I. Roop ◽  
Noah A. Cassidy ◽  
Adam S. Dingens ◽  
Jesse D. Bloom ◽  
Julie Overbaugh
Keyword(s):  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Bound States ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
Heptad Repeat ◽  
Design Strategies ◽  
Model Studies ◽  
Macaque Model ◽  
Hiv 1

Although Rhesus macaques are an important animal model for HIV-1 vaccine development research, most transmitted HIV-1 strains replicate poorly in macaque cells. A major genetic determinant of this species-specific restriction is a non-synonymous mutation in macaque CD4 that results in reduced HIV-1 Envelope (Env)-mediated viral entry compared to human CD4. Recent research efforts employing either laboratory evolution or structure-guided design strategies have uncovered several mutations in Env’s gp120 subunit that enhance binding of macaque CD4 by transmitted/founder HIV-1 viruses. In order to identify additional Env mutations that promote infection of macaque cells, we utilized deep mutational scanning to screen thousands of Env point mutants for those that enhance HIV-1 entry via macaque receptors. We identified many uncharacterized amino acid mutations in the N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR) regions of gp41 that increased entry into cells bearing macaque receptors up to 9-fold. Many of these mutations also modestly increased infection of cells bearing human CD4 and CCR5 (up to 1.5-fold). NHR/CHR mutations identified by deep mutational scanning that enhanced entry also increased sensitivity to neutralizing antibodies targeting the MPER epitope, and to inactivation by cold-incubation, suggesting that they promote sampling of an intermediate trimer conformation between closed and receptor bound states. Identification of this set of mutations can inform future macaque model studies, and also further our understanding of the relationship between Env structure and function.

scholarly journals Identification of HIV-1 Envelope Mutations that Enhance Entry Using Macaque CD4 and CCR5

2019 ◽  
Author(s):  
Jeremy I. Roop ◽  
Noah A. Cassidy ◽  
Adam S. Dingens ◽  
Jesse D. Bloom ◽  
Julie Overbaugh
Keyword(s):  
Animal Model ◽  
Neutralizing Antibodies ◽  
Bound States ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
Heptad Repeat ◽  
Design Strategies ◽  
Model Studies ◽  
Macaque Model ◽  
Hiv 1

AbstractAlthough Rhesus macaques are an important animal model for HIV-1 vaccine development research, most transmitted HIV-1 strains replicate poorly in macaque cells. A major genetic determinant of this species-specific restriction is a non-synonymous mutation in macaque CD4 that results in reduced HIV-1 Envelope (Env)-mediated viral entry compared to human CD4. Recent research efforts employing either laboratory evolution or structure-guided design strategies have uncovered several mutations in Env’s gp120 subunit that enhance binding of macaque CD4 by transmitted/founder HIV-1 viruses. In order to identify additional Env mutations that promote infection of macaque cells, we utilized deep mutational scanning to screen thousands of Env point mutants for those that enhance HIV-1 entry via macaque receptors. We identified many uncharacterized amino acid mutations in the N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR) regions of gp41 that increased entry into cells bearing macaque receptors by up to 38-fold. Many of these mutations also modestly increased infection of cells bearing human CD4 and CCR5 (up to 13-fold). NHR/CHR mutations identified by deep mutational scanning that enhanced entry also increased sensitivity to neutralizing antibodies targeting the MPER epitope, and to inactivation by cold-incubation, suggesting that they promote sampling of an intermediate trimer conformation between closed and receptor bound states. Identification of this set of mutations can inform future macaque model studies, and also further our understanding of the relationship between Env structure and function.ImportanceAlthough Rhesus macaques are the favored non-human primate animal model used in HIV-1 research, most circulating HIV-1 strains poorly infect macaque cells. Studies using macaques to model HIV-1 infection often use evolved, or mutant HIV-1 variants that are able to utilize macaque CD4, but these HIV-1 variants poorly model infection by circulating strains. In this work, we sought to identity HIV-1 mutations that would allow entry into macaque cells, but that would maintain critical characteristics of circulating HIV-1 strains. We employed a powerful experimental method to simultaneously assess the effects of thousands of individual HIV-1 mutations on infection of cells bearing macaque receptors. We identified many previously uncharacterized mutations that enhance infection of circulating HIV-1 strains into cells bearing macaque receptors by up to 38-fold. Identification of these mutations may be of use in future macaque model studies.

scholarly journals Conformational States of a Soluble, Uncleaved HIV-1 Envelope Trimer

2017 ◽  
Vol 91 (10) ◽  
Author(s):  
Yuhang Liu ◽  
Junhua Pan ◽  
Yongfei Cai ◽  
Nikolaus Grigorieff ◽  
Stephen C. Harrison ◽  
...  
Keyword(s):  
Viral Entry ◽  
Clinical Studies ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Recombinant Form ◽  
Soluble Form ◽  
Compact Structure ◽  
Antigenic Properties ◽  
Hiv 1 ◽  
Gp140 Trimer

ABSTRACT The HIV-1 envelope spike [Env; trimeric (gp160)3 cleaved to (gp120/gp41)3] induces membrane fusion, leading to viral entry. It is also the viral component targeted by neutralizing antibodies. Vaccine development requires production, in quantities suitable for clinical studies, of a recombinant form that resembles functional Env. HIV-1 gp140 trimers—the uncleaved ectodomains of (gp160)3—from a few selected viral isolates adopt a compact conformation with many antigenic properties of native Env spikes. One is currently being evaluated in a clinical trial. We report here low-resolution (20 Å) electron cryomicroscopy (cryoEM) structures of this gp140 trimer, which adopts two principal conformations, one closed and the other slightly open. The former is indistinguishable at this resolution from those adopted by a stabilized, cleaved trimer (SOSIP) or by a membrane-bound Env trimer with a truncated cytoplasmic tail (EnvΔCT). The latter conformation is closer to a partially open Env trimer than to the fully open conformation induced by CD4. These results show that a stable, uncleaved HIV-1 gp140 trimer has a compact structure close to that of native Env. IMPORTANCE Development of any HIV vaccine with a protein component (for either priming or boosting) requires production of a recombinant form to mimic the trimeric, functional HIV-1 envelope spike in quantities suitable for clinical studies. Our understanding of the envelope structure has depended in part on a cleaved, soluble trimer, known as SOSIP.664, stabilized by several modifications, including an engineered disulfide. This construct, which is difficult to produce in large quantities, has yet to induce better antibody responses than those to other envelope-based immunogens, even in animal models. The uncleaved ectodomain of the envelope protein, called gp140, has also been made as a soluble form to mimic the native Env present on the virion surface. Most HIV-1 gp140 preparations are not stable, however, and have an inhomogeneous conformation. The results presented here show that gp140 preparations from suitable isolates can adopt a compact, native-like structure, supporting its use as a vaccine candidate.

scholarly journals Augmenting Neutralization breadth against Diverse HIV-1 by increasing the Ab-Ag interface on V2

2021 ◽  
Author(s):  
Nan Gao ◽  
Yanxin Gai ◽  
Lina Meng ◽  
Chu Wang ◽  
Wei Wang ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
Broadly Neutralizing Antibodies ◽  
Binding Surface ◽  
Monomeric Gp120 ◽  
Chinese Rhesus Macaques ◽  
Shiv Infection ◽  
Hiv 1 ◽  
Trimeric Envelope

Understanding maturation pathways of broadly neutralizing antibodies (bnAbs) against HIV-1 in non-human primates can be highly informative for HIV-1 vaccine development. We now obtained a lineage of J038 from Chinese rhesus macaques after 7-years of SHIV infection. J038 has short complementary determining loops and neutralizes 54% of global circulating HIV-1 strains. Its binding induces a unique 'up' conformation for one of the V2 loops in the trimeric envelope glycoprotein (Env) and is heavily dependent on glycan, which provides nearly half of the binding surface. The unmutated common ancestor of the J038 lineage antibodies binds monomeric gp120 and neutralizes the autologous virus. Continuous maturation enhances neutralization potency and breadth of J038 lineage antibodies via expanding antibody-Env contact areas surrounding the core region contacted by germline-encoded residues. Developmental details and recognition features of J038 lineage antibodies revealed here provide a new pathway for maturation elicitation of V2-targeting bnAbs.

scholarly journals Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1

2018 ◽  
Author(s):  
Kai Xu ◽  
Priyamvada Acharya ◽  
Rui Kong ◽  
Cheng Cheng ◽  
Gwo-Yu Chuang ◽  
...  
Keyword(s):  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Fusion Peptide ◽  
Broadly Neutralizing Antibodies ◽  
Vaccine Research ◽  
Cryo Electron Microscopy ◽  
Promising Target ◽  
Conformational Diversity ◽  
Hiv 1

A central goal of HIV-1-vaccine research is the elicitation of antibodies capable of neutralizing diverse primary isolates of HIV-1. Here we show that focusing the immune response to exposed N-terminal residues of the fusion peptide, a critical component of the viral entry machinery and the epitope of antibodies elicited by HIV-1 infection, through immunization with fusion peptide-coupled carriers and prefusion-stabilized envelope trimers, induces cross-clade neutralizing responses. In mice, these immunogens elicited monoclonal antibodies capable of neutralizing up to 31% of a cross-clade panel of 208 HIV-1 strains. Crystal and cryo-electron microscopy structures of these antibodies revealed fusion peptide-conformational diversity as a molecular explanation for the cross-clade neutralization. Immunization of guinea pigs and rhesus macaques induced similarly broad fusion peptide-directed neutralizing responses suggesting translatability. The N terminus of the HIV-1-fusion peptide is thus a promising target of vaccine efforts aimed at eliciting broadly neutralizing antibodies.

scholarly journals Fab-dimerized glycan-reactive antibodies neutralize HIV and are prevalent in humans and rhesus macaques

2020 ◽  
Author(s):  
Wilton B. Williams ◽  
R. Ryan Meyerhoff ◽  
RJ Edwards ◽  
Hui Li ◽  
Nathan I. Nicely ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
List Type ◽  
Immunodeficiency Virus ◽  
Variable Heavy ◽  
Novel Strategy ◽  
Fragment Antigen Binding ◽  
B Cell Precursors ◽  
Hiv 1

SummaryThe HIV-1 envelope (Env) is comprised by mass of over 50% glycans. A goal of HIV-1 vaccine development is the induction of Env glycan-reactive broadly neutralizing antibodies (bnAbs). The 2G12 bnAb recognizes an Env glycan cluster using a unique variable heavy (VH) domain-swapped conformation that results in fragment antigen-binding (Fab) dimerization. Here we describe Fab-dimerized glycan (FDG)-reactive antibodies without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques that neutralized heterologous HIV-1 isolates. FDG precursors were boosted by vaccination in macaques, and were present in HIV-1-naïve humans with an average estimated frequency of one per 340,000 B cells. These data demonstrate frequent HIV-1 Env glycan-reactive bnAb B cell precursors in macaques and humans and reveal a novel strategy for their induction by vaccination.HighlightsDiscovery of Fab-dimerized HIV-1 glycan-reactive antibodies with a non-domain-swapped architectureFab-dimerized antibodies neutralize heterologous HIV-1 isolates.Antibodies with this architecture can be elicited by vaccination in macaques.Fab-dimerized antibodies are found in HIV-1 naïve humans.

scholarly journals Structural and genetic convergence of HIV-1 neutralizing antibodies in vaccinated non-human primates

2021 ◽  
Vol 17 (6) ◽  
pp. e1009624
Author(s):  
Fangping Cai ◽  
Wei-Hung Chen ◽  
Weimin Wu ◽  
Julia A. Jones ◽  
Misook Choe ◽  
...  
Keyword(s):  
Immune System ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
Gene Segment ◽  
Atomic Level ◽  
Antigen Binding ◽  
Binding Modes ◽  
Rational Vaccine Design ◽  
Hiv 1

A primary goal of HIV-1 vaccine development is the consistent elicitation of protective, neutralizing antibodies. While highly similar neutralizing antibodies (nAbs) have been isolated from multiple HIV-infected individuals, it is unclear whether vaccination can consistently elicit highly similar nAbs in genetically diverse primates. Here, we show in three outbred rhesus macaques that immunization with Env elicits a genotypically and phenotypically conserved nAb response. From these vaccinated macaques, we isolated four antibody lineages that had commonalities in immunoglobulin variable, diversity, and joining gene segment usage. Atomic-level structures of the antigen binding fragments of the two most similar antibodies showed nearly identical paratopes. The Env binding modes of each of the four vaccine-induced nAbs were distinct from previously known monoclonal HIV-1 neutralizing antibodies, but were nearly identical to each other. The similarities of these antibodies show that the immune system in outbred primates can respond to HIV-1 Env vaccination with a similar structural and genotypic solution for recognizing a particular neutralizing epitope. These results support rational vaccine design for HIV-1 that aims to reproducibly elicit, in genetically diverse primates, nAbs with specific paratope structures capable of binding conserved epitopes.

scholarly journals Conformation of HIV-1 Envelope governs rhesus CD4 usage and simian-human immunodeficiency virus replication

2021 ◽  
Author(s):  
Geraldine Vilmen ◽  
Anna C Smith ◽  
Hector Cervera Benet ◽  
Rajni Kant Shukla ◽  
Ross C Larue ◽  
...  
Keyword(s):  
Amino Acid ◽  
Viral Entry ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
Conformational State ◽  
Single Amino Acid ◽  
Human Immunodeficiency Virus Replication ◽  
Amino Acid Substitutions ◽  
Entry Barrier ◽  
Hiv 1

Infection of rhesus macaques with simian-human immunodeficiency viruses (SHIVs) is the preferred model system for vaccine development because SHIVs encode HIV-1 envelope glycoproteins (Env) – a key target of HIV-1 neutralizing antibodies. Since the goal of vaccines is to prevent new infections, SHIVs encoding circulating HIV-1 Env are desired as challenge viruses. Development of such biologically relevant SHIVs has been challenging as they fail to infect rhesus macaques, mainly because most circulating HIV-1 Env do not use rhesus CD4 (rhCD4) receptor for viral entry. Most primary HIV-1 Env exist in a closed conformation and occasionally transit to downstream, open conformation through an obligate intermediate conformation. Here, we provide genetic evidence that open Env conformations can overcome the rhCD4 entry barrier and increase replication of SHIVs in rhesus lymphocytes. Consistent with prior studies, we found that circulating HIV-1 Env do not use rhCD4 efficiently for viral entry. However, using HIV-1 Env with single amino acid substitutions that alter their conformational state, we found that transitions to intermediate and open Env conformation allow usage of physiological levels of rhCD4 for viral entry. We engineered these single amino acid substitutions in the transmitted/founder HIV-1BG505 Env encoded by SHIV-BG505 and found that open Env conformation enhances SHIV replication in rhesus lymphocytes. Lastly, CD4-mediated SHIV pull-down, sensitivity to soluble CD4, and fusogenicity assays indicated that open Env conformation promotes efficient rhCD4 binding and viral-host membrane fusion. These findings identify conformational state of HIV-1 Env as a major determinant for rhCD4 usage, viral fusion, and SHIV replication.

scholarly journals Antigenicity and Immunogenicity of HIV-1 Envelope Trimers Complexed to a Small-Molecule Viral Entry Inhibitor

2020 ◽  
Vol 94 (21) ◽  
Author(s):  
S. Munir Alam ◽  
Kenneth Cronin ◽  
Robert Parks ◽  
Kara Anasti ◽  
Haitao Ding ◽  
...  
Keyword(s):  
Small Molecule ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Conformational Transition ◽  
Rhesus Macaques ◽  
Entry Inhibitor ◽  
Tier 2 ◽  
Membrane Bound ◽  
High Mannose ◽  
Hiv 1

ABSTRACT Small-molecule viral entry inhibitors, such as BMS-626529 (BMS-529), allosterically block CD4 binding to HIV-1 envelope (Env) and inhibit CD4-induced structural changes in Env trimers. Here, we show that the binding of BMS-529 to clade C soluble chimeric gp140 SOSIP (ch.SOSIP) and membrane-bound trimers with intact transmembrane domain (gp150) prevented trimer conformational transitions and enhanced their immunogenicity. When complexed to BMS-529, ch.SOSIP trimers retained their binding to broadly neutralizing antibodies (bNAbs) and to their unmutated common ancestor (UCA) antibodies, while exposure of CD4-induced (CD4i) non-bNAb epitopes was inhibited. BMS-529-complexed gp150 trimers in detergent micelles, which were isolated from CHO cells, bound to bNAbs, including UCA and intermediates of the CD4 binding site (bs) CH103 bNAb lineage, and showed limited exposure of CD4i epitopes and a glycosylation pattern with a preponderance of high-mannose glycans. In rabbits, BMS-529-complexed V3 glycan-targeting ch.SOSIP immunogen induced in the majority of immunized animals higher neutralization titers against both autologous and select high mannose-bearing heterologous tier 2 pseudoviruses than those immunized with the noncomplexed ch.SOSIP. In rhesus macaques, BMS-529 complexed to CD4 bs-targeting ch.SOSIP immunogen induced stronger neutralization against tier 2 pseudoviruses bearing high-mannose glycans than noncomplexed ch.SOSIP trimer immunogen. When immunized with gp150 complexed to BMS-529, rhesus macaques showed neutralization against tier 2 pseudoviruses with targeted glycan deletion and high-mannose glycan enrichment. These results demonstrated that stabilization of Env trimer conformation with BMS-529 improved the immunogenicity of select chimeric SOSIP trimers and elicited tier 2 neutralizing antibodies of higher potency than noncomplexed trimers. IMPORTANCE Soluble forms of HIV-1 envelope trimers exhibit conformational heterogeneity and undergo CD4-induced (CD4i) exposure of epitopes of non-neutralizing antibodies that can potentially hinder induction of broad neutralizing antibody responses. These limitations have been mitigated through recent structure-guided approaches and include trimer-stabilizing mutations that resist trimer conformational transition and exposure of CD4i epitopes. The use of small-molecule viral inhibitors that allosterically block CD4 binding represents an alternative strategy for stabilizing Env trimer in the pre-CD4-triggered state of both soluble and membrane-bound trimers. In this study, we report that the viral entry inhibitor BMS-626529 restricts trimer conformational transition and improves the immunogenicity of select Env trimer immunogens.

scholarly journals A derivative of the D5 monoclonal antibody that targets the gp41 N-heptad repeat of HIV-1 with broad tier-2 neutralizing activity

2021 ◽  
Author(s):  
Adonis A. Rubio ◽  
Maria V. Filsinger Interrante ◽  
Benjamin N. Bell ◽  
Clayton L. Brown ◽  
Theodora U. J. Bruun ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Passive Immunization ◽  
Heptad Repeat ◽  
Target Cells ◽  
Tier 2 ◽  
Viral Glycoprotein ◽  
Neutralizing Activity ◽  
Tier 1 ◽  
Hiv 1

HIV-1 infection is initiated by the viral glycoprotein Env, which, after interaction with cellular coreceptors, adopts a transient conformation known as the pre-hairpin intermediate (PHI). The N-heptad repeat (NHR) is a highly conserved region of gp41 exposed in the PHI; it is the target of the FDA-approved drug enfuvirtide and of neutralizing monoclonal antibodies (mAbs). However, to date these mAbs have only been weakly effective against tier-1 HIV-1 strains, which are most sensitive to neutralizing antibodies. Here, we engineered and tested 11 IgG variants of D5, an anti-NHR mAb, by recombining previously described mutations in four of D5’s six antibody complementarity-determining regions. One variant, D5_AR, demonstrated 6-fold enhancement in ID50 against lentivirus pseudotyped with HXB2 Env. D5_AR exhibited weak cross-clade neutralizing activity against a diverse set of tier-2 HIV-1 viruses, which are less sensitive to neutralizing antibodies than tier-1 viruses and are the target of current antibody-based vaccine efforts. In addition, the neutralization potency of D5_AR IgG was greatly enhanced in target cells expressing FcγRI, with ID50 values below 0.1 μg/mL; this immunoglobulin receptor is expressed on macrophages and dendritic cells, which are implicated in the early stages of HIV-1 infection of mucosal surfaces. D5 and D5_AR have equivalent neutralization potency in IgG, Fab, and scFv formats, indicating that neutralization is not impacted by steric hindrance. Taken together, these results provide support for vaccine strategies that target the PHI by eliciting antibodies against the gp41 NHR and support investigation of anti-NHR mAbs in non-human primate passive immunization studies. Importance Despite advances in anti-retroviral therapy, HIV remains a global epidemic and has claimed more than 32 million lives. Accordingly, developing an effective HIV vaccine remains an urgent public health need. The gp41 N-heptad repeat (NHR) of the HIV-1 pre-hairpin intermediate (PHI) is highly conserved (>90%) and is inhibited by the FDA-approved drug enfuvirtide, making it an attractive vaccine target. However, to date anti-NHR antibodies have not been potent. Here, we engineered D5_AR, a more potent variant of the anti-NHR antibody D5, and established its ability to inhibit HIV-1 strains that are more difficult to neutralize and are more representative of circulating strains (tier-2 strains). The neutralizing activity of D5_AR was greatly potentiated in cells expressing FcγRI; FcγRI is expressed on cells that are implicated at the earliest stages of sexual HIV-1 transmission. Taken together, these results bolster efforts to target the gp41 NHR and the PHI for vaccine development.

scholarly journals A derivative of the D5 monoclonal antibody that targets the gp41 N-heptad repeat of HIV-1 with broad tier-2 neutralizing activity

2020 ◽  
Author(s):  
Adonis A. Rubio ◽  
Maria V. Filsinger Interrante ◽  
Benjamin N. Bell ◽  
Clayton L. Brown ◽  
Celia C. LaBranche ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Heptad Repeat ◽  
Effective Vaccine ◽  
Target Cells ◽  
Tier 2 ◽  
Viral Glycoprotein ◽  
Neutralizing Activity ◽  
Tier 1 ◽  
Hiv 1

AbstractHIV-1 infection is initiated by the viral glycoprotein Env, which, after interaction with cellular coreceptors, adopts a transient conformation known as the pre-hairpin intermediate (PHI). The N-heptad repeat (NHR) is a highly conserved region of gp41 exposed in the PHI; it is the target of the FDA-approved drug enfuvirtide and of neutralizing monoclonal antibodies (mAbs). However, to date these mAbs have only been weakly effective against tier-1 HIV-1 strains, which are most sensitive to neutralizing antibodies. Here, we engineered and tested 11 IgG variants of D5, an anti-NHR mAb, by recombining previously described mutations in four of D5’s six antibody complementarity-determining regions. One variant, D5_AR, demonstrated 6-fold enhancement in ID50 against lentivirus pseudotyped with HXB2 Env. Importantly, D5_AR exhibited weak cross-clade neutralizing activity against a diverse set of tier-2 HIV-1 viruses, which are less sensitive to neutralizing antibodies than tier-1 viruses and are the target of current antibody-based vaccine efforts. In addition, the neutralization potency of D5_AR IgG was greatly enhanced in target cells expressing FcγRI with ID50 values below 0.1 μg/mL; this immunoglobulin receptor is expressed on macrophages and dendritic cells, which are implicated in the early stages of HIV-1 infection of mucosal surfaces. D5 and D5_AR have equivalent neutralization potency in IgG, Fab, and scFv formats, indicating that neutralization is not impacted by steric hindrance. Taken together, these results provide support for vaccine strategies that target the PHI by eliciting antibodies against the gp41 NHR.ImportanceDespite advances in anti-retroviral therapy, HIV remains a global epidemic and has claimed more than 32 million lives. Accordingly, developing an effective vaccine remains an urgent public health need. The gp41 N-heptad repeat (NHR) of the HIV-1 pre-hairpin intermediate (PHI) is highly conserved (>90%) and is inhibited by the FDA-approved drug enfuvirtide, making it an attractive vaccine target. However, to date NHR antibodies have not been potent. Here, we engineered D5_AR, a more potent variant of the anti-NHR antibody D5, and established its ability to inhibit HIV-1 strains that are more difficult to neutralize and are more representative of circulating strains (tier-2 strains). The neutralizing activity of D5_AR was greatly potentiated in cells expressing FcγRI; FcγRI is expressed on cells that are implicated at the earliest stages of sexual HIV-1 transmission. Taken together, these results bolster efforts to target the gp41 NHR and the PHI for vaccine development.

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