Short Communication: HIV Type 1 Subtype C Variants Transmitted Through the Bottleneck of Breastfeeding Are Sensitive to New Generation Broadly Neutralizing Antibodies Directed Against Quaternary and CD4-Binding Site Epitopes

Two to three years after infection, a fraction of HIV-1–infected individuals develop serologic activity that neutralizes most viral isolates. Broadly neutralizing antibodies that recognize the HIV-1 envelope protein have been isolated from these patients by single-cell sorting and by neutralization screens. Here, we report a new method for anti–HIV-1 antibody isolation based on capturing single B cells that recognize the HIV-1 envelope protein expressed on the surface of transfected cells. Although far less efficient than soluble protein baits, the cell-based capture method identified antibodies that bind to a new broadly neutralizing epitope in the vicinity of the V3 loop and the CD4-induced site (CD4i). The new epitope is expressed on the cell surface form of the HIV-1 spike, but not on soluble forms of the same envelope protein. Moreover, the new antibodies complement the neutralization spectrum of potent broadly neutralizing anti-CD4 binding site (CD4bs) antibodies obtained from the same individual. Thus, combinations of potent broadly neutralizing antibodies with complementary activity can account for the breadth and potency of naturally arising anti–HIV-1 serologic activity. Therefore, vaccines aimed at eliciting anti–HIV-1 serologic breadth and potency should not be limited to single epitopes.

Download Full-text

Short Communication: In VitroSynergy between Peptides or Neutralizing Antibodies Targeting the N- and C-Terminal Heptad Repeats of HIV Type 1 gp41

AIDS Research and Human Retroviruses ◽

10.1089/aid.2008.0129 ◽

2008 ◽

Vol 24 (12) ◽

pp. 1537-1544 ◽

Cited By ~ 10

Author(s):

Renee Hrin ◽

Donna L. Montgomery ◽

Fubao Wang ◽

Jon H. Condra ◽

Zhiqiang An ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Short Communication ◽

Hiv Type 1 ◽

Heptad Repeats

Download Full-text

Selection Pressure on HIV-1 Envelope by Broadly Neutralizing Antibodies to the Conserved CD4-Binding Site

Journal of Virology ◽

10.1128/jvi.07139-11 ◽

2012 ◽

Vol 86 (10) ◽

pp. 5844-5856 ◽

Cited By ~ 60

Author(s):

X. Wu ◽

C. Wang ◽

S. O'Dell ◽

Y. Li ◽

B. F. Keele ◽

...

Keyword(s):

Binding Site ◽

Neutralizing Antibodies ◽

Selection Pressure ◽

Broadly Neutralizing Antibodies ◽

Cd4 Binding Site ◽

Hiv 1

Download Full-text

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

10.1101/2021.11.02.466200 ◽

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.

Download Full-text

Sequences in Glycoprotein gp41, the CD4 Binding Site, and the V2 Domain Regulate Sensitivity and Resistance of HIV-1 to Broadly Neutralizing Antibodies

Journal of Virology ◽

10.1128/jvi.01352-12 ◽

2012 ◽

Vol 86 (22) ◽

pp. 12105-12114 ◽

Cited By ~ 22

Author(s):

S. M. O'Rourke ◽

B. Schweighardt ◽

P. Phung ◽

K. A. Mesa ◽

A. L. Vollrath ◽

...

Keyword(s):

Binding Site ◽

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Cd4 Binding Site ◽

Glycoprotein Gp41 ◽

Hiv 1

Download Full-text

I-101 Quaternary contact improves the potency of broadly neutralizing antibodies to the CD4-binding site of HIV-1

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/01.qai.0000557987.57581.a7 ◽

2019 ◽

Vol 81 ◽

pp. 49

Author(s):

Paolo Lusso ◽

Qingbo Liu ◽

Yen-Ting Lai ◽

Mark Louder ◽

Peter D. Kwong ◽

...

Keyword(s):

Binding Site ◽

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Cd4 Binding Site ◽

Hiv 1

Download Full-text

Structural survey of HIV-1-neutralizing antibodies targeting Env trimer delineates epitope categories and suggests vaccine templates

10.1101/312579 ◽

2018 ◽

Cited By ~ 3

Author(s):

Gwo-Yu Chuang ◽

Jing Zhou ◽

Reda Rawi ◽

Chen-Hsiang Shen ◽

Zizhang Sheng ◽

...

Keyword(s):

B Cell ◽

Binding Site ◽

Neutralizing Antibodies ◽

Vaccine Design ◽

Immune Recognition ◽

Broadly Neutralizing Antibodies ◽

Independent Sequence ◽

Cd4 Binding Site ◽

Hiv 1 ◽

Cell Ontogeny

HIV-1 broadly neutralizing antibodies are desired for their therapeutic potential and as templates for vaccine design. Such antibodies target the HIV-1-envelope (Env) trimer, which is shielded from immune recognition by extraordinary glycosylation and sequence variability. Recognition by broadly neutralizing antibodies thus provides insight into how antibody can bypass these immune-evasion mechanisms. Remarkably, antibodies neutralizing >25% of HIV-1 strains have now been identified that recognize all major exposed surfaces of the prefusion-closed Env trimer. Here we analyzed all 206 broadly neutralizing antibody-HIV-1 Env complexes in the PDB with resolution suitable to define their interaction chemistries. These segregated into 20 antibody classes based on ontogeny and recognition, and into 6 epitope categories (V1V2, glycan-V3, CD4-binding site, silent face center, fusion peptide, and subunit interface) based on recognized Env residues. We measured antibody neutralization on a 208-isolate panel and analyzed features of paratope and B cell ontogeny. The number of protruding loops, CDR H3 length, and level of somatic hypermutation for broadly HIV-1 neutralizing antibodies were significantly higher than for a comparison set of non-HIV-1 antibodies. For epitope, the number of independent sequence segments was higher (P < 0.0001), as well as the glycan component surface area (P = 0.0005). Based on B cell ontogeny, paratope, and breadth, the CD4-binding site antibody IOMA appeared to be a promising candidate for lineage-based vaccine design. In terms of epitope-based vaccine design, antibody VRC34.01 had few epitope segments, low epitope-glycan content, and high epitope-conformational variability, which may explain why VRC34.01-based design is yielding promising vaccine results.

Download Full-text

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

Journal of Virology ◽

10.1128/jvi.01142-09 ◽

2009 ◽

Vol 83 (21) ◽

pp. 10892-10907 ◽

Cited By ~ 77

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.

Download Full-text