Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding

Scheid, Johannes F.; Mouquet, Hugo; Ueberheide, Beatrix; Diskin, Ron; Klein, Florian; Oliveira, Thiago Y.; Pietzsch, John; Fenyö, David; Abadir, Alexander; Velinzon, Klara; Hurley, Arlene; Myung, Sunnie; Boulad, Farid; Poignard, Pascal; Burton, Dennis R.; Pereyra, Florencia; Ho, David D.; Walker, Bruce D.; Seaman, Michael S.; Björkman, Pamela J.; Chait, Brian T.; Nussenzweig, Michel C.

doi:10.1126/science.1207227

Cited by 1,058 publications

(1,480 citation statements)

References 49 publications

Supporting

Mentioning

1,443

Contrasting

Unclassified

Order By: Relevance

“…However, unlike 35022, the binding of these two bnAbs results in destabilization of the trimer. Similarly, a bnAb isolated using a gp120 bait strategy, 8ANC19540 was found to also bind the gp120‐gp41 interface, and to bind to glycans at 276, 234, and 637, with a footprint falling between those of PGT151 and 35022 37, 43. Strikingly, this bnAb can bind to Env both in a closed conformation and partially reverse the open‐conformation induced by concomitant CD4 binding 79.…”

Section: Specificity Of Hiv Bnabsmentioning

confidence: 86%

“…cDNA was generated from each well and heavy‐ and light‐chain pairs cloned, recombinantly expressed and then screened for neutralization activity. Similar approaches with different baits were used to isolated additional gp120‐specific bnAbs including 3BNC117, 3BNC60,40 and 10‐1074 41. In this method, selection is based purely on the ability to bind the Env bait, and many non‐neutralizing mAbs may also be cloned unless there is counter selection with an epitope‐specific knockout probe.…”

Section: Identification Of Hiv Bnabsmentioning

confidence: 99%

“…This bnAb, in contrast to VRC01, does not induce conformational changes in gp120 upon binding 25. Many additional CD4‐binding site bnAbs were isolated using RSC356 or other Env baits40 and one by EBV immortalization of B cells followed by an ELISA‐based binding screen 75. Structural studies have enabled comparison of the CD4‐binding site bnAbs and the definition of two subclasses: those that bind predominantly using their CDRH3 and those that are genetically restricted and use either the VH1‐2 or VH1‐46 V gene 76.…”

Section: Specificity Of Hiv Bnabsmentioning

confidence: 99%

See 2 more Smart Citations

Identification and specificity of broadly neutralizing antibodies against HIV

McCoy

Burton

2017

Immunological Reviews

Self Cite

204

191

View full text Add to dashboard Cite

SummaryBeginning in 2009, studies of the humoral responses of HIV‐positive individuals have led to the identification of scores, if not hundreds, of antibodies that are both broadly reactive and potently neutralizing. This development has provided renewed impetus toward an HIV vaccine and led directly to the development of novel immunogens. Advances in identification of donors with the most potent and broad anti‐HIV serum neutralizing responses were crucial in this effort. Equally, development of methods for the rapid generation of human antibodies from these donors was pivotal. Primarily these methods comprise single B‐cell culture coupled to high‐throughput neutralization screening and flow cytometry‐based sorting of single B cells using HIV envelope protein baits. In this review, the advantages and disadvantages of these methodologies are discussed in the context of the specificities targeted by individual antibodies and the need for further improvements to evaluate HIV vaccine candidates.

show abstract

Section: Specificity Of Hiv Bnabsmentioning

confidence: 86%

Section: Identification Of Hiv Bnabsmentioning

confidence: 99%

Section: Specificity Of Hiv Bnabsmentioning

confidence: 99%

See 1 more Smart Citation

Identification and specificity of broadly neutralizing antibodies against HIV

McCoy

Burton

2017

Immunological Reviews

Self Cite

204

191

View full text Add to dashboard Cite

show abstract

“…The CH235 lineage progressed over 6 years of infection to extraordinary heterologous neutralization breadth (16). Like the 8ANC131 CD4 mimic bnAb, CH235 used V H 1-46 (16, 26). Co-crystal structural analysis revealed that the angle of approach to gp120 of the CH235 lineage antibodies was the same as for other VRC01-class of antibodies and did not change during bnAb affinity maturation (Figure 4A) (16).…”

Section: Antibody-virus Co-evolutionmentioning

confidence: 99%

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

Bonsignori

Liao

Gao

et al. 2017

Immunological Reviews

156

146

View full text Add to dashboard Cite

Summary Induction of HIV-1 broadly neutralizing antibodies (bnAbs) to date has only been observed in the setting of HIV-1 infection, and then only years after HIV transmission. Thus, the concept has emerged that one path to induction of bnAbs is to define the viral and immunologic events that occur during HIV-1 infection, and then to mimic those events with a vaccine formulation. This concept has led to efforts to map both virus and antibody events that occur from the time of HIV-1 transmission to development of bnAbs. This work has revealed that a virus-antibody “arms race” occurs in which a HIV-1 transmitted/founder (TF) Env induces autologous neutralizing antibodies that can not only neutralize the TF virus but also can select virus escape mutants that in turn select affinity-matured neutralizing antibodies. From these studies has come a picture of bnAb development that has led to new insights in host-pathogen interactions and, as well, led to insight into immunologic mechanisms of control of bnAb development. Here we review the progress to date in elucidating bnAb B cell lineages in HIV-1 infection, discuss new research leading to understanding the immunologic mechanisms of bnAb induction, and address issues relevant to the use of this information for the design of new HIV-1 sequential envelope vaccine candidates.

show abstract

“…The most important of the maturation mechanisms is SHM particularly in the heavy variable region [89][90][91][92][93][94][95]. A high degree of amino acid SHMs ranging from 9.4% for M66.6 (gp41 MPER antibody) up to 47.9% for VRC06 (CD4bs antibody) is a characteristic feature of HIV-1 BrNAbs [96].…”

Section: Aromatic Residues In Bovine Cdrh3 Pave the Wave Toward Hiv Nmentioning

confidence: 99%

Broad Neutralizing Antibodies to HIV Env and Other Complex Viral Antigens from Vaccinated Cows

Heydarchi¹,

Quiroz²,

Purcell³

2016

J Vaccines Vaccin

View full text Add to dashboard Cite

The idea of using antibodies to restrain HIV viral replication has been a growing interest since many years ago. HIV-patient serum with elite virus-neutralizing breadth has led to the preparation of broadly neutralizing antibodies (BrNAbs) with long and highly mutated CDRH3 domains that can neutralize a broad array of viral strains and prevent transmission in animal models. Recent advances have resulted in the discovery of BrNAbs that are more potent and can neutralize many HIV-1 subtypes. However, elicitation of these antibodies in infected individuals usually requires a long time of antigen exposure. Though BrNAbs are shown to be successful either therapeutically or prophylactically against HIV-1, production of these antibodies in bulk, commercial-sized batches are expensive and non-affordable particularly for poor countries. Therefore, more durable preventative or therapeutic strategies are required. Immunization of the cows with HIV Env is shown to be capable of producing 20 kg purified anti-HIV-1 BrNAbs and this amount could be sufficient for 2 million × 10 mg doses for formulation and pre-clinical testing as an HIV microbicide. In addition, bovine immunoglobulins typically have variable third heavy complementarity determining regions (CDRH3) that may potentially facilitate access to antigenic epitopes that are very difficult for other species to engage. Thus, cows could be engaged to elicit anti-HIV antibodies with the features of human BrNAbs and bovine colostrum could be a promising and cheap resource for the development of combination microbicides.

show abstract

Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding

Cited by 1,058 publications

References 49 publications

Identification and specificity of broadly neutralizing antibodies against HIV

Identification and specificity of broadly neutralizing antibodies against HIV

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

Broad Neutralizing Antibodies to HIV Env and Other Complex Viral Antigens from Vaccinated Cows

Contact Info

Product

Resources

About