Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01

Zhou, Tongqing; Georgiev, Ivelin S.; Wu, Xueling; Yang, Zhi Yong; Dai, Keren; Finzi, Andrés; Kwon, Young Do; Scheid, Johannes F.; Shi, Wei; Xu, Li; Yang, Yongping; Zhu, Jiang; Nussenzweig, Michel C.; Sodroski, Joseph; Shapiro, Lawrence; Nabel, Gary J.; Mascola, John R.; Kwong, Peter D.

doi:10.1126/science.1192819

Cited by 1,056 publications

(1,366 citation statements)

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“…7). For both isolates, VRC01 was shown to be highly dependent on N279, as described previously 23 . In contrast, NC-Cow1 was not dependent on N279, but was instead dependent on residues in the C2 and C5 regions of gp120.…”

Section: Main Textmentioning

confidence: 56%

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Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows

Sok

Vadnais

et al. 2017

Nature

156

198

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No immunogen to date has reliably elicited broadly neutralizing antibodies (bnAbs) to HIV in humans or animal models. Advances in the design of immunogens (BG505 SOSIP) that antigenically mimic the HIV envelope glycoprotein (Env)1 have improved the elicitation of potent isolate-specific Ab responses in rabbits2 and macaques3, but so far failed to induce bnAbs. One possible contributor to this failure is that the relevant antibody repertoires are poorly suited to target somewhat occluded conserved epitope regions on Env relative to exposed variable epitopes. To test this hypothesis, we immunized four cows with BG505 SOSIP. The antibody repertoire of cows contains long third heavy chain complementary determining regions (HCDR3) with an ultralong subset that can reach over 70 amino acids in length4–9. Remarkably, BG505 SOSIP immunization resulted in rapid elicitation of broad and potent serum antibody responses in all four cows. Longitudinal serum analysis for one cow showed the development of neutralization breadth (20%, n = 117 cross-clade isolates) in 42 days and 96% breadth (n = 117) at 381 days. A monoclonal antibody (mAb) isolated from this cow harbored an ultralong HCDR3 of 60 amino acids and neutralized 72% of cross-clade isolates (n = 117) with a potent median IC50 of 0.028 μg/ml. We note that breadth was elicited with a single trimer immunogen and did not require additional envelope diversity. Immunization of cows may provide an avenue to rapidly generate antibody prophylactics and therapeutics to address disease agents that have evolved to avoid human antibody responses.

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Section: Main Textmentioning

confidence: 56%

“…Of note, VRC01-class antibodies rely on a critical salt bridge interaction with an aspartic acid residue at position 368 of gp120 23 that is disrupted at low pH (Extended Data Fig. 8), which is characteristic of conditions found in the vagina.…”

Section: Main Textmentioning

confidence: 99%

Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows

Sok

Vadnais

et al. 2017

Nature

156

198

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“…This approach negates the need to screen thousands of individual B‐cell culture supernatants and allows a more streamlined process for isolating bnAbs. The first CD4‐binding site bnAb isolated, apart from b12,12 was VRC01, which partially mimics the binding of CD4 to its receptor site 74. The RSC3 bait used to capture the VRC01 B‐cell lineage was modified to preferentially bind b12 and a negative bait that could not bind b12 was used for counter selection 39.…”

Section: Specificity Of Hiv Bnabsmentioning

confidence: 99%

Identification and specificity of broadly neutralizing antibodies against HIV

McCoy

Burton

2017

Immunological Reviews

210

193

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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.

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“…VRC01 binds to highly conserved amino acid residues which are almost invariant and maintained across viruses, critical for CD4 binding and viral entry (eg, the conserved CD4 binding loop contacts shown in Figure 2, that are important for all VRC01‐like antibodies) 65, 66. However, VRC01 also directly contacts amino acids in the hypervariable part of V5 (positions 460‐465) 65, 66. This short region of Env is extremely variable, and laden with insertions and deletions to the extent that it is extremely difficult to align in a meaningful way.…”

Section: Antibody Epitope Diversitymentioning

confidence: 99%

Polyvalent vaccine approaches to combat HIV‐1 diversity

Korber

Hraber

Wagh

et al. 2017

Immunological Reviews

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SummaryA key unresolved challenge for developing an effective HIV‐1 vaccine is the discovery of strategies to elicit immune responses that are able to cross‐protect against a significant fraction of the diverse viruses that are circulating worldwide. Here, we summarize some of the immunological implications of HIV‐1 diversity, and outline the rationale behind several polyvalent vaccine design strategies that are currently under evaluation. Vaccine‐elicited T‐cell responses, which contribute to the control of HIV‐1 in natural infections, are currently being considered in both prevention and treatment settings. Approaches now in preclinical and human trials include full proteins in novel vectors, concatenated conserved protein regions, and polyvalent strategies that improve coverage of epitope diversity and enhance the cross‐reactivity of responses. While many barriers to vaccine induction of broadly neutralizing antibody (bNAb) responses remain, epitope diversification has emerged as both a challenge and an opportunity. Recent longitudinal studies have traced the emergence of bNAbs in HIV‐1 infection, inspiring novel approaches to recapitulate and accelerate the events that give rise to potent bNAb in vivo. In this review, we have selected two such lineage‐based design strategies to illustrate how such in‐depth analysis can offer conceptual improvements that may bring us closer to an effective vaccine.

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Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01

Cited by 1,056 publications

References 44 publications

Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows

Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows

Identification and specificity of broadly neutralizing antibodies against HIV

Polyvalent vaccine approaches to combat HIV‐1 diversity

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