High-Resolution Longitudinal Study of HIV-1 Env Vaccine–Elicited B Cell Responses to the Virus Primary Receptor Binding Site Reveals Affinity Maturation and Clonal Persistence

Wang, Yimeng; Sundling, Christopher; Wilson, Richard F.; O’Dell, Sijy; Chen, Yajing; Dai, Keren; Phad, Ganesh E.; Zhu, Jiang; Xiao, Yongli; Mascola, John R.; Hedestam, Gunilla B. Karlsson; Wyatt, Richard T.; Li, Yuxing

doi:10.4049/jimmunol.1502543

Cited by 27 publications

(56 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…JR-FL-reactive Env ϩ memory B cells accounted for approximately 0.15% of IgG ϩ B cells (Fig. 1B), which was lower than the Env ϩ memory B cell frequency (ϳ5%) sorted by the autologous antigen, YU2gp140-F, reported previously (15). This suggested that JR-FL SOSIP.664 was a more selective probe than the probes deployed previously.…”

Section: Resultsmentioning

confidence: 63%

“…1A, lower panel). To define the cross-reactive tier 2 virus neutralizing B cell response in macaque K17, we sorted antigen-specific memory B cells by fluorescence-activated cell sorting (FACS) and applied Ig cloning methods optimized for NHP B cell repertoire analysis (10,15). We employed a heterologous Env trimer, JR-FL SOSIP.664, a native clade B Env spike mimetic derived from primary isolate JR-FL (25), as the sorting probe.…”

Section: Resultsmentioning

confidence: 99%

“…We performed clonal lineage assignment for the 80 unique clones and assigned them to 46 clonal lineages, using the criteria that clones with (i) the same VJ segment usage, (ii) the same CDR3 length, and (iii) high nucleotide sequence homology in CDR3 (Ͼ75%) are likely derived from the same naive ancestor B cell and thus belong to the same clonal lineage. With each clonal lineage represented with at least one MAb, we expressed 50 MAbs as full-length (FL) IgG1 as described previously for further characterization (10,15).…”

Section: Resultsmentioning

confidence: 99%

“…A color code is used to illustrate the plasma ID 50 Genetic analysis of JR-FL SOSIP.664-sorted Env ؉ antibody Ig repertoire. To assess the genetic composition of the JR-FL SOSIP.664-sorted antibody repertoire, we analyzed the heavy-chain V gene usage of the 107 sequences and compared this with the antibody repertoire observed by sorting Env-specific memory B cells from two rhesus macaques (F125 and F128) using a YU2gp140-F probe as previously reported (15). We found that the JR-FL SOSIP-sorted Env ϩ antibody repertoire was relatively focused, with skewed usage of VH5.7 and VH5.46 gene segments ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…These studies revealed the specificities of neutralizing antibody responses in Env-vaccinated animals by isolating MAbs that recapitulate the plasma neutralizing capacity. The determined neutralizing specificities are mostly restricted to tier 1 viruses (10,(15)(16)(17)(18) or autologous tier 2 viruses (12,19,20). Thus, characterization of vaccine-elicited tier 2 virus NAb responses at a clonal level would provide an improved understanding of Env-specific Ab repertoires induced by vaccination, which is more relevant for future translational vaccine studies, in contrast to the characterization of infection-induced bNAbs pursued extensively in previous studies.…”

mentioning

confidence: 99%

See 4 more Smart Citations

HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited by Immunization in Nonhuman Primates

Wang

O’Dell

Turner

et al. 2017

J Virol

Self Cite

View full text Add to dashboard Cite

Elicitation of broadly neutralizing antibody (bNAb) responses is a major goal for the development of an HIV-1 vaccine. Current HIV-1 envelope glycoprotein (Env) vaccine candidates elicit predominantly tier 1 and/or autologous tier 2 virus neutralizing antibody (NAb) responses, as well as weak and/or sporadic cross-reactive tier 2 virus NAb responses with unknown specificity. To delineate the specificity of vaccine-elicited cross-reactive tier 2 virus NAb responses, we performed single memory B cell sorting from the peripheral blood of a rhesus macaque immunized with YU2gp140-F trimers in adjuvant, using JR-FL SOSIP.664, a native Env trimer mimetic, as a sorting probe to isolate monoclonal Abs (MAbs). We found striking genetic and functional convergence of the SOSIP-sorted Ig repertoire, with predominant VH4 or VH5 gene family usage and Env V3 specificity. Of these vaccine-elicited V3-specific MAbs, nearly 20% (6/33) displayed cross-reactive tier 2 virus neutralization, which recapitulated the serum neutralization capacity. Substantial similarities in binding specificity, neutralization breadth and potency, and sequence/structural homology were observed between selected macaque cross-reactive V3 NAbs elicited by vaccination and prototypic V3 NAbs derived from natural infections in humans, highlighting the convergence of this subset of primate V3-specific B cell repertories. Our study demonstrated that cross-reactive primary virus neutralizing B cell lineages could be elicited by vaccination as detected using a standardized panel of tier 2 viruses. Whether these lineages could be expanded to acquire increased breadth and potency of neutralization merits further investigation.IMPORTANCE Elicitation of antibody responses capable of neutralizing diverse HIV-1 primary virus isolates (designated broadly neutralizing antibodies [bNAbs]) remains a high priority for the vaccine field. bNAb responses were so far observed only in response to natural infection within a subset of individuals. To achieve this goal, an improved understanding of vaccine-elicited responses, including at the monoclonal Ab level, is essential. Here, we isolated and characterized a panel of vaccine-elicited cross-reactive neutralizing MAbs targeting the Env V3 loop that moderately neutralized several primary viruses and recapitulated the serum neutralizing antibody response. Striking similarities between the cross-reactive V3 NAbs elicited by vaccination in macaques and natural infections in humans illustrate commonalities between

show abstract

Section: Resultsmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited by Immunization in Nonhuman Primates

Wang

O’Dell

Turner

et al. 2017

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

Immunization-Elicited Broadly Protective Antibody Reveals Ebolavirus Fusion Loop as a Site of Vulnerability

Zhao

Howell

et al. 2017

Cell

Self Cite

106

167

View full text Add to dashboard Cite

Summary While neutralizing antibodies are highly effective against ebolavirus infections, current experimental ebolavirus vaccines primarily elicit species-specific antibody responses. Here we describe an immunization-elicited macaque antibody (CA45) that clamps the internal fusion loop with the N-terminus of the ebolavirus glycoproteins (GP) and potently neutralizes Ebola, Sudan, Bundibugyo, and Reston viruses. CA45, alone or in combination with an antibody that blocks receptor binding, provided full protection against all pathogenic ebolaviruses in mice, guinea pigs, and ferrets. Analysis of memory B cells from the immunized macaque suggests that elicitation of broadly neutralizing antibodies (bNAbs) for ebolaviruses is possible but difficult, potentially due to the rarity of bNAb clones and their precursors. Unexpectedly, germline-reverted CA45, while exhibiting negligible binding to full-length GP, bound a proteolytically remodeled GP with picomolar affinity, suggesting that engineered ebolavirus vaccines could trigger rare bNAb precursors more robustly. These findings have important implications for developing pan-ebolavirus vaccine and immunotherapeutic cocktails.

show abstract

The HIV-1 Envelope Glycoprotein C3/V4 Region Defines a Prevalent Neutralization Epitope following Immunization

et al. 2019

Self Cite

View full text Add to dashboard Cite

Summary Despite recent progress in engineering native trimeric HIV-1 envelope glycoprotein (Env) mimics as vaccine candidates, Env trimers often induce vaccine-matched neutralizing antibody (NAb) responses. Understanding the specificities of autologous NAb responses and the underlying molecular mechanisms restricting the neutralization breadth is therefore informative to improve vaccine efficacy. Here, we delineate the response specificity by single B cell sorting and serum analysis of guinea pigs immunized with BG505 SOSIP.664 Env trimers. Our results reveal a prominent immune target containing both conserved and strain-specific residues in the C3/V4 region of Env in trimer-vaccinated animals. The defined NAb response shares a high degree of similarity with the early NAb response developed by a naturally infected infant from whom the HIV virus strain BG505 was isolated and later developed a broadly NAb response. Our study describes strain-specific responses and their possible evolution pathways, thereby highlighting the potential to broaden NAb responses by immunogen re-design.

show abstract

High-Resolution Longitudinal Study of HIV-1 Env Vaccine–Elicited B Cell Responses to the Virus Primary Receptor Binding Site Reveals Affinity Maturation and Clonal Persistence

Cited by 27 publications

References 53 publications

HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited by Immunization in Nonhuman Primates

HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited by Immunization in Nonhuman Primates

Immunization-Elicited Broadly Protective Antibody Reveals Ebolavirus Fusion Loop as a Site of Vulnerability

The HIV-1 Envelope Glycoprotein C3/V4 Region Defines a Prevalent Neutralization Epitope following Immunization

Contact Info

Product

Resources

About