Laurent Verkoczy

Laurent Verkoczy
Duke University Medical Center | DUMC · Duke Human Vaccine Institute

Ph.D.

About

177
Publications
5,569
Reads
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2,422
Citations
Citations since 2016
25 Research Items
1286 Citations
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2016201720182019202020212022050100150200250
2016201720182019202020212022050100150200250
2016201720182019202020212022050100150200250
Additional affiliations
January 2009 - December 2011
January 2008 - December 2009
Duke University Medical Center
Position
  • Duke University
August 2005 - August 2016
Duke University Medical Center
Position
  • Managing Director

Publications

Publications (177)
Article
Full-text available
Many of the best HIV-1 broadly neutralizing antibodies (bnAbs) known have poly-/autoreactive features that disfavor normal B cell development and maturation, posing a major hurdle in developing an effective HIV-1 vaccine. Key to resolving this problem is to understand if, and to what extent, neutralization breadth-conferring mutations acquired by b...
Preprint
HIV-1 and its SIV precursors share a broadly neutralizing antibody (bNAb) epitope in variable loop 2 (V2) at the envelope glycoprotein (Env) trimer apex. Here, we tested the immunogenicity of germline-targeting versions of a chimpanzee SIV (SIVcpz) Env in human V2-apex bNAb heavy-chain precursor-expressing knock-in mice and as chimeric simian-chimp...
Article
HIV-1 envelope (Env) proteins designed to induce neutralizing antibody responses allow study of the role of affinities (equilibrium dissociation constant [KD]) and kinetic rates (association/dissociation rates) on B cell antigen recognition. It is unclear whether affinity discrimination during B cell activation is based solely on Env protein bindin...
Preprint
HIV-1 Envelope (Env) proteins designed to induce neutralizing antibody responses allow study of the role of affinities (equilibrium dissociation constant, KD) and kinetic rates (association/dissociation rates) on B cell antigen recognition. It is unclear whether affinity discrimination during B cell activation is based solely on Env protein binding...
Article
Full-text available
Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by immunoglobulin gene rearrangments with infrequent naive B cell precursors and with unusual genetic...
Article
Engineering better bnAbs A highly effective HIV vaccine has been the goal of vaccinologists for nearly 35 years. A successful vaccine would need to induce broadly neutralizing antibodies (bnAbs) that are capable of neutralizing multiple HIV strains (see the Perspective by Agazio and Torres). Steichen et al. report a strategy in which the first vacc...
Article
2F5 is an HIV-1 broadly neutralizing Ab that also binds the autoantigens kynureninase (KYNU) and anionic lipids. Generation of 2F5-like Abs is proscribed by immune tolerance, but it is unclear which autospecificity is responsible. We sampled the BCR repertoire of 2F5 knock-in mice before and after the first and second tolerance checkpoints. Nearly...
Article
Full-text available
Epitope-targeted HIV vaccine design seeks to focus antibody responses to broadly neutralizing antibody (bnAb) sites by sequential immunization. A chimpanzee simian immunodeficiency virus (SIV) envelope (Env) shares a single bnAb site, the variable loop 2 (V2)-apex, with HIV, suggesting its possible utility in an HIV immunization strategy. Here, we...
Preprint
Full-text available
Epitope-targeted HIV vaccine design seeks to focus antibody responses to broadly neutralizing antibody (bnAb) sites by sequential immunization. Chimpanzee SIV Envelope (Env) shares a single bnAb site, the V2-apex, with HIV, suggesting its possible utility in an HIV immunization strategy. Accordingly, we generated a chimpanzee SIV Env trimer, MT145K...
Article
Full-text available
The events required for the induction of broad neutralizing antibodies (bnAbs) following HIV-1 envelope (Env) vaccination are unknown, and their induction in animal models as proof of concept would be critical. Here, we describe the induction of plasma antibodies capable of neutralizing heterologous primary (tier 2) HIV-1 strains in one macaque and...
Article
Full-text available
A strategy for HIV-1 vaccine development is to define envelope (Env) evolution of broadly neutralizing antibodies (bnAbs) in infection and to recreate those events by vaccination. Here, we report host tolerance mechanisms that limit the development of CD4-binding site (CD4bs), HCDR3-binder bnAbs via sequential HIV-1 Env vaccination. Vaccine-induced...
Article
Full-text available
Activation-induced cytidine deaminase (AID) is required to purge autoreactive immature and transitional-1 (immature/T1) B cells at the first tolerance checkpoint, but how AID selectively removes self-reactive B cells is unclear. We now show that B cell antigen receptor (BCR) and endosomal Toll-like receptor (TLR) signals synergize to elicit high le...
Article
A major challenge for HIV-1 vaccine research is developing a successful immunization approach for inducing broadly neutralizing antibodies (bnAbs). A key shortcoming in meeting this challenge has been the lack of animal models capable of identifying impediments limiting bnAb induction and ranking vaccine strategies for their ability to promote bnAb...
Article
A vaccine that can effectively prevent HIV-1 transmission remains paramount to ending the HIV pandemic, but to do so, will likely need to induce broadly neutralizing antibody (bnAb) responses. A major technical hurdle toward achieving this goal has been a shortage of animal models with the ability to systematically pinpoint roadblocks to bnAb induc...
Article
Full-text available
In the RV144 gp120 HIV vaccine trial, decreased transmission risk was correlated with Abs that reacted with a linear epitope at a lysine residue at position 169 (K169) in the HIV-1 envelope (Env) V2 region. The K169 V2 response was restricted to Abs bearing Vλ rearrangements that expressed aspartic acid/glutamic acid in CDR L2. The AE.A244 gp120 in...
Article
The HIV-1 envelope protein (Env) has evolved to subvert the host immune system, hindering viral control by the host. The tryptophan metabolic enzyme kynureninase (KYNU) is mimicked by a portion of the HIV Env gp41 membrane proximal region (MPER) and is cross-reactive with the HIV broadly neutralizing Ab (bnAb) 2F5. Molecular mimicry of host protein...
Article
Induction of broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development. bnAbs occur in some HIV-1–infected individuals and frequently have characteristics of autoantibodies. We have studied cohorts of HIV-1–infected individuals who made bnAbs and compared them with those who did not do so, and determined immune traits associate...
Article
Development of an HIV vaccine is a global priority. A major roadblock to a vaccine is an inability to induce protective broadly neutralizing antibodies (bnAbs). HIV gp41 bnAbs have characteristics that predispose them to be controlled by tolerance. We used gp41 2F5 bnAb germline knock-in mice and macaques vaccinated with immunogens reactive with ge...
Article
Full-text available
Complementarity Determining Region 3 of the immunoglobulin (Ig) H chain (CDR-H3) lies at the center of the antigen-binding site where it often plays a decisive role in antigen recognition and binding. Amino acids encoded by the diversity (DH) gene segment are the main component of CDR-H3. Each DH has the potential to rearrange into one of six DH re...
Article
The past 2 years have seen a number of basic and translational science advances in the quest for development of an effective HIV-1 vaccine. These advances include discovery of new envelope targets of potentially protective antibodies, demonstration that CD8+ T cells can control HIV-1 infection, development of immunogens to overcome HIV-1 T-cell epi...
Article
The unusual traits of broadly neutralizing antibodies for HIV-1 are stimulating new strategies to induce their production through vaccination.
Article
This review discusses progress in understanding the impact of immune tolerance on inducing broadly neutralizing antibodies (bnAbs), and how such knowledge can be incorporated into novel immunization approaches. Over 120 bnAbs have now been isolated, all of which bear unusual features associated with host tolerance controls, but paradoxically may al...
Article
Full-text available
A primary correlate of protection for most effective viral vaccines is induction of antibodies with potent virus neutralization [1]. HIV-1 differs from other viruses for which successful vaccines have been made, because as a highly mutable, integrating retrovirus, it is resistant to both immune responses and antiretroviral therapy upon establishmen...
Article
Full-text available
Broadly HIV-1-neutralizing antibodies (BnAbs) display one or more unusual traits, including a long heavy chain complementarity-determining region 3 (HCDR3), polyreactivity, and high levels of somatic mutations. These shared characteristics suggest that BnAb development might be limited by immune tolerance controls. It has been postulated that HIV-1...
Article
Full-text available
We have shown that the protective HIV-1 Ab, 2F5, avidly reacts with a conserved mammalian self-Ag, kynureninase, and that the development of B cells specific for the 2F5 epitope is constrained by immunological tolerance. These observations suggest that the capacity to mount Ab responses to the 2F5 epitope is mitigated by tolerance, but such capacit...
Article
Full-text available
In this brief review, we discuss immune tolerance as a factor that determines the magnitude and quality of serum antibody responses to HIV-1 infection and vaccination in the context of recent work. We propose that many conserved, neutralizing epitopes of HIV-1 are weakly immunogenic because they mimic host antigens. In consequence, B cells that str...
Article
Full-text available
A goal of HIV-1 vaccine development is to elicit broadly neutralizing Abs (BnAbs), but current immunization strategies fail to induce BnAbs, and for unknown reasons, often induce nonneutralizing Abs instead. To explore potential host genetic contributions controlling Ab responses to the HIV-1 Envelope, we have used congenic strains to identify a cr...
Article
Full-text available
A goal of HIV-1 vaccine development is to elicit broadly neutralizing Abs (BnAbs). Using a knock-in (KI) model of 2F5, a human HIV-1 gp41 membrane proximal external region (MPER)-specific BnAb, we previously demonstrated that a key obstacle to BnAb induction is clonal deletion of BnAb-expressing B cells. In this study of this model, we provide a pr...
Article
Full-text available
Developing an HIV-1 vaccine has been hampered by the inability of immunogens to induce broadly neutralizing Abs (BnAbs) that protect against infection. Previously, we used knockin (KI) mice expressing a prototypical gp41-specific BnAb, 2F5, to demonstrate that immunological tolerance triggered by self-reactivity of the 2F5 H chain impedes BnAb indu...
Article
The recent isolation of broad neutralizing antibodies (bnAbs) from HIV-1 clonally infected patients has invigorated the HIV-1 vaccine development field. However, all bnAbs have one or more unusual traits: polyreactivity, significantly higher frequency of somatic hypermutations and/or long HCDR3 regions-traits that pre-dispose bnAbs to immune tolera...
Article
Attempts to formulate a protective HIV-1 vaccine through classic vaccine design strategies have not been successful. Elicitation of HIV-1-specific broadly neutralizing antibodies (bnAbs) at high titers that are present before exposure might be required to achieve protection. Recently, the application of new technologies has facilitated the study of...
Article
Full-text available
Genetic factors, as well as antigenic stimuli, can influence antibody repertoire formation. Moreover, the affinity of antigen for unmutated naïve B cell receptors determines the threshold for activation of germinal center antibody responses. The gp41 2F5 broadly neutralizing antibody (bNAb) uses the VH2-5 gene, which has 10 distinct alleles that us...
Article
Full-text available
The HIV-1 broadly neutralizing Ab (bnAb) 2F5 has been shown to be poly-/self-reactive in vitro, and we previously demonstrated that targeted expression of its VDJ rearrangement alone was sufficient to trigger a profound B cell developmental blockade in 2F5 V(H) knockin (KI) mice, consistent with central deletion of 2F5 H chain-expressing B cells. I...
Article
Although antibodies can be elicited by HIV-1 infection or immunization, those that are broadly neutralizing (bnAbs) are undetectable in most individuals, and when they do arise in HIV-1 infection, only do so years after transmission. Until recently, the reasons for difficulty in inducing such bnAbs have been obscure. Recent technological advances i...
Article
The B cell arm of the immune response becomes activated soon after HIV-1 transmission, yet the initial antibody response does not control HIV-1 replication, and it takes months for neutralizing antibodies to develop against the autologous virus. Antibodies that can be broadly protective are made only in a minority of subjects and take years to deve...
Article
Full-text available
The conserved membrane-proximal external region (MPER) of HIV-1 envelope is a target for the rare broadly neutralizing 2F5, Z13, and 4E10 monoclonal antibodies (mAbs). One strategy to elicit such antibodies is to design an immunogen with increased exposure of the 2F5 and 4E10 mAb epitopes. In this study we characterize a single leucine to serine su...
Article
Full-text available
We previously reported that some of the rare broadly reactive, HIV-1 neutralizing antibodies are polyreactive, leading to the hypothesis that induction of these types of neutralizing antibody may be limited by immunologic tolerance. However, the notion that such antibodies are sufficiently autoreactive to trigger B cell tolerance is controversial....
Article
Full-text available
The membrane proximal external region (MPER) of HIV-1 gp41 has several features that make it an attractive antibody-based vaccine target, but eliciting an effective gp41 MPER-specific protective antibody response remains elusive. One fundamental issue is whether the failure to make gp41 MPER-specific broadly neutralizing antibodies like 2F5 and 4E1...
Data
Surface plasmon resonance analysis of C57BL/6 and BALB/c naïve serum reactivity to the gp41 MPER 2F5 epitope. 1∶5 dilutions of serum from unimmunized 12 wk-old BALB/c and C57BL/6 mice or 10 micrograms of purified 2F5 mAb (used as a positive control) were captured over biotinylated gp41 MPER peptide, anchored to an L1 sensor chip, as described in Ma...
Data
Surface plasmon resonance analysis comparing IgMa and IgMb binding to various gp41 MPER peptides. 10 micrograms of purified monomeric or F(ab)2 fragments derived from TNP-KLH-specific IgMa and IgMb mAbs were injected over the following biotinylated peptides: gp41 MPER (aka Sp62, containing the 20 aa “optimal/higher affinity” gp41 MPER 2F5 epitope),...
Data
Cross comparison of HIV-1 Env-specific B cell tetramer binding to mAb-coated beads and mAb cell lines. A) Beads coated with human mAbs 7B9 and F39F (specific to the HIV-1 Env gp120 V3 loop, previously described in [8], [77]), the human mAb 7B2 (specific to the HIV-1 Env gp41 immunodominant (ID) domain; kindly provided by James Robinson, Tulane Univ...
Data
Surface plasmon resonance analysis of IgMa and IgMb F(ab)2 fragment binding to TNP-BSA. 10 micrograms of purified F(ab)2 fragments derived from the TNP-KLH-specific IgMa and IgMb mAbs (BD clones G155-228 and C48-6, respectively) were injected over a sensor chip immobilized with a 2,4,6-Trinitrophenyl hapten-Bovine Serum Albumin conjugate (TNP-BSA,...
Article
Full-text available
We identified a novel GTPase, SLIP-GC, with expression limited to a few tissues, in particular germinal center B cells. It lacks homology to any known proteins, indicating that it may belong to a novel family of GTPases. SLIP-GC is expressed in germinal center B cells and in lymphomas derived from germinal center B cells such as large diffuse B cel...
Article
Physcomitrella patens, recently renamed Aphanoregma patens, has been transformed with the plasmid, pBI426. On selective medium approx. 30% of regenerants expressed the transformed phenotype transiently (transients). The remaining 70% (transformants) retained their transformed phenotype (GUS-positive and resistant to G418) indefinitely when subcultu...
Chapter
Analysis of the pattern of immunoglobulin mutation across species has helped to reveal some of the molecular properties of this process. Strong evidence for the involvement of a cytosine deaminase and error-prone deoxyribonucleic acid (DNA) polymerases on the DNA encoding the immunoglobulin variable regions confirms earlier predictions made from ph...