The Effects of Somatic Hypermutation on Neutralization and Binding in the PGT121 Family of Broadly Neutralizing HIV Antibodies

Sok, Devin; Laserson, Uri; Laserson, Jonathan; Liu, Yiping; Vigneault, François; Julien, Jean-Philippe; Briney, Bryan; Ramos, Alejandra; Saye, Karen; Le, Khoa; Mahan, Alison E.; Wang, Shenshen; Kardar, Mehran; Yaari, Gur; Walker, Laura M.; Simen, Birgitte B.; John, Elizabeth St.; Chan-Hui, Po-Ying; Swiderek, Kristine M.; Kleinstein, Stephen H.; Alter, Galit; Seaman, Michael S.; Chakraborty, Arup K.; Koller, Daphne; Wilson, Ian A.; Church, George M.; Burton, Dennis R.; Poignard, Pascal

doi:10.1371/journal.ppat.1003754

Cited by 171 publications

(247 citation statements)

References 54 publications

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“…As noted above, neither we (Bonsignori M. et al, submitted) nor others (20, 99, 100) have found binding of a TF Env to the V3-glycan UCA. Rather, peptides from the base of the gp120 V3 loop bound to the UCA suggesting Env fragments may initiate V3-glycan bnAb lineages (Bonsignori M. et al, submitted).…”

Section: Env Regimens That Derive From Antibody-virus Co-evolution Stmentioning

confidence: 58%

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

Bonsignori

Liao

Gao

et al. 2017

Immunological Reviews

164

150

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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.

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Section: Env Regimens That Derive From Antibody-virus Co-evolution Stmentioning

confidence: 58%

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

Bonsignori

Liao

Gao

et al. 2017

Immunological Reviews

164

150

View full text Add to dashboard Cite

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“…We and others have shown positive correlations between the level of somatic hypermutation and breadth of neutralization in a number of cases (2,37,38). Strikingly, in this case, there is little correlation between the breadth of antibody neutralization and the degree of somatic hypermutation among the somatic variants described (Fig.…”

Section: Somatic Variant Pgdm1400 Is Broader and More Potent Thanmentioning

confidence: 60%

A Recombinant HIV Envelope Trimer Selects for Quaternary Dependent Antibodies Targeting the Trimer Apex

SokDevin

GilsMarit

Pauthner

et al. 2014

AIDS Research and Human Retroviruses

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Broadly neutralizing antibodies (bnAbs) targeting the trimer apex of HIV envelope are favored candidates for vaccine design and immunotherapy because of their great neutralization breadth and potency. However, methods of isolating bnAbs against this site have been limited by the quaternary nature of the epitope region. Here we report the use of a recombinant HIV envelope trimer, BG505 SOSIP.664 gp140, as an affinity reagent to isolate quaternary-dependent bnAbs from the peripheral blood mononuclear cells of a chronically infected donor. The newly isolated bnAbs, named "PGDM1400-1412," show a wide range of neutralization breadth and potency. One of these variants, PGDM1400, is exceptionally broad and potent with cross-clade neutralization coverage of 83% at a median IC 50 of 0.003 μg/mL. Overall, our results highlight the utility of BG505 SOSIP.664 gp140 as a tool for the isolation of quaternary-dependent antibodies and reveal a mosaic of antibody responses against the trimer apex within a clonal family.HIV | broadly neutralizing antibodies | BG505 SOSIP | B cell | vaccine M ultiple methods have been developed to isolate HIV broadly neutralizing antibodies (bnAbs) (1-12). Hybridoma and phage display techniques were used to isolate the first generation of bnAbs including b12, 2F5, 2G12, 4E10, and Z13 (13-20). These antibodies exhibit a range of neutralization breadth against primary isolates from 30 to 90% but have moderate neutralization potency (median IC 50 of ∼2-4 μg/mL). Access to infected donors who have high serum titers of bnAbs (21,22) and the availability of newer approaches for isolating human mAbs have recently enabled the discovery of a new generation of more potent bnAbs (1-4, 6-8).One of the newer approaches involves the sorting and activation of large numbers of memory B cells using cytokine-secreting feeder cells and the subsequent high-throughput screening of supernatants for neutralization. This method led to the identification and characterization of the first of the new generation of bnAbs, PG9 and PG16 (1), and since then has revealed several sites of vulnerability to bnAb recognition on HIV envelope (Env) (1-4, 6, 7). An alternative method of bnAb isolation involves the use of soluble Env molecules or scaffold proteins as baits to select single IgG + memory B cells of interest by cell sorting (6,8,9,23,24). However, soluble baits have not been successful in isolating antibody responses targeting quaternary epitopes, including the trimer-apex site surrounding the N160 glycan, because the protein constructs used to date have not properly mimicked native Env trimers. To address this problem, GFP-labeled 293T cells that express cell-surface Env, called "GFP-293TBaL cells," were used recently to isolate antibodies 3BC176 and 3BC315 (10, 25).These antibodies do not bind soluble monomeric gp120 but do bind Env trimer, demonstrating the utility of the approach, but the method was reported to be less efficient than the use of soluble protein baits (10,25).The favorable antigenic profile of the solub...

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“…On the basis of studies of bNmAbs, we recognize that NAbs against HIV-1 are known to develop through somatic hypermutation during chronic infection (65,66). It is unknown whether a vaccine can promote adequate affinity maturation during the course of an immunization regimen to elicit protective Abs, primarily because it is not known to what extent germline B cell receptors (BCRs) influence affinity maturation and selection of B cells giving rise to bNAbs in GCs.…”

Section: Discussionmentioning

confidence: 99%

Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

Hessell

Malherbe

Pissani

et al. 2016

The Journal of Immunology

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Advancement in immunogen selection and vaccine design that will rapidly elicit a protective Ab response is considered critical for HIV vaccine protective efficacy. Vaccine-elicited Ab responses must therefore have the capacity to prevent infection by neutralization-resistant phenotypes of transmitted/founder (T/F) viruses that establish infection in humans. Most vaccine candidates to date have been ineffective at generating Abs that neutralize T/F or early variants. In this study, we report that coimmunizing rhesus macaques with HIV-1 gp160 DNA and gp140 trimeric protein selected from native envelope gene sequences (envs) induced neutralizing Abs against Tier 2 autologous viruses expressing cognate envelope (Env). The Env immunogens were selected from envs emerging during the earliest stages of neutralization breadth developing within the first 2 years of infection in two clade B–infected human subjects. Moreover, the IgG responses in macaques emulated the targeting to specific regions of Env known to be associated with autologous and heterologous neutralizing Abs developed within the human subjects. Furthermore, we measured increasing affinity of macaque polyclonal IgG responses over the course of the immunization regimen that correlated with Tier 1 neutralization. In addition, we report firm correlations between Tier 2 autologous neutralization and Tier 1 heterologous neutralization, as well as overall TZM-bl breadth scores. Additionally, the activation of Env-specific follicular helper CD4 T cells in lymphocytes isolated from inguinal lymph nodes of vaccinated macaques correlated with Tier 2 autologous neutralization. These results demonstrate the potential for native Env derived from subjects at the time of neutralization broadening as effective HIV vaccine elements.

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The Effects of Somatic Hypermutation on Neutralization and Binding in the PGT121 Family of Broadly Neutralizing HIV Antibodies

Cited by 171 publications

References 54 publications

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

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

A Recombinant HIV Envelope Trimer Selects for Quaternary Dependent Antibodies Targeting the Trimer Apex

Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

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