Immunoglobulin Gene Insertions and Deletions in the Affinity Maturation of HIV-1 Broadly Reactive Neutralizing Antibodies

Kepler, Thomas B.; Liao, Hua Xin; Alam, S. Munir; Bhaskarabhatla, Rekha; Zhang, Ruijun; Yandava, Chandri; Stewart, Shelley; Anasti, Kara; Kelsoe, Garnett; Parks, Robert; Lloyd, Krissey E.; Stolarchuk, Christina; Pritchett, Jamie; Solomon, Erika; Friberg, Emma; Morris, Lynn; Karim, Salim Safurdeen. Abdool; Cohen, Myron S.; Walter, Emmanuel B.; Moody, M. Anthony; Wu, Xueling; Altae-Tran, Han; Georgiev, Ivelin S.; Kwong, Peter D.; Boyd, Scott D.; Fire, Andrew; Mascola, John R.; Haynes, Barton F.

doi:10.1016/j.chom.2014.08.006

Cited by 139 publications

(135 citation statements)

References 48 publications

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“…Similarly, amino acid substitutions in CH235 at these positions were also frequently seen in non-HIV-1 antibodies (16). These commonalities extended to other V H 1-2*02 and V H 1-46 CD4 mimic bnAbs (16) and V H 1-2*02 V3-glycan bnAbs (Bonsignori M. et al, submitted), implying that intrinsic mutability at specific nucleotide sites is a more general biological phenomenon that plays a role in dictating the degree of somatic mutations (16, 32, 65, 66). …”

Section: Antibody-virus Co-evolutionmentioning

confidence: 85%

“…Moreover, with evidence for a role of host immune tolerance control mechanisms in limiting the induction of bnAbs (32, 41), the biology of bnAbs has begun to be elucidated. The role of the structure of the Env immunogen is undoubtedly important, as the Env must contain sufficiently native bnAb epitopes to bind in optimal affinities and correct orientation to the UCA, i.e.…”

Section: B Cell Lineage Immunogen Designmentioning

confidence: 99%

“…However, in children, examples of plasma bnAb breath occurring within the first year of HIV-1 infection have been reported (28, 29). Because many bnAbs have unusual traits of high levels of somatic mutations, long third heavy chain complementarity regions (CDR H3s) and/or poly- or auto-reactivity, it has been postulated that bnAb maturation is disfavored due to control by host tolerance mechanisms (31, 32) (Kelsoe and Haynes, this volume; Verkoczy, Tian and Alt, this volume). Thus, if the key events of virus Env and bnAb lineage evolution could be defined in the setting of HIV-1 infection, then a path to successful induction of bnAbs could be the recapitulation of these events in the setting of vaccination.…”

Section: Introductionmentioning

confidence: 99%

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

Bonsignori

Liao

Gao

et al. 2017

Immunological Reviews

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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: Antibody-virus Co-evolutionmentioning

confidence: 85%

Section: B Cell Lineage Immunogen Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Bonsignori

Liao

Gao

et al. 2017

Immunological Reviews

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164

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“…This process, known as affinity maturation, involves strong competition and selection for B-cell receptor binding to antigen [70]. Thus, in contrast to the diversity of the naive repertoire, which arises primarily by recombination, B cells exposed to antigen evolve primarily by point mutations (although insertion-deletion mutations occur too [71]). These so-called somatic hypermutations are induced by activation-induced cytidine deaminase (AID) [72,73], which preferentially mutates cytosines to uracils [74].…”

Section: Brief Overview Of B Cells and Their Evolutionmentioning

confidence: 99%

The evolution within us

Cobey

Wilson

Matsen

2015

Phil. Trans. R. Soc. B

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One contribution of 13 to a theme issue 'The dynamics of antibody repertoires'. The B-cell immune response is a remarkable evolutionary system found in jawed vertebrates. B-cell receptors, the membrane-bound form of antibodies, are capable of evolving high affinity to almost any foreign protein. High germline diversity and rapid evolution upon encounter with antigen explain the general adaptability of B-cell populations, but the dynamics of repertoires are less well understood. These dynamics are scientifically and clinically important. After highlighting the remarkable characteristics of naive and experienced B-cell repertoires, especially biased usage of genes encoding the B-cell receptors, we contrast methods of sequence analysis and their attempts to explain patterns of B-cell evolution. These phylogenetic approaches are currently unlinked to explicit models of B-cell competition, which analyse repertoire evolution at the level of phenotype, the affinities and specificities to particular antigenic sites. The models, in turn, suggest how chance, infection history and other factors contribute to different patterns of immunodominance and protection between people. Challenges in rational vaccine design, specifically vaccines to induce broadly neutralizing antibodies to HIV, underscore critical gaps in our understanding of B cells' evolutionary and ecological dynamics.

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“…In general, the presence of reactive memory B cells correlates with the ability to produce a bnAb response (42)(43)(44)(45). It seems that, for both influenza and HIV, bnAbs require significantly more somatic mutation than seems common in vaccine-induced antibodies in otherwise antigen-naive humans (46,47), suggesting that bnAbs might be elicited by repeated immunization against multiple strains, rather than fortuitous gene use. H5.3 is illustrative of the lack of breadth typical of vaccine-induced antibodies, and our results indicate that breadth and potency directly conflict in H5.3 interactions.…”

Section: Resultsmentioning

confidence: 99%

Vaccine-elicited antibody that neutralizes H5N1 influenza and variants binds the receptor site and polymorphic sites

Winarski

Thornburg

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Antigenic drift of circulating seasonal influenza viruses necessitates an international vaccine effort to reduce the impact on human health. A critical feature of the seasonal vaccine is that it stimulates an already primed immune system to diversify memory B cells to recognize closely related, but antigenically distinct, influenza glycoproteins (hemagglutinins). Influenza pandemics arise when hemagglutinins to which no preexisting adaptive immunity exists acquire the capacity to infect humans. Hemagglutinin 5 is one subtype to which little preexisting immunity exists and is only a few acquired mutations away from the ability to transmit efficiently between ferrets, and possibly humans. Here, we describe the structure and molecular mechanism of neutralization by H5.3, a vaccine-elicited antibody that neutralizes hemagglutinin 5 viruses and variants with expanded host range. H5.3 binds in the receptor-binding site, forming contacts that recapitulate many of the sialic acid interactions, as well as multiple peripheral interactions, yet is not sensitive to mutations that alter sialic acid binding. H5.3 is highly specific for a subset of H5 strains, and this specificity arises from interactions to the periphery of the receptor-binding site. H5.3 is also extremely potent, despite retaining germ line-like conformational flexibility. structural biology | immunity | antigen recognition | affinity maturation | influenza I nfluenza remains a major public health concern because seasonal influenza infects 600 million to 1.1 billion people annually, resulting in 3-5 million cases of severe disease, and 250,000-500,000 deaths (1). By comparison, the four influenza pandemics of the 20th century, caused by novel influenza strains infecting the immunologically naive human population, resulted in 50-100 million deaths (1-4). Influenza A immunity is principally mediated by the antibody response to the viral glycoprotein, hemagglutinin (HA) (5). HA is expressed as a preprotein, HA0, assembled as a trimer on the viral envelope, and cleaved by host proteases into HA1 and HA2. HA1 is a largely globular domain responsible for receptor binding, and HA2 is a rod-shaped helical bundle responsible for membrane fusion (Fig. 1A) (5). There are 18 genetically distinct subtypes of influenza A HA (H1-H18), of which only H1 and H3 currently circulate among humans (1,(6)(7)(8)(9).Despite the widespread presence of H5N1 influenza viruses in wild birds, the virus is not currently transmissible within the human population. Human-to-human transmission is inefficient and is partially restricted by the receptor specificity of the virus; human-type HAs preferentially recognize α2,6-linked sialic acid whereas avian-type HAs prefer α2,3-linked sialic acid (1, 10-12). However, there have been >600 human cases of H5N1 infection since 2004, resulting from the direct transmission of the virus from birds to humans, associated with an ∼60% mortality rate. There is the potential for a significant pandemic if H5 viruses develop the ability to spread efficiently b...

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Immunoglobulin Gene Insertions and Deletions in the Affinity Maturation of HIV-1 Broadly Reactive Neutralizing Antibodies

Cited by 139 publications

References 48 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

The evolution within us

Vaccine-elicited antibody that neutralizes H5N1 influenza and variants binds the receptor site and polymorphic sites

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