Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: Implications for evasion of immune responses and design of vaccine immunogens

Xiao, Xiaodong; Chen, Weizao; Yang, Feng; Zhu, Zhongyu; Prabakaran, Ponraj; Wang, Yanping; Zhang, Meiyun; Longo, Nancy S.; Dimitrov, Dimiter S.

doi:10.1016/j.bbrc.2009.09.029

Cited by 244 publications

(265 citation statements)

References 46 publications

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“…ERs for all mutations were calculated by dividing the frequency of a given mutation at a given position in the sorted sample by the frequency of the same mutation in the unsorted sample, as described previously (25,26). Mutagenesis of one segment of V H (position [14][15][16][17][18][19][20][21][22][23][24][25] in the original V H library resulted in errors which led to low expression of the respective segment. This result was likely related to a mutational error in the original stop template used in the mutagenesis reaction for this V H segment 14-25, which affected expression of the variants.…”

Section: Methodsmentioning

confidence: 99%

“…Thus far, the roles of SHM have been studied primarily by examining the functional consequences of reverting the somatic mutation of selected antibodies back to the germline sequences (15)(16)(17)(18)(19)(20)(21). Although these studies have demonstrated that antibodies depend on somatic mutations to achieve high-affinity antigen binding, the approach is limited to the small set of mutations present in a given antibody.…”

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confidence: 99%

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Mutational landscape of antibody variable domains reveals a switch modulating the interdomain conformational dynamics and antigen binding

Koenig¹,

Lee²,

Walters³

et al. 2017

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

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Somatic mutations within the antibody variable domains are critical to the immense capacity of the immune repertoire. Here, via a deep mutational scan, we dissect how mutations at all positions of the variable domains of a high-affinity anti-VEGF antibody G6.31 impact its antigen-binding function. The resulting mutational landscape demonstrates that large portions of antibody variable domain positions are open to mutation, and that beneficial mutations can be found throughout the variable domains. We determine the role of one antigen-distal light chain position 83, demonstrating that mutation at this site optimizes both antigen affinity and thermostability by modulating the interdomain conformational dynamics of the antigen-binding fragment. Furthermore, by analyzing a large number of human antibody sequences and structures, we demonstrate that somatic mutations occur frequently at position 83, with corresponding domain conformations observed for G6.31. Therefore, the modulation of interdomain dynamics represents an important mechanism during antibody maturation in vivo. Deciphering the molecular mechanism of SHMs in improving antibodies is critical for understanding the evolution of the immune repertoire. It is well recognized that mutations at the CDRs or FWR structurally adjacent to the CDRs can modulate and optimize the antigen-binding interface (4-7), and several studies have used saturated mutagenesis of CDR position to explore the effect of various mutations on affinity and specificity (8-11).The role of SHM in antigen-distal FWR is less well understood, however. Previous studies have suggested that the antigen-distal FWR contributes primarily to the variable domain structural integrity; thus, mutations at these positions would be either detrimental to or neutral for antigen-binding function (12)(13)(14). Other authors have characterized the potential of antigen-distal framework mutation as beneficial for antigen-binding function. For example, framework mutations can compensate for the destabilizing effect of mutations at CDRs needed for antigen binding (15). In other cases, non-CDR SHMs have been shown to be required for the neutralization activity of broadly neutralizing anti-HIV antibodies (16).Thus far, the roles of SHM have been studied primarily by examining the functional consequences of reverting the somatic mutation of selected antibodies back to the germline sequences (15-21). Although these studies have demonstrated that antibodies depend on somatic mutations to achieve high-affinity antigen binding, the approach is limited to the small set of mutations present in a given antibody.Here we took a systematic approach to assessing the mutability of the whole variable domain for maintaining or improving folding stability and antigen binding. We used a welloptimized anti-vascular endothelial cell growth factor (VEGF), G6.31, with high affinity (K d = 0.4 nM) and excellent thermostability [fragment antigen-binding (Fab) melting temperature (T m ) = 84°C]. G6.31 derives its HC and LC variable domains ...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Mutational landscape of antibody variable domains reveals a switch modulating the interdomain conformational dynamics and antigen binding

Koenig¹,

Lee²,

Walters³

et al. 2017

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

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“…Diversion of pre-existing B cell responses to non-HIV antigens may be at play for some bnAb UCAs as well. Whereas the UCA of some bnAbs interact with Env antigens (15, 17,18, 58, 93), others may not (87, 94–97) (Stamatatos, this volume). Thus, an alternative strategy in which non-HIV-1 antigens need be included as immunogens may be necessary to drive the initial maturation of non-HIV-reactive UCAs to maturation intermediates amenable to diversion toward HIV-1 specificity.…”

Section: B Cell Lineage Immunogen Designmentioning

confidence: 99%

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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“…5,14,17,71 Lastly, homing of B cells to the cervix may allow rescue of B cells with potentially auto-reactive specificity to forbidden epitopes on HIV-1 generated by systemic immunization to the external mucosal environment. 72 The authors note that some level of caution should be taken in extrapolating somatic mutation and mucosal-systemic B-cell trafficking patterns from repertoire analysis conducted on B cells from a single individual. We recognize that a larger and more robust study involving samples from multiple subjects collected at different time points can now be done using cuttingedge technology; however, this study remains as a comparator for the current technology.…”

confidence: 99%