Structural dynamics reveal isolate-specific differences at neutralization epitopes on HIV Env

Hodge, Edgar A.; Naika, Gajendra S.; Kephart, Sally; Nguyen, Adam; Zhu, Richard; Benhaim, Mark A.; Guo, Wenjin; Moore, John P.; Hu, Shiu‐Lok; Sanders, Rogier W.; Lee, Kelly K.

doi:10.1016/j.isci.2022.104449

Cited by 17 publications

(26 citation statements)

References 88 publications

(127 reference statements)

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“…In the current report, we sought to generate a comprehensive human B cell epitope map of OspA using our available collection of unique OspA-specific MAbs. For the purpose of epitope mapping, we principally employed hydrogen exchange–mass spectrometry (HX-MS), an emerging methodology that provides insights into protein dynamics and protein–protein interactions that has proven especially useful in deciphering antibody–antigen interactions across an array of targets, including toxins like ricin, − botulinum neurotoxin, SEB, viruses like HIV-1 and SARS-CoV-2, , and bacteria like Neisseria meningitidis , to name just a few. The methodology affords considerably greater resolution than can be achieved through antigen truncation or site-directed mutagenesis, but notably less than afforded by X-ray crystallography or cryo-electron microscopy, due to the fact that HX-MS relies on peptidic analysis of antigen targets. , Nonetheless, the HX reaction is conducted in solution and capable of capturing antibody-induced changes in backbone flexibility, where strong reductions in HX are interpreted as points of protein–protein contact …”

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confidence: 99%

Human B Cell Epitope Map of the Lyme Disease Vaccine Antigen, OspA

Haque

Ejemel²,

Vance

et al. 2022

ACS Infect. Dis.

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The Lyme disease (LD) vaccine formerly approved for use in the United States consisted of recombinant outer surface protein A (OspA) from Borrelia burgdorferi sensu stricto (ss), the bacterial genospecies responsible for the vast majority of LD in North America. OspA is an ∼30 kDa lipoprotein made up of 21 antiparallel β-strands and a C-terminal α-helix. In clinical trials, protection against LD following vaccination correlated with serum antibody titers against a single epitope near the C-terminus of OspA, as defined by the mouse monoclonal antibody (MAb), LA-2. However, the breadth of the human antibody response to OspA following vaccination remains undefined even as next-generation multivalent OspA-based vaccines are under development. In this report, we employed hydrogen exchange–mass spectrometry (HX-MS) to localize the epitopes recognized by a unique panel of OspA human MAbs, including four shown to passively protect mice against experimental B. burgdorferi infection and one isolated from a patient with antibiotic refractory Lyme arthritis. The epitopes grouped into three spatially distinct bins that, together, encompass more than half the surface-exposed area of OspA. The bins corresponded to OspA β-strands 8–10 (bin 1), 11–13 (bin 2), and 16–20 plus the C-terminal α-helix (bin 3). Bin 3 was further divided into sub-bins relative to LA-2’s epitope. MAbs with complement-dependent borreliacidal activity, as well as B. burgdorferi transmission-blocking activity in the mouse model were found within each bin. Therefore, the resulting B cell epitope map encompasses functionally important targets on OspA that likely contribute to immunity to B. burgdorferi.

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mentioning

confidence: 99%

Human B Cell Epitope Map of the Lyme Disease Vaccine Antigen, OspA

Haque

Ejemel²,

Vance

et al. 2022

ACS Infect. Dis.

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“…1). Here, we propose two scenarios that could lead to the production of this type of antibody: This hypothesis is supported by studies of the dynamics of Env trimers showing structural changes occurring in the absence of CD4 that suggest that trimers can be in equilibrium between closed and more open conformations (65). Support for this model comes from biological studies.…”

Section: Discussionmentioning

confidence: 73%

Antibody Recognition of CD4-Induced Open HIV-1 Env Trimers

Yang

Dam

Gershoni

et al. 2022

J Virol

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“…First, although cryo-electron tomography studies of Env conformations on HIV-1 virions show Env trimers in a closed, prefusion conformation (61–64), it is possible that ligand-free Env trimers can transiently adopt an open conformation that mimics a CD4-induced open conformation. This hypothesis is supported by studies of the dynamics of Env trimers showing structural changes occurring in the absence of CD4 that suggest that trimers can be in equilibrium between closed and more open conformations (65). Support for this model comes from biological studies.…”

Section: Discussionmentioning

confidence: 82%

Antibody recognition of CD4-induced open HIV-1 Env trimers

Yang¹,

Dam²,

Gershoni

et al. 2022

Preprint

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HIV-1 envelope (Env), a heterotrimer of gp120-gp41 subunits, mediates fusion of the viral and host cell membranes after interactions with the host receptor CD4 and a coreceptor. CD4 binding induces rearrangements in Env trimer, resulting in a CD4-induced (CD4i) open Env conformation. Structural studies of antibodies isolated from infected donors have defined antibody-Env interactions, with one class of antibodies specifically recognizing the CD4i open Env conformation. Here, we characterize a group of monoclonal antibodies isolated from HIV-1 infected donors (V2i mAbs) that display characteristics of CD4i antibodies. Binding experiments demonstrate that the V2i mAbs preferentially recognize CD4-bound open Env trimers. Structural characterizations of V2i mAb-Env-CD4 trimer complexes using single-particle cryo-electron microscopy show recognition by V2i mAbs using different angles of approach to the gp120 V1V2 domain and the β2/β3 strands on a CD4i open conformation Env with no direct interactions of the mAbs with CD4. We also characterize CG10, a CD4i antibody that was raised in mice immunized with a gp120-CD4 complex, complexed with Env trimer and CD4. CG10 exhibits similar characteristics to the V2i antibodies: i.e., recognition of the open Env conformation, but shows direct contacts to both CD4 and gp120. Structural comparisons of these and previously characterized CD4i antibody interactions with Env provide a suggested mechanism for how these antibodies are elicited during HIV-1 infection.

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Structural dynamics reveal isolate-specific differences at neutralization epitopes on HIV Env

Cited by 17 publications

References 88 publications

Human B Cell Epitope Map of the Lyme Disease Vaccine Antigen, OspA

Human B Cell Epitope Map of the Lyme Disease Vaccine Antigen, OspA

Antibody Recognition of CD4-Induced Open HIV-1 Env Trimers

Antibody recognition of CD4-induced open HIV-1 Env trimers

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