Structural Conservation Predominates Over Sequence Variability in the Crown of HIV Type 1's V3 Loop

Almond, David; Kimura, Tetsuya; Kong, Xiang‐Peng; Swetnam, James; Zolla‐Pazner, Susan; Cardozo, Timothy

doi:10.1089/aid.2009.0254

Cited by 36 publications

(41 citation statements)

References 32 publications

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“…Human MAb 447-52D, first isolated as a heterohybridoma derived from an HIV-1 infected patient (71,72), binds to the V3 variable loop of the HIV-1 gp120 and exhibits significant neutralizing breadth, mostly within clade B (23,73,74). The core epitope of the V3 sequence was mapped by immunochemical studies to the highly conserved GPGR motif in the crown of the clade B V3 loop (75)(76)(77).…”

Section: Resultsmentioning

confidence: 99%

Visualization of Retroviral Envelope Spikes in Complex with the V3 Loop Antibody 447-52D on Intact Viruses by Cryo-Electron Tomography

Dutta

Li²,

Roux

et al. 2014

J Virol

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The gp120 portion of the envelope spike on human immunodeficiency virus type 1 (HIV-1) plays a critical role in viral entry into host cells and is a key target for the humoral immune response, and yet many structural details remain elusive. We have used cryoelectron tomography to visualize the binding of the broadly neutralizing monoclonal antibody (MAb) 447-52D to intact envelope spikes on virions of HIV-1 MN strain. Antibody 447-52D has previously been shown to bind to the tip of the V3 loop. Our results show antibody arms radiating from the sides of the gp120 protomers at a range of angles and place the antibodybound V3 loop in an orientation that differs from that predicted by most current models but consistent with the idea that antibody binding dislodges the V3 loop from its location in the Env spike, making it flexible and disordered. These data reveal information on the position of the V3 loop and its relative flexibility and suggest that 447-52D neutralizes HIV-1 MN by capturing the V3 loop, blocking its interaction with the coreceptor and altering the structure of the envelope spike. IMPORTANCE Antibody neutralization is one of the primary ways that the body fights infection with HIV. Because HIV is a highly mutable vi-

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Section: Resultsmentioning

confidence: 99%

Visualization of Retroviral Envelope Spikes in Complex with the V3 Loop Antibody 447-52D on Intact Viruses by Cryo-Electron Tomography

Dutta

Li²,

Roux

et al. 2014

J Virol

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“…The final two V3 inserts, V3 2219 and V3 3074 , were designed by making appropriate mutations in the consensus C V3 crown in the critical residues of the "signature motifs." Signature motifs were derived previously based on the 3D shapes of epitopes in V3 that are recognized by human MAbs which are able to neutralize diverse strains of viruses from multiple clades (3,14,64). Briefly, by studying the crystal structures of MAb/epitope complexes (13,36,60,61), identifying the key V3 residues that are recognized by the MAb, and determining the stringency with which these residues are required for neutralization by that MAb, a signature motif for the epitope recognized by that MAb can be defined.…”

Section: Resultsmentioning

confidence: 99%

“…The V3-scaffold immunogens used here were rationally designed using a large body of structural data derived from crystals of V3 peptides complexed to V3-specific MAbs (13,18,36,60,61), bioinformatics analyses, and molecular modeling studies (3,14,36,64,71). This resulted in V3 epitopes which captured conserved V3 structures shared between the various viral subtypes and which were spliced into a structurally compatible region of a protein scaffold, cholera toxin B (66).…”

Section: Discussionmentioning

confidence: 99%

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Cross-Clade HIV-1 Neutralizing Antibodies Induced with V3-Scaffold Protein Immunogens following Priming with gp120 DNA

Zolla‐Pazner

Kong

Jiang

et al. 2011

J Virol

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The V3 epitope is a known target for HIV-1 neutralizing antibodies (NAbs), and V3-scaffold fusion proteins used as boosting immunogens after gp120 DNA priming were previously shown to induce NAbs in rabbits. Here, we evaluated whether the breadth and potency of the NAb response could be improved when boosted with rationally designed V3-scaffold immunogens. Rabbits were primed with codon-optimized clade C gp120 DNA and boosted with one of five V3-cholera toxin B fusion proteins (V3-CTBs) or with double combinations of these. The inserts in these immunogens were designed to display V3 epitopes shared by the majority of global HIV-1 isolates. Double combinations of V3-CTB immunogens generally induced more broad and potent NAbs than did boosts with single V3-CTB immunogens, with the most potent and broad NAbs elicited with the V3-CTB carrying the consensus V3 of clade C (V3 C -CTB), or with double combinations of V3-CTB immunogens that included V3 C -CTB. Neutralization of tier 1 and 2 pseudoviruses from clades AG, B, and C and of peripheral blood mononuclear cell (PBMC)-grown primary viruses from clades A, AG, and B was achieved, demonstrating that priming with gp120 DNA followed by boosts with V3-scaffold immunogens effectively elicits cross-clade NAbs. Focusing on the V3 region is a first step in designing a vaccine targeting protective epitopes, a strategy with potential advantages over the use of Env, a molecule that evolved to protect the virus by poorly inducing NAbs and by shielding the epitopes that are most critical for infectivity.

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“…In addition, several techniques were developed to generate monoclonal antibodies and to study immune complexes (e.g. virion-bound antibodies) as well as antibody-secreting cells [14, [35][36][37][38][39][40][41][42][43][44] . For example, the neutralizing activity of antibodies and their specificity can be assessed by measuring the neutralization of different Env-pseudotyped viruses, i.e.…”

Section: Analysis Of Isotypes Functions and Specificities Of Hiv-spementioning

confidence: 99%

HIV-Specific Antibody Responses in HIV-Infected Patients: From a Monoclonal to a Polyclonal View

Gallerano¹,

Cabauatan²,

Sibanda³

et al. 2015

Int Arch Allergy Immunol

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HIV infections represent a major global health threat, affecting more than 35 million individuals worldwide. High infection rates and problems associated with lifelong antiretroviral treatment emphasize the need for the development of prophylactic and therapeutic immune intervention strategies. It is conceivable that insights for the design of new immunogens capable of eliciting protective immune responses may come from the analysis of HIV-specific antibody responses in infected patients. Using sophisticated technologies, several monoclonal neutralizing antibodies were isolated from HIV-infected individuals. However, the majority of polyclonal antibody responses found in infected patients are nonneutralizing. Comprehensive analyses of the molecular targets of HIV-specific antibody responses identified that during natural infection antibodies are mainly misdirected towards gp120 epitopes outside of the CD4-binding site and against regions and proteins that are not exposed on the surface of the virus. We therefore argue that vaccines aiming to induce protective responses should include engineered immunogens, which are capable of focusing the immune response towards protective epitopes.

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Structural Conservation Predominates Over Sequence Variability in the Crown of HIV Type 1's V3 Loop

Cited by 36 publications

References 32 publications

Visualization of Retroviral Envelope Spikes in Complex with the V3 Loop Antibody 447-52D on Intact Viruses by Cryo-Electron Tomography

Visualization of Retroviral Envelope Spikes in Complex with the V3 Loop Antibody 447-52D on Intact Viruses by Cryo-Electron Tomography

Cross-Clade HIV-1 Neutralizing Antibodies Induced with V3-Scaffold Protein Immunogens following Priming with gp120 DNA

HIV-Specific Antibody Responses in HIV-Infected Patients: From a Monoclonal to a Polyclonal View

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