Immunogenicity of synthetic HIV-1 gp120 V3-loop peptide-conjugate immunogens

Conley, Anthony J.; Conard, Patricia; Bondy, Steven; Dolan, Catherine A.; Hannah, John; Leanza, W. J.; Marburg, Stephen; Rivetna, Meheryar N.; Rusiecki, Victoria K.; Sugg, Elizabeth E.; Middlesworth, Francis Van; Warne, Susan A.; Ulrich, J. Terry; Rudbach, Jon A.; Tolman, Richard L.; Emini, Emilio A.

doi:10.1016/0264-410x(94)90123-6

Cited by 37 publications

(30 citation statements)

References 12 publications

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“…Antigens used to select MAbs with these characteristics, such as V3-FP, provide a template for the design of immunogens that will focus the immune response on the V3 loop and should induce high-affinity, broadly reactive Abs to conformational epitopes on V3. The apparent requirement for conformational aspects of V3 revealed by our studies may also provide an explanation for the disappointing results with previously used V3 immunogens (1,7,23) which lacked the appropriate conformational aspects of the V3 loop.…”

Section: Vol 78 2004mentioning

confidence: 58%

The V3 Loop Is Accessible on the Surface of Most Human Immunodeficiency Virus Type 1 Primary Isolates and Serves as a Neutralization Epitope

Górny¹,

Revesz

Williams³

et al. 2004

J Virol

107

111

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Antibodies (Abs) against the V3 loop of the human immunodeficiency virus type 1 gp120 envelope glycoprotein were initially considered to mediate only type-specific neutralization of T-cell-line-adapted viruses. However, recent data show that cross-neutralizing V3 Abs also exist, and primary isolates can be efficiently neutralized with anti-V3 monoclonal Abs (MAbs). The neutralizing activities of anti-V3 polyclonal Abs and MAbs may, however, be limited due to antigenic variations of the V3 region, a lack of V3 exposure on the surface of intact virions, or Ab specificity. For clarification of this issue, a panel of 32 human anti-V3 MAbs were screened for neutralization of an SF162-pseudotyped virus in a luciferase assay. MAbs selected with a V3 fusion protein whose V3 region mimics the conformation of the native virus were significantly more potent than MAbs selected with V3 peptides. Seven MAbs were further tested for neutralizing activity against 13 clade B viruses in a single-round peripheral blood mononuclear cell assay. While there was a spectrum of virus sensitivities to the anti-V3 MAbs observed, 12 of the 13 viruses were neutralized by one or more of the anti-V3 MAbs. MAb binding to intact virions correlated significantly with binding to solubilized gp120s and with the potency of neutralization. These results demonstrate that the V3 loop is accessible on the native virus envelope, that the strength of binding of anti-V3 Abs correlates with the potency of neutralization, that V3 epitopes may be shared rather than type specific, and that Abs against the V3 loop, particularly those targeting conformational epitopes, can mediate the neutralization of primary isolates.The third variable domain (V3) of the human immunodeficiency virus type 1 (HIV-1) gp120 envelope glycoprotein is critical for the formation of syncytia and for virus entry into target cells (24,55). These functions are mediated by the interaction of the V3 loop with chemokine receptors and are maintained despite the sequence variation that characterizes this region of the virus envelope (18, 51). Indeed, contrary to its name, the V3 loop is characterized by a constant size of 30 to 35 amino acids, a conserved type II ␤-turn at its tip, a disulfide bond at its base, and a net positive charge (26, 28). Conserved features are also suggested by the structure of the V3 loop discerned by nuclear magnetic resonance studies (47, 52), and conserved elements in the V3 crown and stem are mandatory features for coreceptor interactions (9, 50). All of these structural constraints appear to be imposed by the required interaction of the V3 loop with the coreceptors for HIV-1, CXCR4 or CCR5, and suggest that this region of the virus envelope should induce antibodies (Abs) that are crossreactive among isolates and inhibitory to virus infectivity.Initial studies of anti-V3 Abs, induced by brief immunization protocols in animals and tested against a limited number of T-cell-line-adapted (TCLA) strains of the virus, suggested, however, that anti-V3 Abs were type spec...

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Section: Vol 78 2004mentioning

confidence: 58%

The V3 Loop Is Accessible on the Surface of Most Human Immunodeficiency Virus Type 1 Primary Isolates and Serves as a Neutralization Epitope

Górny¹,

Revesz

Williams³

et al. 2004

J Virol

107

111

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“…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). T-lymphoid cell line-adapted HIV-1 strains, as well as some primary isolates that express this sequence motif, are efficiently neutralized by 447-52D (23,71,78). The atomic structure of 447-52D in complex with V3 peptides shows that the antibody binds to the distal tip such that the pseudo 2-fold long axis of the Fab arm and the extended V3 loop are in rough alignment, i.e., the Fab arm protrudes from the tip of the V3 loop as shown in Fig.…”

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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“…Due to the structural insights gained thus far, it appears that immunogen design strategies that target V3 need to take into account V3 structure and not simply focus on sequence. Design strategies include stabilization of V3 peptides on protein scaffolds or chimeras [34,79,109,162,313], conformationally constraining V3 via mutagenesis or chemically [13,14,28,118,122,277,278,336,337], conjugation of V3 peptides to foreign or carrier proteins [59,64,65,154], and identifying V3 variants or consensus sequences representative of potential V3 structures [93,94,138,206,325].…”

Section: Targeting the Chemokine Receptor Bind-ing Sitementioning

confidence: 99%

Designing Immunogens to Elicit Broadly Neutralizing Antibodies to the HIV-1 Envelope Glycoprotein

Lin

Nara²

2007

CHR

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To date HIV-1 vaccines have not been able to elicit potent, long lasting, and broadly neutralizing antibodies to the virus. Our knowledge of HIV envelope glycoprotein (Env) structure/function and the existence of a handful of broadly neutralizing antibodies is guiding rational immunogen design. We review here the potential targets on the HIV Env (the glycan shield, the CD4 binding site, the coreceptor binding site, Env fusion intermediates, and the membrane proximal region) and their associated rational immunogen design strategies. Moreover, we discuss immune dampening and immune refocusing strategies designed to counter immunodominant, decoy responses generated by the virus. In this regard, an immunogen design strategy of "in vitro de-evolution" is presented, which begins to distill the HIV Env to its most critical, core functional domains. While we are beginning to have some understanding as to where we would like out immune system to go, we find that our immune repertoire may actually have limits that preclude successful completion of the task at hand. The repertoire limits appear to be a byproduct of autoantibody tolerance mechanisms and the complex structural requirements for effective, potent broadly neutralizing antibodies. Nevertheless, the hope is that through novel insights and creative solutions that we will be able to design immunogens capable of eliciting broadly neutralizing antibodies to the HIV envelope glycoprotein.

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Immunogenicity of synthetic HIV-1 gp120 V3-loop peptide-conjugate immunogens

Cited by 37 publications

References 12 publications

The V3 Loop Is Accessible on the Surface of Most Human Immunodeficiency Virus Type 1 Primary Isolates and Serves as a Neutralization Epitope

The V3 Loop Is Accessible on the Surface of Most Human Immunodeficiency Virus Type 1 Primary Isolates and Serves as a Neutralization Epitope

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

Designing Immunogens to Elicit Broadly Neutralizing Antibodies to the HIV-1 Envelope Glycoprotein

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