Antigenicity and Immunogenicity of RV144 Vaccine AIDSVAX Clade E Envelope Immunogen Is Enhanced by a gp120 N-Terminal Deletion

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To evaluate antibody specificities induced by simian immunodeficiency virus (SIV) versus human immunodeficiency virus type 1 (HIV-1) envelope antigens in nonhuman primate (NHP), we profiled binding antibody responses to linear epitopes in NHP studies with HIV-1 or SIV immunogens. We found that, overall, HIV-1 Env IgG responses were dominated by V3, with the notable exception of the responses to the vaccine strain A244 Env that were dominated by V2, whereas the anti-SIVmac239 Env responses were dominated by V2 regardless of the vaccine regimen.

mentioning

confidence: 68%

Vaccine-Induced Linear Epitope-Specific Antibodies to Simian Immunodeficiency Virus SIVmac239 Envelope Are Distinct from Those Induced to the Human Immunodeficiency Virus Type 1 Envelope in Nonhuman Primates

Shen

Duffy

Howington

et al. 2015

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“…Genes for four HIV-1 T/F gp120s, including three subtype B proteins (B.040, B.65321, and B.6240) and one subtype C protein (C.1086) obtained from subjects acutely infected with HIV-1 by single-genome amplification, were described previously (27,28). All gp120 genes were codon optimized by converting amino acid sequences to nucleotide sequences by employing the codon usage of highly expressed human housekeeping genes (29) synthesized de novo for expression as gp120 with deletion of either 7 (C.1086⌬7gp120) or 11 (B.040⌬11gp120, B.65321⌬11gp120, and B.6240⌬11gp120) amino acid residues at the N terminus of the mature HIV-1 Env proteins (30,31). These genes were then cloned into a mammalian expression plasmid, pcDNA3.1/hygromycin (Invitrogen, Grand Island, NY).…”

Section: Cellsmentioning

confidence: 99%

Envelope Glycoprotein Binding to the Integrin α ₄ β ₇ Is Not a General Property of Most HIV-1 Strains

Perez

Chen

Liao

et al. 2014

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The HIV-1 surface glycoprotein gp120 has been reported to bind and signal through ␣ 4 ␤ 7 by means of a tripeptide motif in the V2 loop that mimics structures present in the natural ligands for ␣ 4 ␤ 7 , suggesting that ␣ 4 ␤ 7 may facilitate HIV-1 infection of CD4 ؉ T cells in the gut. Furthermore, immune correlates in the RV144 vaccine efficacy trial generated the hypothesis that V1V2 antibodies to an epitope near the putative ␣ 4 ␤ 7 binding motif may play a role in protection against HIV-1 infection. In the interest of developing an assay to detect antibodies that block gp120 binding to ␣ 4 ␤ 7 , we used retinoic acid (RA)-activated human peripheral blood mononuclear cells (PBMCs) and transfected HEK293T (293T) cells expressing the integrin complex to study the ␣ 4 ␤ 7 binding properties of 16 HIV-1 envelope glycoproteins. The natural ligand for ␣ 4 ␤ 7 , mucosal addressin cell adhesion molecule-1 (MAdCAM-1), bound efficiently to RA-activated PBMCs and transfected 293T cells, and this binding was blocked by antibodies to ␣ 4 . gp120 from multiple HIV-1 subtypes bound to RA-activated PBMCs from three donors in a CD4-dependent manner, but little or no ␣ 4 ␤ 7 binding was detected. Similarly, little or no binding to ␣ 4 ␤ 7 on transfected 293T cells was detected with multiple gp120s and gp140s, including gp120s from transmitted/founder strains, or when gp120 was produced in CHO, 293T, and 293S/GnT1 ؊/؊ cells. Finally, we found no evidence that infectious HIV-1 virions produced in either PBMCs or 293T cells could bind ␣ 4 ␤ 7 on transfected 293T cells. Infectious HIV-1 virions and most gp120s/gp140s appear to be poor ligands for the ␣ 4 ␤ 7 integrin complex under the conditions tested here. IMPORTANCECertain HIV-1 gp120 envelope glycoproteins have been shown to bind the gut-homing receptor ␣ 4 ␤ 7 , and it has been suggested that this binding facilitates mucosal transmission and virus replication in the gut mucosa. Additional evidence has generated the hypothesis that antibodies that bind near the putative ␣ 4 ␤ 7 binding motif in the V2 loop of gp120, possibly disrupting gp120-␣ 4 ␤ 7 binding, may be important for HIV-1 vaccines. Our evidence indicates that infectious HIV-1 virions and many gp120s lack detectable ␣ 4 ␤ 7 binding activity, suggesting that this homing receptor may play a limited role in direct HIV-1 infection of cells. Integrins are cell receptors that play important immunomodulatory functions, such as cell adhesion, cellular trafficking, immune responses, as well as control of tumor growth and metastasis (1). These integrin receptors are composed of ␣ and ␤ subunits, and their surface expression plays a key role in the migration of cells to different tissues (2). The ␣ 4 subunit is expressed on T and B lymphocytes, monocytes, natural killer cells, and dendritic cells, where it can associate with ␤ 1 or ␤ 7 subunits (2, 3). The ␣ 4 ␤ 7 heterodimer acts as a gut-homing receptor, mediating lymphocyte migration to the intestinal mucosa through interaction with the mucosal addressin cell adhe...

“…It is widely believed that an effective antibody-based HIV-1 vaccine would need to elicit antibodies capable of recognizing diverse Env isolates, ideally including "broadly" neutralizing antibodies (NAbs) as well as nonneutralizing antibodies with antibody-dependent cellular cytotoxicity (ADCC) effector functions, which appeared to correlate with protection in the RV144 HIV-1 vaccine trial (9). Indeed, the hopeful results of the RV144 trial, which provided evidence that vaccine-induced protection against HIV-1 may be possible (10), suggested that monomeric gp120 is a relevant HIV-1 vaccine immunogen and highlighted the importance of understanding the structural features that distinguish gp120 proteins and influence gp120 reactivity with neutralizing and ADCCactive antibodies (11)(12)(13).…”

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confidence: 99%

Isolate-Specific Differences in the Conformational Dynamics and Antigenicity of HIV-1 gp120

Davenport

Guttman

Guo

et al. 2013

dThe HIV-1 envelope glycoprotein (Env) mediates viral entry into host cells and is the sole target of neutralizing antibodies. Much of the sequence diversity in the HIV-1 genome is concentrated within Env, particularly within its gp120 surface subunit. While dramatic functional diversity exists among HIV-1 Env isolates-observable even in the context of monomeric gp120 proteins as differences in antigenicity and immunogenicity-we have little understanding of the structural features that distinguish Env isolates and lead to isolate-specific functional differences, as crystal structures of truncated gp120 "core" proteins from diverse isolates reveal a high level of structural conservation. Because gp120 proteins are used as prospective vaccine immunogens, it is critical to understand the structural factors that influence their reactivity with antibodies. Here, we studied four full-length, glycosylated gp120 monomers from diverse HIV-1 isolates by using small-angle X-ray scattering (SAXS) to probe the overall subunit morphology and hydrogen/deuterium-exchange with mass spectrometry (HDX-MS) to characterize the local structural order of each gp120. We observed that while the overall subunit architecture was similar among isolates by SAXS, dramatic isolate-specific differences in the conformational stability of gp120 were evident by HDX-MS. These differences persisted even with the CD4 receptor bound. Furthermore, surface plasmon resonance (SPR) and enzyme-linked immunosorbance assays (ELISAs) showed that disorder was associated with poorer recognition by antibodies targeting conserved conformational epitopes. These data provide additional insight into the structural determinants of gp120 antigenicity and suggest that conformational dynamics should be considered in the selection and design of optimized Env immunogens.