Cross-clade recognition and neutralization by the V3 region from clade C human immunodeficiency virus-1 envelope
ABSTRACT To understand the cross-reactivity of antibodies directed against variable regions of human immunodeficiency virus-1 (HIV-1) envelope (Env), chimeric immunogens were prepared from different clades with modifications in variable regions, and the resulting neutralizing antibody response was evaluated. The V3-specific neutralization activity induced by a clade B immunogen was limited to clade B viruses and was blocked by a clade B V3 peptide, but not by analogous clade A or C V3 peptides. In contrast, the V3 response elicited by a clade C immunogen cross-reacted with sensitive clade B viruses. The V3 region from a clade C virus, when introduced into a clade B sequence, elicited cross-clade activity, which could be reversed by V3 peptides derived from clades A and C. Thus, the anti-V3 antibody response elicited by a clade C immunogen could cross-react with heterologous clade viruses. Additionally, we describe a V1-specific immune response that mediated neutralization limited to the homologous HIV IIIB isolate and may be partially responsible for the commonly observed strain-specific neutralization responses elicited by vaccine immunogens.
- SourceAvailable from: Loic Martin
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- "This observation that the elicitation of anti-V3 antibodies was not enhanced by both gp140-miniCD4 complex immunogens was also supported by HxB2-neutralization results. Sera from both the gp140-miniCD4, cross-linked or mixed, complex immunized groups neutralized HxB2, a virus that is not sensitive to anti-V3 antibodies , more potently (although without statistical significance) than sera from the group that was immunized by gp140 alone (Fig. 4). These data suggested that the structural alterations upon Env-CD4 protein binding and alterations upon gp140-miniCD4 interaction may differ concerning V3 loop exposure and subsequent V3-specific antibody elicitation. "
ABSTRACT: The identification of HIV-1 envelope glycoprotein (Env) structures that can generate broadly neutralizing antibodies (BNAbs) is pivotal to the development of a successful vaccine against HIV-1 aimed at eliciting effective humoral immune responses. To that end, the production of novel Env structure(s) that might induce BNAbs by presentation of conserved epitopes, which are otherwise occluded, is critical. Here, we focus on a structure that stabilizes Env in a conformation representative of its primary (CD4) receptor-bound state, thereby exposing highly conserved "CD4 induced" (CD4i) epitope(s) known to be important for co-receptor binding and subsequent virus infection. A CD4-mimetic miniprotein, miniCD4 (M64U1-SH), was produced and covalently complexed to recombinant, trimeric gp140 envelope glycoprotein (gp140) using site-specific disulfide linkages. The resulting gp140-miniCD4 (gp140-S-S-M64U1) complex was recognized by CD4i antibodies and the HIV-1 co-receptor, CCR5. The gp140-miniCD4 complex elicited the highest titers of CD4i binding antibodies as well as enhanced neutralizing antibodies against Tier 1 viruses as compared to gp140 protein alone following immunization of rabbits. Neutralization against HIV-2(7312/V434M) and additional serum mapping confirm the specific elicitation of antibodies directed to the CD4i epitope(s). These results demonstrate the utility of structure-based approach in improving immunogenic response against specific region, such as the CD4i epitope(s) here, and its potential role in vaccine application.PLoS ONE 01/2012; 7(1):e30233. DOI:10.1371/journal.pone.0030233 · 3.23 Impact Factor
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- "The V3 region of gp120, while variable in sequence, possesses conserved structural and immunologic features that induce neutralizing Abs (Gorny et al. 1993, Gorny et al. 2002, Stanfield et al. 2006, Bell et al. 2008, Wu et al. 2006). Numerous human anti-V3 mAbs have been produced and characterized, and while many of these mAbs are narrow in their focus, several have broad cross-clade neutralizing activity (Gorny et al. 2004, Gorny et al. 2006, Gorny et al. 2002, Binley et al. 2004, Bell et al. 2008, Pantophlet et al. 2008, Zolla-Pazner et al. 2008, Zolla-Pazner et al. 2004). "
ABSTRACT: V3 loop is a major neutralizing determinant of the HIV-1 gp120. Using 3D structures of cholera toxin B subunit (CTB), complete V3 in the gp120 context, and V3 bound to a monoclonal antibody (mAb), we designed two V3-scaffold immunogen constructs (V3-CTB). The full-length V3-CTB presenting the complete V3 in a structural context mimicking gp120 was recognized by the large majority of our panel of 24 mAbs. The short V3-CTB presenting a V3 fragment in the conformation observed in the complex with the 447-52D Fab, exhibited high-affinity binding to this mAb. The immunogens were evaluated in rabbits using DNA-prime/protein-boost protocol. Boosting with the full-length V3-CTB induced high anti-V3 titers in sera that potently neutralize multiple HIV virus strains. The short V3-CTB was ineffective. The results suggest that very narrow antigenic profile of an immunogen is associated with poor Ab response. An immunogen with broader antigenic activity elicits robust Ab response.Virology 09/2010; 405(2):513-23. DOI:10.1016/j.virol.2010.06.027 · 3.32 Impact Factor
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- "Therefore, it is necessary to reduce the dose of each individual peptide    . The V3 loop is the primary target for many neutralizing antibodies    and is involved in other aspects of infectivity. Thus, sequence changes in V3 affect chemokine receptor usage and therefore modulate the cell types that are infected   . "
ABSTRACT: To be effective, vaccines against the highly variable HIV-1 must elicit antibodies to a huge number of clinical isolates. For this purpose, new strategies to overcome this variability are needed. We previously reported a useful immunogenic strategy which consists of conjugating multiple antigen peptides (MAPs) to HBsAg. This vaccine candidate reduces the dose of immunogen required and increases the cross-reactivity towards other HIV strains. In the present study, we have expanded on those results by working with other carrier proteins. Thus, JY1-peptide (V3 regions of gp120 of HIV-1, subtype D) and JY1-MAP8 were synthesized and coupled to several carrier proteins such as KLH, HBsAg and P64k (recombinant meningococcal protein). Mice were immunized with various conjugates and their antigenicity, immunogenicity, and the level of cross-reactivity to a panel of five heterologous V3 peptides were compared. Our results show that conjugate JY1-MAP8 were not only more immunogenic than conjugate, they were also more or equally as immunogenic as 4-fold more JY1-MAP8 alone. Furthermore, conjugates to HBsAg and KLH were more immunogenic than those to P64k. Moreover, conjugates to HBsAg, KLH and P64k showed enhanced cross-reactivity to heterologous V3 peptides compared to JY1-peptide and JY1-MAP8. The analysis showed that conjugate-based immunogens are more prompt to elicit immunogenicity and cross-reactivity. These results can find application in the development of HIV vaccine candidates.International immunopharmacology 09/2009; 9(12):1452-9. DOI:10.1016/j.intimp.2009.08.026 · 2.47 Impact Factor