Antigenic conservation and immunogenicity of the HIV coreceptor binding site

Howard Hughes Institute, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 06/2005; 201(9):1407-19. DOI: 10.1084/jem.20042510
Source: PubMed

ABSTRACT Immunogenic, broadly reactive epitopes of the HIV-1 envelope glycoprotein could serve as important targets of the adaptive humoral immune response in natural infection and, potentially, as components of an acquired immune deficiency syndrome vaccine. However, variability in exposed epitopes and a combination of highly effective envelope-cloaking strategies have made the identification of such epitopes problematic. Here, we show that the chemokine coreceptor binding site of HIV-1 from clade A, B, C, D, F, G, and H and circulating recombinant form (CRF)01, CRF02, and CRF11, elicits high titers of CD4-induced (CD4i) antibody during natural human infection and that these antibodies bind and neutralize viruses as divergent as HIV-2 in the presence of soluble CD4 (sCD4). 178 out of 189 (94%) HIV-1-infected patients had CD4i antibodies that neutralized sCD4-pretreated HIV-2 in titers (50% inhibitory concentration) as high as 1:143,000. CD4i monoclonal antibodies elicited by HIV-1 infection also neutralized HIV-2 pretreated with sCD4, and polyclonal antibodies from HIV-1-infected humans competed specifically with such monoclonal antibodies for binding. In vivo, variants of HIV-1 with spontaneously exposed coreceptor binding surfaces were detected in human plasma; these viruses were neutralized directly by CD4i antibodies. Despite remarkable evolutionary diversity among primate lentiviruses, functional constraints on receptor binding create opportunities for broad humoral immune recognition, which in turn serves to constrain the viral quasispecies.

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    • "Env has developed multiple mechanisms to evade the host humoral immune response, including trimeric exclusion, occluded (co)receptor binding sites by conformational masking, (Chen et al., 2005; Decker et al., 2005; Edwards et al., 2001; Kwong et al., 2002; Labrijn et al., 2003; Wei et al., 2003) and the shielding of conserved epitopes by the highly variable flexible loops and a ''glycan shield'', which collectively limit the induction of BrNAbs (Wei et al., 2003). It can be hypothesized that a founder virus with more exposed conserved epitopes might elicit NAbs with a greater breadth (Walker and Burton, 2010). "
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    ABSTRACT: The need for an effective vaccine to prevent the global spread of human immunodeficiency virus type 1 (HIV-1) is well recognized. Passive immunization and challenge studies in non-human primates testify that broadly neutralizing antibodies (BrNAbs) can accomplish protection against infection. In recent years, the introduction of new techniques has facilitated the discovery of an unprecedented number of new human BrNAbs that target and delineate diverse conserved epitopes on the envelope glycoprotein spike (Env). The epitopes of these BrNAbs can serve as templates for immunogen design aimed to induce similar antibodies. Here we will review the characteristics of the different classes of BrNAbs and their target epitopes, as well as factors associated with their development and implications for vaccine design.
    Virology 01/2013; 435(1):46-56. DOI:10.1016/j.virol.2012.10.004 · 3.28 Impact Factor
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    • "The HIV-1 envelope glycoprotein (Env) is a major target of the neutralizing antibodies wherein HIV-1 Env develops cascade of mechanism towards humoral immune evasion by conferring inaccessibility of important/key residues on Env trimers that acts as targets of neutralizing antibodies. Several mechanisms attributed to this phenomenon have been documented; however (1) the number of potential glycosylation sites (PNGS) and (2) the length of variable loops especially in the context of V1V2 and V3 associated with neutralization sensitivity/resistance of HIV-1 were extensively reported (Bunnik et al., 2008; Cao et al., 1997; Chackerian et al., 1997; Chen et al., 2005; Decker et al., 2005; Doores and Burton, 2010; Doores et al., 2010; Edwards et al., 2001; Fischer et al., 1995; Go et al., 2008; Kwong et al., 1998; Land et al., 2003; Mascola and Montefiori, 2010; Moore et al., 2009; Pantophlet and Burton, 2006; Rong et al., 2007; Sagar et al., 2006; van Gils et al., 2010, 2011; Wei et al., 2003; Wyatt et al., 1995). It was previously shown that alteration in PNGS in V1, V2 and V3 significantly modulated sensitivity of Envpseudotyped HIV-1 to PG9 and PG16 MAbs (Doores and Burton, 2010). "
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    ABSTRACT: Recent discovery of several potent and broadly neutralizing monoclonal antibodies (MAbs) (such as PG9 and PG16) to HIV-1 provided clues on newer vaccine targets. In the present study, we found an env clone obtained from a slow progressor showing significant resistance to PG9 and PG16 MAbs in sharp contrast to other contemporaneous autologous env clones. By constructing chimeric envelopes and specific substitutions we found that both loop length and spatial orientation of glycan residues in addition to the net charge of the β sheet C region that directly binds to PG9 CDRH3 within V2 loop significantly modulated HIV-1 sensitivity to PG9 and PG16 MAbs. Similar observation were made with several other Envs which varied in length, glycan content and net charge in PG9 contacting complementary region in V2 loop. Our data indicated that subtle change within V2 loop alone modulates exposition of quaternary epitopes that are targets of PG9/PG16 MAbs.
    Virology 04/2012; 426(1):34-41. DOI:10.1016/j.virol.2012.01.011 · 3.28 Impact Factor
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    • "Similarly, CD4i antibodies can also be readily induced after immunization with HIV Env stabilized core proteins (Dey et al. 2009). Although such antibodies are seen frequently in HIV-infected individuals (Decker et al. 2005; Gray et al. 2007), they do not mediate neutralization, although it remains possible that they may contribute to protection through ADCC function. "
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    ABSTRACT: The development of a highly effective AIDS vaccine will likely depend on success in designing immunogens that elicit broadly neutralizing antibodies to naturally circulating strains of HIV-1. Although the antibodies induced after natural infection with HIV-1 are often directed to strain-specific or nonneutralizing determinants, it is now evident that 10%-25% of HIV-infected individuals generate neutralizing antibody responses of considerable breadth. In the past, only four broadly neutralizing monoclonal antibodies had been defined, but more than a dozen monoclonal antibodies of substantial breadth have more recently been isolated. An understanding of their recognition sites, the structural basis of their interaction with the HIV Env, and their development pathways provides new opportunities to design vaccine candidates that will elicit broadly protective antibodies against this virus.
    Cold Spring Harbor Perspectives in Medicine 09/2011; 1(1):a007278. DOI:10.1101/cshperspect.a007278 · 7.56 Impact Factor
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