Article

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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    • "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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