Env Domains Involved in Coreceptor Interactions

The gp120 subunit of Env binds to both CD4 and CCR5/ CXCR4. It contains five variable regions (V1-V5) interspersed between five conserved domains (C1-C5), and is very heavily glycosylated. The third variable region, or V3-loop, plays a major role in governing whether Env interacts with CXCR4, CCR5, or both coreceptors. The first and second variable loops, termed the V1/V2 region, play a more subsidiary role. Amino acid changes in the V3 loop can result in a coreceptor switch, while changes in V1/V2 do so less commonly [26-29]. Other regions of gp120 are also involved in coreceptor binding as revealed by the crystal structure of a core of HIV-1HXBc2 gp120 glycoprotein coupled with site-directed mutagenesis (see Fig. 2) [30,31].

Figure 1 Model of HIV entry. The interaction of gp120 with CD4 at the cell surface induces conformational changes in Env that result in the exposure of a coreceptor binding site. Binding to a 7TM-coreceptor molecule induces further conformational changes that may involve fusion peptide insertion into the target cell membrane. The ectodomain of gp41 is then likely to fold back upon itself to form a coiled-coil bundle, causing apposition then fusion of viral and cellular membranes. (Adapted from Doms, R. W., Virology, 276, 229-237, 2000.)

Figure 1 Model of HIV entry. The interaction of gp120 with CD4 at the cell surface induces conformational changes in Env that result in the exposure of a coreceptor binding site. Binding to a 7TM-coreceptor molecule induces further conformational changes that may involve fusion peptide insertion into the target cell membrane. The ectodomain of gp41 is then likely to fold back upon itself to form a coiled-coil bundle, causing apposition then fusion of viral and cellular membranes. (Adapted from Doms, R. W., Virology, 276, 229-237, 2000.)

CCR5 binding site

CCR5 binding site

Figure 2 CCR5 binding site on gp120. Space-filling model of gp120 with the conserved bridging sheet domain and two-domain sCD4 in ribbon format. Residues involved in CCR5 binding are indicated, as are the V1/V2 and V3 loop stems. Model was rendered with RasMol 2.7.1 from the Protein Databank file 1GC1.PDB, gp120 crystal structure [30].

Figure 2 CCR5 binding site on gp120. Space-filling model of gp120 with the conserved bridging sheet domain and two-domain sCD4 in ribbon format. Residues involved in CCR5 binding are indicated, as are the V1/V2 and V3 loop stems. Model was rendered with RasMol 2.7.1 from the Protein Databank file 1GC1.PDB, gp120 crystal structure [30].

To aid in crystallization, the gp120 was deglycosylated, the V3 and V1/V2 loops were genetically deleted, and the protein was cocrystallized with a two-domain soluble CD4 molecule and a Fab fragment of a monoclonal antibody that binds to an epitope in gp120 that is induced by CD4 binding (Fig. 2). The epitope recognized by this antibody is highly conserved across different virus strains and is located between the base of the V3 loop and the base of the V1/V2 region, near or within the bridging sheet domain (Fig. 2). Interestingly, mutations in this conserved domain diminish the ability of gp120 to bind to CCR5 [31]. The model that logically follows is that CD4 binding results in the exposure or generation of this highly conserved portion of gp120, perhaps as the result of repositioning of the V2 and V3 loops [30,32]. This conserved domain and V3 together form a CCR5 receptor-binding domain. This is in some ways reminiscent of how chemokines bind to their receptors, which is thought to likewise involve two regions of the chemokine.

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