Theoretical Studies on the Interactions and Interferences of HIV-1 Glycoprotein gp120 and Its Coreceptor CCR5

Abstract

The interaction between the HIV gp120 protein and coreceptor CCR5 or CXCR4 of the host cell is critical in mediating the HIV entry process. A model for the CCR5-gp120 complex has been developed. In the model, the N-terminus of CCR5 binds to three discontinuous domains of gp120, including the fourth conserved (C4) region, β19/β20 connecting loop, and V3 loop. The second extra-cellular loop (ECL2) of CCR5 also interacts with the crown part of the gp120 V3 loop. The bindings of the three CCR5 antagonists, maraviroc, aplaviroc, and vicriviroc, to the trans-membrane domain of CCR5 have been modeled. The bindings are found to affect the conformation of the ECL2 domain, which in turn drives the N-terminus of CCR5 to an altered state. Aplaviroc is more hydrophilic than maraviroc and vicriviroc, and its binding is more interfered by solvent, resulting in a quite different effect to the structure of CCR5 compared with those of the other two molecules. The above results are in accord with experimental observations and provide a structural basis for further design of CCR5 antagonists.

HIV-1 Resistance to Maraviroc Conferred by a CD4 Binding Site Mutation in the Envelope Glycoprotein gp120

“…Models of these interactions suggest that multiple regions in gp120 are involved with coreceptor binding. The tip of the third variable loop (V3 loop) of gp120 interacts with the second extracellular loop of the coreceptor (ECL2), while the N terminus of the coreceptor interacts with the V3 loop stem, the bridging sheet (between the V1-V2 stem), and the fourth conserved region (C4) of gp120 (2,3). Coreceptor engagement drives further conformational changes which result in insertion of gp41 fusion peptide (4), formation of the gp41 six-alpha-helix bundle (5), viral and host cell membrane fusion, and release of the viral RNA-containing core into the cell cytoplasm.…”

Incompatible Natures of the HIV-1 Envelope in Resistance to the CCR5 Antagonist Cenicriviroc and to Neutralizing Antibodies

“…CCR5 antagonists are suggested to block HIV-1 infection by means of a structural change in CCR5, which prevents interaction between HIV-1 and the CCR5 antagonist-bound form of CCR5 (2)(3)(4)(5). The V3 loop and CD4i region of HIV-1 Env are important for interaction with CCR5 and therefore play a key role in resistance to CCR5 antagonists.…”

“…Most CCR5 antagonists reported so far bind a hydrophobic pocket of CCR5, causing a structural rearrangement of extracellular loop 2 and the N-terminal region, which interact with HIV-1 Env glycoprotein (2)(3)(4)(5). Many CCR5 antagonists, such as TAK-779 (6), TAK-220 (7), vicriviroc (VCV) (8), aplaviroc (9), and maraviroc (MVC) (10), have been developed, yet only MVC is clinically used for the treatment of HIV-1-infected patients.…”

Effect of maraviroc on non-R5 tropic HIV-1: refined analysis of subjects from the phase IIb study A4001029

“…Structural analysis was performed using the CCR5-maraviroc-gp120 binding complex recently developed [10].…”

“…For these reasons, we raised the question of whether the mutations observed in these nonresponsive subjects may have an impact on interaction with the coreceptors. Because of the absence of a CXCR4 crystallographic model, we focused on the interaction network of CCR5 with gp120, or with maraviroc in the adopted HIV-1 CCR5-maraviroc-gp120 binding structure complex [10,15]. After molecular dynamic simulations of CCR5-gp120 complexes in the presence of maraviroc, the productive interactions V3 sequences in subjects 2 and 11 with CCR5 increased or were superimposable to those observed for the reference YU2-WT-V3-complex (Supplementary Table 2).…”