HIV envelope: challenges and opportunities for development of entry inhibitors

Abstract

The HIV envelope proteins glycoprotein 120 (gp120) and glycoprotein 41 (gp41) play crucial roles in HIV entry, therefore they are of extreme interest in the development of novel therapeutics. Studies using diverse methods, including structural biology and mutagenesis, have resulted in a detailed model for envelope-mediated entry, which consists of multiple conformations, each a potential target for therapeutic intervention. In this review, the challenges, strategies and progress to date for developing novel entry inhibitors directed at disrupting HIV gp120 and gp41 function are discussed.

Figure 1

Organization of HIV envelope proteins. Numbering corresponds to that of strain HXB2 of HIV-1 . Putative glycosylation sites are denoted by asterisks. Domain abbreviations: SP, signal peptide; C1–C5, conserved domains 1 to 5; V1–V5, variable domains 1 to 5; FP, fusion peptide; HR1, heptad repeat 1 (HR1 is sometimes referred to as N-Helix); DL, disulfide loop; HR2, heptad repeat 2 (HR2 is sometimes referred to as C-Helix); MPER, membrane proximal ectodomain region; TM, transmembrane domain; CD, cytoplasmic domain. High resolution structural information is available for gp120 and gp41 domains colored as in Figure 2, Figure 3.

Figure 2

Structures of gp120 and gp41. (a) Ribbon diagram of the HIV gp120 core . For clarity, the CD4 and antibody domains that are bound to the gp120 core are not shown. (b) Ribbon diagram of the SIV gp41 ectodomain . In this structure, the HR1, disulfide loop and HR2 domains are colored cyan, yellow and red, respectively.

Figure 3

Intermolecular interactions of gp120 and gp41. (a) Space filling representation of the gp120 core. Gp120 residues that form interactions with CD4 (residues 112, 255, 257, 368, 370, 371, 427, 430 and 473, HIV-1 strain HXB2 numbering) and CR (residues 121, 419, 421 and 422, HIV-1 strain HXB2 numbering) are colored purple and pink, respectively, and based on the X-ray structure of the gp120 core in complex with CD4 domains and an antibody bound to the CR binding site . gp120 residues that form putative interactions with the gp41 disulfide loop (residues 36, 40, 44, 45, 53, 491, 493, 494, 495, 496, 497, 498, 499 and 501, HIV-1 strain HXB2 numbering) are colored yellow and based on mutagenesis studies , , . (b) Space filling representation of the gp41 ectodomain. Gp41 residues that form putative interactions with gp120 (residues 27, 30, 31, 33, 38, 42, 45, 47, 48, 49, 50, 51, 52, 53, 58, 67, 70, 71 and 72, HIV-1 strain HXB2 numbering) are colored green and based on the mutagenesis studies , , . The orientation of gp120 and gp41 is identical to that shown in Figure 2.

Figure 4

Role of envelope proteins in HIV entry. The CD4 and CR of the target cell are colored purple and pink, respectively. gp120 is colored green with the V3 loop colored light green. The gp41 domains shown are the fusion peptide (light purple), HR1 (cyan), disulfide loop (yellow), HR2 (red), and MPER (orange). (i) In the first step, the free state of gp120 binds to the CD4 receptor and subsequently the V3 loop of gp120 engages CR to form the receptor-bound state. (ii) In the next step, gp120 dissociates from gp41, gp41 undergoes a large conformational change, and the newly exposed fusion peptide inserts into the target cell membrane to form the tethered state. (iii) In the final step, the HR1 and HR2 interact, thereby bringing the target and virus membranes in close proximity to allow for membrane fusion and virus entry.