Thirty years on: HIV receptor gymnastics and the prevention of infection

Abstract

During 30 years of research on human immunodeficiency virus (HIV), our knowledge of its cellular receptors--CD4, CCR5 and CXCR4--has illuminated aspects of the pathogenesis of the acquired immune deficiency syndrome (AIDS). Studying how the HIV envelope glycoproteins interact with the receptors led to anti-retroviral drugs based on blocking the docking or fusion of virus to the host cell. Genetic polymorphisms of CCR5 determine resistance to HIV infection and the rate of progression to AIDS. Eliciting neutralizing antibodies to the sites of receptor interaction on HIV glycoproteins is a promising approach to HIV vaccine development.

Figure 1

The London Eye as a ’model’ of HIV. (a) The model depicts the diploid RNA genome and the outer envelope of the HIV particle composed of a lipid bilayer studded with glycoprotein spikes. (b) Close-up of trimeric spike showing globular gp120 and transmembrane gp41.

Figure 2

Model of HIV entry. CD4 receptors and chemokine co-receptors are shown on the host cell. The gp120 surface subunit and gp41 transmembrane subunit of the HIV envelope glycoprotein are shown on the viral membrane (envelope). After gp120 binds to CD4, the envelope glycoprotein undergoes conformational changes that facilitate gp120 interaction with the chemokine co-receptor. Additional conformational changes in the gp41 transmembrane subunit transiently expose two heptad-repeat domains (HR1 and HR2) that subsequently self-assemble to form a six-helix bundle structure. Formation of several gp41 six-helix bundles bring the host and viral membranes together for fusion, while several six-helix bundles likely coalesce to form a fusion pore that allows the viral core to pass into the host cell cytoplasm. Arrows indicate potential steps in the entry process for inhibition. (Reproduced from [32] with kind permission of the authors).