HIV-1 Entry and Membrane Fusion Inhibitors.

HIV-1 (human immunodeficiency virus type 1) infection begins with the attachment of the virion to a host cell by its envelope glycoprotein (Env), which subsequently induces fusion of viral and cell membranes to allow viral entry. Upon binding to primary receptor CD4 and coreceptor (e.g., chemokine receptor CCR5 or CXCR4), Env undergoes large conformational changes and unleashes its fusogenic potential to drive the membrane fusion. The structural biology of HIV-1 Env and its complexes with the cellular receptors not only has advanced our knowledge of the molecular mechanism of how HIV-1 enters the host cells but also provided a structural basis for the rational design of fusion inhibitors as potential antiviral therapeutics. In this review, we summarize our latest understanding of the HIV-1 membrane fusion process and discuss related therapeutic strategies to block viral entry.

Peptide-based inhibitors of the HIV envelope protein and other class I viral fusion proteins.

Viruses need to deliver their genomic information into the host cell lumen to establish productive infection. Enveloped viruses accomplish this task by fusing their membrane with a host cell membrane. Membrane fusion is facilitated by specialized viral membrane proteins, which mediate binding and entry into host cells. The architecture of the fusion machinery of envelope proteins can differ between viruses, and class I, II and III fusion systems have been described. However, the conformational rearrangements associated with membrane fusion are comparable and constitute attractive targets for intervention. The fusion apparatus of the human immunodeficiency virus (HIV) envelope protein (Env), a class I fusion protein, is located in the transmembrane unit gP41 of Env. The fusion machinery is activated by Env binding to CD4 and a chemokine coreceptor, and the structural rearrangements in gp41 associated with membrane fusion comprise the insertion of a fusion peptide into the target cell membrane and the formation of a stable six-helix bundle structure. These processes can be efficiently inhibited by peptides mimicking conserved functional elements in gp41. A prominent example for such peptides, termed fusion inhibitors, is the peptide T-20 (enfuvirtide, Fuzeon) which is used as salvage therapy of HIV/AIDS. Here, we will discuss how HIV mediates fusion with host cell membranes and how this process can be blocked by peptides targeting gp41. In addition, we will discuss peptide inhibitors of other class I viral fusion proteins.