HIV-1 entry

The HIV-1 entry process consists of three major steps:

1. The attachment of the viral envelope (Env) surface glycoprotein 120 (gp120) to the CD4 receptor on the surface of T-cells

2. The subsequent interaction of the Env-CD4 complex with a co-receptor (usually CCR5 or CXCR4)

3. Virus-cell membrane fusion mediated by the Env transmembrane (TM) gp41 subunit.

More specifically, Env is arranged on the virus particle in trimeric spikes, comprising three gp120 and three gp41 molecules, anchored within the viral membrane via the gp41 TM domains. Attachment of the Env gp120 subunit to a CD4 receptor, leads to conformational changes in Env, allowing interactions with cellular co-receptors, the most important of which are the seven transmembrane domain chemokine receptors CCR5 and CXCR4. Further conformational changes expose the gp41 subunit, leading to the insertion of its hydrophobic N-terminal fusion peptide (FP) into the target cell membrane.

Subsequent changes within the gp41 ectodomain involve the interaction of two leucine zipper-like motifs called heptad repeat 1 (HR1) and heptad repeat 2 (HR2), also termed the N- and C-terminal helices, respectively. Ultimately, HR1 and HR2 from three gp41 molecules assemble into a six-helix bundle structure, also called a triple-hairpin structure or trimer-of-hairpins that juxtaposes the viral and cellular membranes, resulting in membrane fusion.

HIV-1 fusion inhibitors (eg. T20)

Generally, HIV-1 fusion inhibitors are compounds that are able to bind to one of the HR motifs within gp41 and freeze a transient fusion intermediate from progressing into the six-helix bundle structure, thus blocking viral entry. One of the first and most intensively characterized members of the fusion inhibitor group is the T20 fusion inhibitor. T20 (also called DP178, enfuvirtide, pentafuside, fuzeon) is a synthetic 36 amino acid peptide homologous to the C-terminal region of HR2 (amino acid positions 127-162). By competitively binding to the HR1 sequence in the gp41 pre-hairpin structure, T20 blocks the formation of the six-helix bundle structure that is necessary for membrane fusion and viral entry.

See the HIV-1 entry process and T20 action in this short flash movie.

More excellent short movies on HIV-1 entry and fusion inhibitors at www.trimeris.com

Find a lot of HIV research literater at Chris Baldwin's personal blog.

Relevant publications

Baldwin CE, Sanders RW and Berkhout B. Inhibiting HIV-1 entry with fusion inhibitors. Current Medical Cemistry, 2003, Sep;10(17):1633-42.

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