HIV ENV is a polyprotein precursor (gp160), which is processed by cellular proteases to give a non-covalent complex of an external glycoprotein (SU / gp120) and a transmembrane glycoprotein (TM / gp41).
Host endoproteases (including furin) cleave HIV Env
polyprotein in the highly conserved domain at the carboxy terminus, consisting of residues:
[see GUAVAh Furin interaction profile].
Viral entry describes a complex process that involves various steps, including the fusion of the viral membrane to the host cellular membrane.
Currently, there is only one fusion inhibitor that has been approved for HIV treatment, Enfuviritide.
This 36 amino acid polypeptide binds to the haptad repeat (HR) regions of the gp41 viral protein and engages in a coil-coil interaction.
This interaction prevents the virus particle from attaching to the host cell membrane and thus, prevents the entry and infection of HIV.
Drug Resistance Mutations:
D, E, V, S
G36D/E mutations are associated with a large decrease in Enfuviritide susceptibility (>10 fold).
E, A, M, G
V38E/A mutations are associated with a large decrease in Enfuviritide susceptibility (>10 fold).
Mutation is associated with a large decrease in Enfuviritide susceptibility (>10 fold).
N42S occurs in ~15% of viruses from Enfuviritide-naive patients and does not decrease drug susceptibility.
D, K, S
N43D mutation is associated with a large decrease in Enfuviritide susceptibility (>10 fold).
9 - Characterization of envelope glycoprotein gp41 genotype and phenotypic susceptibility to enfuvirtide at baseline and on treatment in the phase III clinical trials TORO-1 and TORO-2.
Melby T, Sista P, DeMasi R, Kirkland T, Roberts N, Salgo M, Heilek-Snyder G, Cammack N, Matthews TJ, Greenberg ML.
AIDS Res Hum Retroviruses 22(5):375-85 (2006) [pubmed: 16706613]
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