16th International HIV Drug Resistance Workshop 12-16 June 2007, Barbados

ROLE OF GAG POLYPROTEINS AND PROTEOLYSIS IN HIV ASSEMBLY AND MATURATION

Antivir Ther. 2007; 12:P4 (abstract no. P2)

H-G Kräusslich
University Heidelberg, Heidelberg, Germany

HIV assembly is driven by the structural polyprotein Gag which consists of four globular domains and several intervening peptides. In the budding process, Gag layers associate with the plasma membrane of the infected cell in a perpendicular orientation giving a hexagonal arrangement with the N-terminal matrix (MA) domain closely apposed to the lipid bilayer. Once severed from the cell, Gag polyproteins are cleaved in the extracellular virion in an ordered manner leading to a morphological rearrangement giving the condensed cone-shaped core of the mature, infectious virion that is required for infectivity. The immature Gag shell is a stable structure that remains largely intact upon stripping of the lipid envelope and proteolytic maturation is essential for successful uncoating to occur. Proteolysis proceeds in an ordered manner where removal of the C-terminal NC-p6 segment of Gag permits condensation of the inner ribonucleoprotein core, cleavage between MA and the capsid (CA) domain removes the CA layer from its membrane-apposed position and allows refolding of the CA N-terminus, and cleavage of a small peptide at the C-terminus leads to dissociation of the CA layer followed by a second assembly step which yields the mature structure. Resistance mutations may affect the efficiency of polyprotein processing and thus alter virion maturation and infectivity. Besides mutations in PR, this may also affect the Gag polyprotein itself, where subtle changes may influence both processing at the local site as well as overall Gag processing. Besides inhibitors of PR, maturation is also affected by the new compound bevirimat which is likely to lock the virus in the maturation process prior to disassembly of the CA layer.

2007-06-12
P2

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