A tale of two HIV-1 maturation inhibitors, bevirimat and PF-46396: insights into Gag assembly and virion maturation

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NCI	VIROL/MICRO-23

* FARE Award Winner

Authors

• K Waki
• A Kamata
• F Soheilian
• K Nagashima
• S Butler
• E O. Freed

Abstract

HIV-1 virion maturation is a promising target for antiviral therapy since it is a pivotal step in the formation of infectious virions. During maturation, the Gag precursor undergoes kinetically regulated processing by the viral protease, inducing morphological changes that form a conical core. Thus, the interruption of virion maturation disrupts the replication cycle. Bevirimat, the first-in-class HIV-1 maturation inhibitor, and a recently identified compound PF-46396 both block HIV-1 maturation by disrupting a late step in Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) processing intermediate to mature CA. Treatment with either compound induces the formation of aberrant cores and a significant loss of infectivity. Structural differences between the two compounds, however, suggest that they might occupy different binding pockets on assembled Gag, their presumed target. This hypothesis is supported by the finding that selections in PF-46396 and bevirimat identified different resistance mutations. PF-46396 resistance mutations were clustered in three regions of the CA and SP1. Intriguingly, a group of CA mutants displayed a striking compound-dependent phenotype. This study provides novel insights into the mechanism of action of HIV-1 maturation inhibitors, and the role of CA and SP1 in HIV-1 assembly and maturation.

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