The role of matrix in HIV-1 envelope glycoprotein incorporation

Abstract

Incorporation of the viral envelope (Env) glycoprotein is a critical requirement for the production of infectious HIV-1 particles. It has long been appreciated that the matrix (MA) domain of the Gag polyprotein and the cytoplasmic tail of Env are central players in the process of Env incorporation, but the precise mechanisms have been elusive. A number of recent developments have thrown light on the contributions of both proteins, prompting a re-evaluation of the role of MA during Env incorporation. The two domains appear to play distinct but complementary roles, with the cytoplasmic tail of Env responsible for directing Env to the site of assembly and the matrix domain accommodating the cytoplasmic tail of Env in the Gag lattice.

Biochemical evidence of a role for matrix trimerization in HIV-1 envelope glycoprotein incorporation

“…Although the long CT is essential for Env incorporation into viral particles in physiologically relevant cell types, it also imposes packaging constraints: The Env CT must fit into the area below the viral membrane, which is also occupied by the MA domain of Gag. Various models have been suggested to explain the role of MA in Env incorporation (4,27,31); here we present data favoring a model of steric accommodation. Because the central aperture of the hexamer-the region implicated in Env incorporation (Introduction)-is distant from the trimer interface, it is unlikely that any putative MA-Env interaction would be directly affected by mutation of residues at the trimer interface.…”

“…Mutations have been identified in MA that prevent the incorporation of Env into particles (22)(23)(24)(25)(26). The majority of these mutations map to the tips of the MA trimer (27), a region of the protein that lies around the central aperture of the hexamer of trimers. These findings implicate this central aperture as the site of Env incorporation in the particle.…”

“…27). To test this hypothesis, we generated MA trimer-defective virus particles in the context of the gp41 truncation mutant CTdel144.…”

Single-amino acid mutation 66SR in Gag-matrix enhances viral single-cycle infectivity of R5-tropic HIV-1rmt

“…6C, while progeny virions of 4gtu and 5gtu were at similar levels, 66SR+ 5gtu produced those at a level reduced to around 40% to that of 5gtu. Gag-MA is demonstrated to fulfill its function at various steps in the HIV-1 assembly process (1,8,9). It is therefore conceivable that 66SR mutation in Gag-MA may negatively affect this stage.…”

“…CT (1,9). Recent study showed that Gag -MA mutations (62QR and 66SR) rescue defects in virion-incorporation of Env/viral replication caused by Gag-MA mutations or by gp41 CT deletion (10).…”