The matrix protein (MA) of HIV-1 is initially synthesised as the N-terminal domain of the main structural polyprotein Gag, and recruits Gag to the plasma membrane for virus assembly. Upon virus release, Gag is cleaved by the viral protease to cause maturation: the capsid and nucleocapsid rearrange within the virion while MA remains associated with the virus membrane. We recently determined the structure of MA within immature virus particles where Gag is intact, and within mature virus where Gag has been cleaved. MA forms a hexameric lattice in both particles, but unexpectedly the structures of the two lattices, and their lipid interactions, are different. The known functions of MA are in virus assembly, but our observations imply that rearrangement of MA is associated with a change in virus properties, and that MA is likely to have a second, post-maturation function.
The viral envelope glycoproteins (Env) have been shown to redistribute upon maturation, and Gag cleavage is required for the virus particle to become fusogenic. We will ask whether MA maturation causes rearrangement of Env to make the virus infectious and therefore regulate viral fitness during membrane fusion, entry or even cell-to-cell spread.
How is MA maturation triggered? To identify the mechanism by which MA maturation is triggered, we will perform cryo-electron tomography to determine the structure of the MA layer in a series of virus mutants and in vitro.
Finally, does the mature form of MA promote infection in the target cell? We will collaborate with Müller, Kräusslich and other groups in the SFB to monitor virus infection in the presence of mutations that alter MA maturation, to explore the influence of MA structure on infection.