PROTEOLYTIC REFOLDING OF THE HIV-1 CAPSID PROTEIN AMINO-TERMINUS FACILITATES VIRAL CORE ASSEMBLY

After budding, the human immunodeficiency virus (HIV) must 'mature' in to an infectious viral particle, Viral maturation requires proteolytic processing of the Gag polyprotein at the matrix-capsid junction, whic h liberates the capsid (CA) domain to condense from the spherical prot ein coat of the immature virus into the conical core of the mature vir us, We propose that upon proteolysis, the amino-terminal end of the ca psid refolds into a beta-hairpin/helix structure that is stabilized by formation of a salt bridge between the processed amino-terminus (Pro1 ) and a highly conserved aspartate residue (Asp51), The refolded amino -terminus then creates a new CA-CA interface that is essential for ass embling the condensed conical core, Consistent with this model, we fou nd that recombinant capsid proteins with as few as four matrix residue s fused to their amino-termini formed spheres in vitro, but that remov ing these residues refolded the capsid amino-terminus and redirected p rotein assembly from spheres to cylinders, Moreover, point mutations t hroughout the putative CA-CA interface blocked capsid assembly in vitr o, core assembly in vivo and viral infectivity, Disruption of the cons erved amino-terminal capsid salt bridge also abolished the infectivity of Moloney murine leukemia viral particles, suggesting that lenti- an d onco-viruses mature via analogous pathways.