PHOSPHORYLATION-DEPENDENT HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INFECTION AND NUCLEAR TARGETING OF VIRAL-DNA

In the replication of human immunodeficiency virus type 1 (HIV-1), gag MA (matrix), a major structural protein of the virus, carries out opp osing targeting functions. During virus assembly, gag MA is cotranslat ionally myristoylated, a modification required for membrane targeting of gag polyproteins. During virus infection, however, gag MA, by virtu e of a nuclear targeting signal at its N terminus, facilitates the nuc lear localization of viral DNA and establishment of the provirus, We n ow show that phosphorylation of gag MA on tyrosine and serine prior to and during virus infection facilitates its dissociation from the memb rane, thus allowing it to translocate to the nucleus. Inhibition of ga g MA phosphorylation either on tyrosine or on serine prevents gag MA-m ediated nuclear targeting of viral nucleic acids and impairs virus inf ectivity. The requirement for gag MA phosphorylation in; virus infecti on is underscored by our finding that a serine/threonine kinase is ass ociated with virions of HIV-1. These results reveal a novel level of r egulation of primate lentivirus infectivity.