HIV-I INFECTION OF NONDIVIDING CELLS - C-TERMINAL TYROSINE PHOSPHORYLATION OF THE VIRAL MATRIX PROTEIN IS A KEY REGULATOR

The HIV-1 matrix (MA) protein contains two subcellular localization si gnals with opposing effects. A myristoylated N-terminus governs partic le assembly at the plasma membrane, and a nucleophilic motif facilitat es import of the viral preintegration complex into the nucleus of nond ividing cells. Here, we show that myristoylation acts as the MA domina nt targeting signal in HIV-1 producer cells. During virus assembly, a subset of MA is phosphorylated on the C-terminal tyrosine by a virion- associated cellular protein kinase. Tyrosine-phosphorylated MA is then preferentially transported to the nucleus of target cells. An MA tyro sine mutant virus grows normally in dividing cells, but is blocked for nuclear import in terminally differentiated macrophages. MA tyrosine phosphorylation thus reveals the karyophilic properties of this protei n within the HIV-1 preintegration complex, thereby playing a critical role for infection of nondividing cells.