A novel nuclear export activity in HIV-1 matrix protein required for viralreplication

An important aspect of the pathophysiology of human immunodeficiency virus type-1 (HIV-1) infection is the ability of the virus to replicate in non-di viding cells(1-3). HIV-1 matrix (MA), the amino-terminal domain of the Pr55 gag polyprotein (Pr55), bears a nuclear localization signal that promotes localization of the viral preintegration complex to the nucleus of non-divi ding cells following virus entry(3-5). However, late during infection, MA, as part of Pr55, directs unspliced viral RNA to the plasma membrane(6), the site of virus assembly. How MA can mediate these two opposing targeting fu nctions is not understood. Here we demonstrate that MA has a previously und escribed nuclear export activity. Although MA lacks the canonical leucine-r ich nuclear export signal, nuclear export is mediated through the conserved Crmlp pathway and functions in both mammalian cells and yeast. A mutation that disrupts the MA nuclear export signal (MA-M4) mislocalizes Pr55 and ge nomic viral RNA to the nucleus, thereby severely impairing viral replicatio n. Furthermore, we show that MA-M4 can act in a dominant-negative fashion t o mislocalize genomic viral RNA even in the presence of wild-type MA, We co nclude that the MA nuclear export signal is required to counteract the MA n uclear localization signal, thus ensuring the cytoplasmic availability of t he components required for virion assembly.