The karyophilic properties of human immunodeficiency virus type 1 integrase are not required for nuclear import of proviral DNA

Integrase (IN) is a key component of the preintegration nucleoprotein compl ex (PIC), which transports the retroviral genome from the cytoplasm to the nucleus of newly infected cells. Retroviral IN proteins have intrinsic kary ophilic properties, which for human immunodeficiency virus type I (HIV-I) a re currently attributed to regions that display sequence homology to previo usly characterized nuclear localization signals. We asked here whether the karyophilic properties of HIV-1 IN are involved in the nuclear import of PI G. We mutated three conserved basic regions in the C-terminal domain of IN and analyzed the effects of mutations on subcellular localization of the pr otein, viral particle composition, IN dimerization within virions, and infe ctivity. Alteration of two sequences caused the loss of nuclear accumulatio n of IN and drastically reduced the capacity of the protein to multimerize. Mutation of the most C-terminal sequence had no effect on the subcellular localization and dimerization of IN. Nevertheless, conservation of all thre e sequences was required for viral infectivity, Despite the perturbation of IN subcellular localization, all mutant viruses displayed normal reverse t ranscription and nuclear transport of PICs in newly infected cells. The rep licative defect was instead at the level of integration, for which all muta nts were markedly affected in vivo. Besides reinforcing the association bet ween dimerization of IN and nuclear accumulation of the enzyme, our data de monstrate that subcellular localization of IN alone cannot predict the fate of the PICs.