HIV-1 NUCLEAR IMPORT: IN SEARCH OF A LEADER

Michael I. Bukrinsky¹ and Omar K. Haffar²

1The Picower Institute for Medical Research, Manhasset, NY 11030, ²Cytokine Networks Inc., 101 Elliott Ave West, Suite 428, Seattle, WA 98119

Received 11/7/97 Accepted 11/14/97

6. SUMMARY AND CONCLUSIONS

Intensive research into the mechanisms of HIV nuclear import revealed new levels of complexity that could not be anticipated in the beginning. Nevertheless, recent findings provided reasonable explanations for the controversial observations regarding the role of various HIV proteins in the import process, and the hypothesis compatible with most published findings seems to have emerged. It appears that the HIV-1 PIC is a relatively weak karyophile driven to the nucleus via a karyopherin alphabeta-dependent pathway. Stable interaction between karyopherin alpha and the HIV-1 PIC is mediated by a coordinated action of Vpr and NLSs present on multiple copies of MA and IN. Using the automobile analogy, the NLS-containing proteins (MA and IN) constitute the engine that drives the complex to the nucleus, while Vpr is the computer that regulates the work of the engine. In the absence of Vpr, nuclear import of HIV is very inefficient, unless a cell has Vpr-substituting proteins. The nature of such proteins is unclear, but one of the possibilities is that they belong to a family of 70 kDa heat shock proteins (reviewed in (90)). On the other hand, without NLS-containing proteins, Vpr would not target the complex to the nucleus. The ultimate test of this hypothesis would be to eliminate all potential NLSs within the PIC, while leaving Vpr intact, although it is unlikely that such an experiment can be done, given a likely perturbation of other viral functions by such extensive mutagenesis.

However, it may be that a similar experiment has been already performed using a different approach. Indeed, bis(methyl ketone) compounds targeting the NLS have been shown to effectively block replication of Vpr⁺ HIV-1 strains (85). Since such compounds do not affect Vpr/karyopherin alphainteraction, this result suggests that functional NLSs are required for the Vpr activity. Although the MA NLS was proposed as a target for bis(methyl ketone) compounds (85,86), it may be that other NLSs within the pre-integration complex are also affected. A low-level residual nuclear import activity observed in the presence of these compounds (85,86) may reflect incomplete inactivation of the NLSs. Clearly, Vpr/karyopherin alpha interaction presents a good target for second generation inhibitors of HIV nuclear import.