Blocking Nuclear Import of Pre-Integration Complex: An Emerging Anti-HIV-1 Drug Discovery Paradigm

Although recent progress in highly active antiretroviral therapy (HAART) has provided an effective way to treat AIDS patients, the emergence of drug-resistant HIV-1 strains and drug toxicity during long-term treatment of HIVinfected patients necessitate the search for new targets that can be used to develop novel antiviral agents. One such target is the nuclear import process of the HIV pre-integration complex (PIC). The ability of HIV-1 using host cell nuclear import machinery to translocate the viral PIC into the cell nucleus is the critical determinant in the replication of the virus in non-dividing cells, such as macrophages. Compounds inhibiting HIV-1 nuclear import may be attractive candidates for novel anti-HIV development. In this review, we will describe the mechanisms of HIV-1 PIC translocation into the nucleus and the structure-function of the viral and cellular factors involved in this process, as well as several classes of novel anti- HIV compounds which target the nuclear import of HIV-1 PIC and effectively block viral replication.