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 HIV-infected 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.