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

Abstract

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.

Pharmacological Inhibition of Feline Immunodeficiency Virus (FIV)

“…Both nuclear translocation and proviral DNA integration have been targets for novel antiretroviral therapy (Figure 1, step 4). Studies targeted to these processes have focused on HIV, but may also be applicable to other retroviruses, including FIV [65]. Protein trafficking from the cytoplasm to the nucleus of eukaryotic cells occurs in either passive or active mode.…”

“…By occupying the NLS, CNI-H0294 blocks the interaction of cellular importins with PIC, and prevents nuclear translocation [70]. More recently identified compounds mimic the NLS of MA and by binding to importin α, prevent its interaction with MA [65]. Another novel anti-HIV compound blocked interaction of Vpr with importin α, which prevented HIV replication in primary macrophages [71].…”

“…Retroviral IN catalyzes the integration of retroviral dsDNA into the host cell genome and interacts with PIC, making it an ideal target for two-site interference by antiretroviral compounds [65,72]. Integrase inhibitors are designed to either foil enzyme activity and therefore viral dsDNA integration, or to prevent formation of the PIC by interfering with the interaction of IN with cellular factors [65].…”

“…Integrase inhibitors are designed to either foil enzyme activity and therefore viral dsDNA integration, or to prevent formation of the PIC by interfering with the interaction of IN with cellular factors [65]. Transcriptional co-activator p75 (or lens epithelium-derived growth factor, LEDGF) is a cellular protein that not only plays a crucial role as a functional component of the PIC, but also facilitates IN interaction with nuclear chromatin at integration sites after nuclear transport [73].…”

Strategies to inhibit viral protein nuclear import: HIV-1 as a target

“…In this review, we will describe the current state of our understanding of the interactions regulating nuclear import of the HIV-1 pre-integration complex (PIC) and HIV-1 proteins critical for viral replication, focusing on potential targets for therapeutic interventions. In contrast to a recent article by Zhan et al [111] covering similar topics, we will attempt to provide a critical analysis of the published data.…”