Nuclear Import of the Pre-Integration Complex (PIC): The Achilles Heel of HIV ?

Abstract

Current treatments against the Aquired immune deficiency syndrome (AIDS) are reasonably effective in reducing the amount of human immunodeficiency virus (HIV) present in infected patients, but their side-effects, and the emergence of drug-resistant HIV strains have intensified the renewed search for novel anti-HIV therapies. An essential step in HIV infection is the integration of the viral genome into the host cell chromosomes within the nucleus. Unlike other retroviruses, HIV can transport its genetic material, in the form of the large nucleoprotein pre-integration complex (PIC), into the nucleus through the intact nuclear envelope (NE). This enables HIV to infect non-dividing cells such as macrophages and microglial cells. Detailed knowledge of the signal-dependent pathways by which cellular proteins and RNAs cross the NE has accumulated in the past decade, but although several different components of the PIC have been implicated in its nuclear import, the mechanism of nuclear entry remains unclear. Since specifically inhibiting PIC nuclear import would undoubtedly block HIV infection in non-dividing cells, this critical step of HIV replication is of great interest as a drug target. This review examines the complex and controversial literature regarding three PIC components--the HIV proteins matrix, integrase and Vpr--proposed to facilitate PIC nuclear import, and existing models of HIV PIC nuclear import. It also suggests approaches to move towards a better understanding of PIC nuclear import, through examining the role of individual PIC components in the context of the intact PIC by direct visualisation, in order to develop new anti-HIV therapeutics.

The HIV-1 Integrase Mutant R263A/K264A Is 2-fold Defective for TRN-SR2 Binding and Viral Nuclear Import

“…Following reverse transcription, the preintegration complex (PIC) 5 composed of the viral DNA and a complex of viral and cellular proteins crosses the nuclear membrane via active nuclear import through the nucleopore (3). Nuclear entry precedes provirus establishment through stable insertion of the viral DNA into the host chromatin as catalyzed by HIV-1 integrase (IN) and constitutes a genuine bottleneck during HIV replication (4). As such, it represents an interesting, yet unexploited target for antiviral therapy.…”

Gene Therapy Progress and Prospects: Viral trafficking during infection

“…These have been reviewed extensively elsewhere. 25,26 Briefly, convincing arguments have been made that the nuclear import activity of the PIC is mediated by the viral matrix, Vpr, integrase proteins and a DNA element formed during reverse transcription known as the central DNA flap. There remains a lack of consensus as to which, if any, of these elements are the primary determinant governing nuclear import of the PIC, and it may be that these elements act in a synergistic fashion in many settings.…”

The HIV‐1 Tat Transactivator Protein: a Therapeutic Target?

“…The HIV replication cycle begins and ends with a virion, the process mediated by HIV-1-encoded gene products in conjunction with host cell factors (2,5). The mature HIV virion displays surface (SU) proteins which bind with high affinity (K d *4 nM) to CD4, an immunoglobulin (Ig)-like protein expressed on the surface of particular T cells and primary macrophages.…”

“…The latter types of retroviruses can only replicate in dividing cells since they are unable to gain access to the nucleus except at mitosis when the nuclear envelope (NE) breaks down. In contrast, HIV-1 and other lentiviruses have the ability to replicate in non-dividing cells, because they are able to transport their genomes into the nucleus through the intact NE (2).…”