Targeting the HIV integration process in antiviral therapy.

Summary

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LEADING ARTICLE - Clinical report

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Targeting the HIV integration process in antiviral therapy.

INTRODUCTION

In the global fight against HIV/AIDS, it is important to utilise every weapon available. Current therapy includes an array of drugs inhibiting many different viral processes; inhibitors of reverse transcription, proteolytic maturation, fusion and entry have all been very effective in reducing HIV replication enough to prevent disease progression, especially when used in conjunction with highly active antiretroviral therapy (HAART). However, owing to the high mutation rate of the HIV reverse transcriptase, multiple drug-resistant strains continue to emerge, necessitating continuing searches for new drug targets.

The recent developments in drug discovery targeting viral integrase (IN) have been very promising. HIV IN is a crucial protein for HIV infection and is responsible for the insertion of the provirus into the human genome, permanently linking the viral genome to the host genome, a key part of viral replication. Gaps in scientific knowledge and difficulties in getting around certain biological characteristics have hindered development of IN inhibitors until recently. The successful introduction of the IN inhibitors, raltegravir and elvitegravir, in the clinic has demonstrated the effectiveness of targeting the integration process in antiviral therapy. However, the success of both compounds is somewhat confounded by the emergence of resistant strains.

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Protein-protein interactions (PPI) represent a relatively untapped and potentially rich source of therapeutic targets [1-3]. Recently, there have been significant advances in identification and validation of cellular co-factors involved in HIV infection, and cellular binding partners of HIV IN involved in both integration and nuclear import have been described [4-6]. It has become apparent that inhibition of IN function by interference with its cellular interaction partners would indeed represent a significant addition to the therapeutic arsenal.

INTEGRASE AND HIV REPLICATION

CURRENT ANTIRETROVIRAL THERAPY TARGETS VARIOUS STAGES OF THE HIV LIFE CYCLE

The HIV-1 replication cycle is initiated by the attachment of the viral envelope glycoprotein gp120 to the cellular CD4 receptor (Figure 1). The interaction of gp120 with CD4 triggers a conformational change in the gp120 molecule, allowing binding to the CXCR4 or CCR5 chemokine coreceptor. Another conformational change in the gp41 viral protein brings about fusion of the viral particle with the cellular membrane, which is then followed by viral uncoating. In the next step, reverse transcription of the positive RNA strand is initiated, during which the single-stranded RNA is copied into double-stranded cDNA. This will then be imported into the nucleus as a pre-integration complex (PIC). A...

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