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Integrase Inhibitors: The Latest Lethal Hit to HIV
Integration, along with retrotranscription or reverse transcription, is a hallmark feature of the retroviridae family to which human T-cell leukaemia viruses (HTLV)-I and –II and HIV-1 and 2, the causative agents of AIDS, belong. Integration is required for stable maintenance of the viral genome as well as for efficient viral gene expression and replication. The life-cycle of HIV consists of several stages, briefly summarized as follows: entry, uncoating, retrotranscription, nuclear translocation, integration, transcription, translation, polyprotein cleavage, virion assembly, budding and maturation.
Several of these stages have been recognized as therapeutic intervention targets for a long time. The first drugs targeted reverse transcription (nucleoside reverse transcriptase inhibitor [NRTIs]) and were followed by those that targeted viral polyprotein cleavage (protease inhibitors [PIs]) and reverse transcription again, but with a different mechanism (non-nucleoside reverse transcriptase inhibitors [NNRTIs]). More recently antiretroviral drugs that counteracted viral entry ([EIs]) at two different phases were developed, such as fusion and CCR5 inhibitors. Finally, also integration inhibitors (INI) have been developed and are in clinical use.
The availability of several drugs aiming at different targets of the same pathogen allowed the concept and accomplishment of combination therapy, or HAART (highly active antiretroviral therapy), which soon proved to be extremely efficacious, resulting in a sharp drop in AIDS-related morbidity and mortality accompanied by profound and sustained viral suppression.
In about two decades and a half antiretroviral therapy has evolved from monotherapy to regimens containing at least three drugs in various combinations.
We will here focus on the last drugs joining the complex HIV antiretroviral armamentarium: the integrase inhibitors.
