HIVintegrasen

HIV integrase is an enzyme encoded by the pol gene of the human immunodeficiency virus (HIV) and is essential for viral replication. It catalyzes the integration of viral DNA, produced after reverse transcription, into the host cell genome, a central step in the viral life cycle.

The enzyme performs two catalytic reactions: 3' end processing, which trims the viral DNA ends, and strand transfer, which inserts the processed ends into host DNA. Both reactions require divalent metal ions, typically Mg2+ or Mn2+, at a conserved active site. HIV integrase functions as a multimer, often a dimer or tetramer, and forms nucleoprotein complexes called intasomes with viral DNA. The protein has three structural domains: an N-terminal domain with a zinc-binding HHCC motif important for multimerization, a central catalytic core domain containing the DDE catalytic triad, and a C-terminal DNA-binding domain.

In the host cell, integrase helps insert the proviral DNA into the genome, after which host transcription machinery converts it into viral RNAs and proteins. The activity and targeting of integration are influenced by host factors, notably LEDGF/p75, which tethers integrase to transcriptionally active regions of the genome.

Therapeutically, HIV integrase is a major target in antiretroviral therapy. Integrase strand transfer inhibitors (INSTIs) block the strand transfer step and are widely used in combination regimens. Approved INSTIs include raltegravir, elvitegravir, dolutegravir, bictegravir, and cabotegravir. Resistance can arise through mutations in the integrase gene, especially at positions such as N155, Q148, and Y143, sometimes with compensatory changes, leading to reduced drug susceptibility and cross-resistance.