Multimerization of HIV-1 integrase hinges on conserved SH3-docking platforms

Meytal Galilee; Akram Alian

In the absence of a curative treatment, the highly active antiretroviral therapy (HAART) keeps the HIV-1 virus of AIDS patients under control. HAART combines drugs targeting different stages of viral replication including the integration step catalyzed by the integrase protein (IN) (1) . Integration of viral DNA into host genome involves two steps catalyzed by IN: (i) cleavage of a dinucleotide from each 3'-end of the viral DNA (3'processing), and (ii) insertion of this processed viral DNA into the host DNA (strand-transfer) (2) . Clinical IN strand transfer inhibitors (INSTIs) target the catalytic site of the enzyme to specifically inhibit the DNA joining reaction, however, as with all anti-AIDS treatments, the continued success of these drugs is persistently disrupted by resistance mutations (1, 2) . Although 3'-processing can be carried out by monomeric IN (3) , the assembly of IN functional multimers is imperative for the strand-transfer activity (4) (5) (6) (7) (8) , and for virus particle maturation and production (reviewed in (9, 10) ). In the continued quest to identify and develop new drugs, allosteric inhibitors that bind sites outside the catalytic core and disrupt IN multimerization are emerging with potent therapeutic potential (11) (12) (13) (14) .