Figure 8

Model accounting for the discrepancy between the dual ARV activities of INLAIs at integration and post-integration. The full replication cycle of HIV is represented with steps occurring in target cells (1) separated from the steps occurring in virus-producing cells (2) by a red line. (1) Inhibitory activity at integration and competition by LEDGF in HIV-1 target cells. LEDGF is present as a chromatin-bound protein in the nucleus but is absent in the cytoplasm. After infection of target cells, IN associated with the entering virus (in blue) is imported into the nucleus as part of the pre-integration complex (PIC). Mut101 and INLAIs (yellow triangles) can bind to IN, inhibiting integration by allosteric inhibition of IN strand transfer activity and preventing IN-LEDGF complex formation. In the nucleus of target cells, LEDGF will compete with Mut101 and INLAIs for binding to IN, thus lowering their apparent affinity for IN and counteracting their antiretroviral activity at the integration stage of the replication cycle. (2) After integration, progeny virions are assembled in the cytoplasm and at the plasma membrane. INLAIs can bind to the Pol polyprotein precursor containing IN or to the matured IN, in the absence of competing LEDGF. Upon binding, these inhibitors promote conformational modification and enhancement of the IN-IN interaction resulting in IN inactivation (in red). Mut101 and INLAIs activity at the post-integration stage is stronger than their activity at integration as there is no competition with LEDGF in the cytoplasmic cellular compartment.