Role of phosphorylation in the nuclear biology of HIV-1.

The central events of HIV-1 life cycle occur at the nuclear level where the viral genome is integrated into the host cellular DNA in order to be expressed and replicated. The viral pre-integration complexes (PICs) are actively transported in the nuclear compartment where integration occurs in specific regions of the cellular chromatin. Similar to all viruses, HIV-1 encodes for a limited number of proteins that are insufficient to produce new viral progenies. Several cellular pathways are thus hijacked by HIV-1 to efficiently complete the replication cycle. The majority of viral proteins are substrates for cellular kinases indicating a pivotal role of these cellular enzymes at multiple steps of the HIV-1 life cycle. The nuclear biology of the cell is highly controlled by kinases (nuclear transport, DNA replication, repair and transcription) and many of these kinases also sustain the viral nuclear events. This review summarizes our current knowledge on kinases that are involved in HIV-1 replication cycle at the nuclear level, both directly through their catalytic activity on viral proteins and indirectly being activated by the virus. Among viral proteins directly modified by kinases is integrase (IN) the factor that catalyzes the integration of HIV-1 in the cellular genome. Notably, this recent discovery may shed light onto mechanisms underlying the different susceptibility of the main cell types targeted by HIV-1 (CD-4+ T-cell) depending on their activation status. Alternatively, kinases may act indirectly such as in the case of DNA repair factors activated following HIV-1 infection and demonstrated to regulate the viral life cycle. Finally, inhibition of cellular kinases interacting with HIV-1 at the nuclear level has been shown to severely affect the viral replication cycle, thus suggesting potential new therapeutic approaches.