Role of Phosphorylation in the Nuclear Biology of HIV-1

Abstract

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.

Overlapping Regions in HIV-1 Genome Act as Potential Sites for Host–Virus Interaction

“…Precisely, among the different PTMs that take place in vivo , PP is one of the most important and well studied types of PTM. In previous works, PP has been shown to play a pivotal role in HIV-1 interactome (Francis et al, 2011). Therefore, we were interested in exploring the role of gene overlapping in effecting PP across the protein length.…”

“…Previously, there has been range of studies focusing on the role of PP in the development of productive infection cycle by viruses within their host (Keck et al, 2015). PPs of HIV-1 proteins have been found to be associated with nuclear transport, replication, repair, and transcription (Idriss et al, 1999; Francis et al, 2011; Kudoh et al, 2014). For instance, HIV-1 integrase has been shown to be directly phosphorylated by host kinases in order to integrate into the host genome efficiently (Manganaro et al, 2010).…”

A Cell-Intrinsic Inhibitor of HIV-1 Reverse Transcription in CD4+ T Cells from Elite Controllers

“…HIV-1 gene products can represent direct targets for phosphorylation by host kinases (Francis et al, 2011). We hypothesized that CDK2 can support HIV-1 reverse transcription through phosphorylation of HIV-1 reverse transcriptase (RT).…”

HIV Integrase Inhibitors

“…A parallel can be drawn between retroviral integration and Mu transposition (Mizuuchi & Craigie, 1986). IN posttranslational modifications include phosphorylation and acetylation (Cereseto et al, 2005;Francis, Di Primio, Allouch, & Cereseto, 2011;Manganaro et al, 2010;Terreni et al, 2010). IN posttranslational modifications include phosphorylation and acetylation (Cereseto et al, 2005;Francis, Di Primio, Allouch, & Cereseto, 2011;Manganaro et al, 2010;Terreni et al, 2010).…”