We investigate the life cycle of retroelement, including human immunodeficiency virus type 1 (HIV-1), hepetitis B virus (HBV) and long interspersed element 1 (LINE-1, L1), and host factors involved in their life cycle. LINE-1 is a mobile genetic element comprising about 17% of the human genome. Indeed, we currently focus on the molecular mechanism(s) how these retroelements integrate in the human genome.
(1) DNA damage sensors/DNA repair machinery and retroements' integration
HIV-1 integration is an essential step for HIV-1 life cycle. We have investigated (1) how HIV-1 genome integrates into the human genome, (2) which host factor(s) is required for HIV-1 integration, (3) what happens after HIV-1 integration events, such as HIV-1-induced DNA damage and repair pathway or chromatin remodeling, (4) which host factor(s) determines the HIV-1 integration site. HIV-1 generates dsDNA after reverse transcription. Such HIV-1 dsDNA might be recognized by and activate DNA damage sensor such as ATM kinase. This may facilitate HIV-1 integration into the human genome. In addition, HIV-1 integration itself could induce dsDNA breaks in the human genome and activate the ATM signaling pathway resulting in recruitment of host DNA repair machinery. We have currently focused on Rad18 DNA repair protein, which is known to be an E3 ubiquitin ligase. Rad18 interacts with HIV-1 integrase.
(2) Cell bodies (P-body, Stress granule, PML-NBs.....) and viral infection
We have also interests in a role of host cellular bodies such as P-body, stress granules, and PML-nuclear bodies in viral infection. We have demonstrated for the first time that HCV hijacks the P-body and the stress granule components for HCV replication. In fact, HCV infection disrupted P-body formation of the microRNA effectors DDX3, DDX6, Lsm1, Xrn1, PATL1 and Ago2 and dynamically redistributed these microRNA effectors to the HCV production factory around lipid droplets. Notably, HCV infection also induced stress granules 36h post-infection, and then redistributed the stress granule components G3BP1, ataxin-2, and poly(A)-binding protein 1 (PABP1) to the HCV production factory around lipid droplets. Importantly, these P-body and stress granule components are required for the HCV life cycle (Ariumi et al, J Virol. 2011). We currently investigate the relationship between HIV-1 integration and nuclear body components.
(3) RNA helicases and viral life cycle
RNA helicase plays an important role in host mRNA and viral mRNA transcription, transport, and translation. So far, we have demonstrated that DDX3 and DDX6 DEAD-box RNA helicases are required for HCV replication (Ariumi et al. J Virol. 2007; Ariumi et al. J Virol. 2011). Many viruses utilize RNA helicases in their life cycle, while HIV-1 does not encode an RNA helicase. Thus, host RNA helicase has been involved in HIV-1 replication (Ariumi Y. Front Genet. 2014; Yasuda-Inoue et al. BBRC 2013a, b).