Importance Of Lentiviral Integration Into The Host Genome

Retroviral integration into the host genome is not random and varies dramatically across genera. Lentiviral HIV-1 has been shown to exhibit strong integration site preferences within active gene units, whereas gammaretroviral MLV exhibits a strong preference for enhancers and transcription start sites (Lewinski et al., 2006; Schrà ¶der et al., 2002; Wu et al., 2003). These biases have been attributed to interaction of IN in the context of the pre-integration complex with their cognate host cell factors (Craigie and Bushman, 2014; Debyser et al., 2015; Kvaratskhelia et al., 2014). For example, cellular chromatin associated protein lens epithelial-derived growth factor (LEDGF/p75) interacts with HIV-1 IN and directs lentiviral integration†¦show more content†¦Alpharetroviruses such as ALV exhibit a distinct integration pattern with seemingly random distribution of integration sites throughout chromatin and with only a slight preference for integrating into gene regions (Barr et al., 2005; Mitchell et al., 2004; Narezkina et al., 2004; Withers-Ward et al., 1994). To understand how ALV integration is regulated by host cellular factors, we have performed affinity capture of the ALV IN protein followed by mass spectrometry (MS)-based proteomics experiments to identify protein binding partners. Using this approach we identified structure specific recognition protein 1 (SSRP1) and suppressor of Ty 16 (Spt16), the components of the heterodimeric FACT (facilitates chromatin transcription) complex (Orphanides et al., 1999), as the top protein hits that specifically bound to ALV but not HIV-1 IN. The FACT complex is a highly conserved general histone chaperone protein that is essential for transcription and DNA replication (Abe et al., 2011; Belotserkovskaya and Reinberg, 2004; Orphanides et al., 1998). The complex has also been shown to play important roles in DNA damage responses, centromere deposition, recombination and DNA methylation (Ikeda et al., 2011; Kumari et al., 2009; Okada et al., 2009; Oliveira et al., 2014). The FACT complex is thought to destabilizeShow MoreRelatedStem Cell Gene Therapy Essay903 Words   |  4 Pagestherapy has emerged as an alternative therapeutic option. However, there have been concerns regarding the treatment’s long term safety due to the high occurrence of insertional mutations leading to activation of proto-oncogenes caused by random integration of retroviral vectors (1). The study conducted by Braun et al. showed that although hematopoietic stem cell gene therapy for WAS is a feasible and effective therapeutic option, the use of -retroviral vectors comes with a substantial risk of leukemogenesisRead MoreEssay about Priotities of Gene Therapy2802 Words   |  12 Pagesthe effect of these investments, a special panel was set up by the National Institute of Health. Report and recommendations of the panel released in December 1995 summarized the recent progress of research in gene therapy. It also stated that the importance of this research for clinical medicine has been greatly overestimated by the scientists and industry, and further exaggerated by scientific press and mass media. According to the report, scientific evidence of consistent improvement in patients