Ighly important for the outcome of the infection. Integration into a
Ighly important for the outcome of the infection. Integration into a region of active transcription promotes viral gene expression, whereas integration into transcriptionally repressed PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/27906190 chromatin could potentially promote viral latency [21-23]. If HIV-1 DNA is integrated into actively transcribed genes, the viral genes would need to be repressed to allow persistence of the infection. The mechanisms that control viral gene expression are not yet understood fully. Several factors are involved in the infection of latent and resting cells and in the preferential integration found at the periphery of the nucleus in such latent T cells [24-26]. On theother hand, for the host, integration events can lead to the activation of proto-oncogenes or the inactivation of essential cellular genes [27]. For all these reasons it appears essential to elucidate the molecular mechanisms governing integration site selection to set up safe and efficient gene therapy approaches. To this end, genome-wide studies have been undertaken and have revealed that Necrosulfonamide web retroviruses target different regions of the host chromatin. These studies have shown that some members of the Spumaretrovirus and Gammaretrovirus families favor transcription start sites of actively transcribed genes (TSSs) PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/26024392 and CpG islands, the Lentiviruses that have been studied integrate preferentially into active transcription units (TUs), the Alpha?and Deltaretroviruses tested exhibit only a weak preference for TUs, and some Betaretroviruses integrate in an almost random fashion (reviewed in [28]). Globally, retroviruses can thus be classified into three separate categories: those that preferentially target TSSs and CpG islands, those that display a strong bias toward integration into TUs and those that exhibit little or no particular preference for any chromosomal feature. Interestingly these three groups comprise viruses that share the same target site duplication signature as mentioned above. This raises the question of the relationship between these genomic signatures, closely linked to intasome structures and target DNA bending, and integration selectivity. HIV-1 and MLV integration site preferences have been shown to rely essentially on the interaction of IN with specific host cell factors – i.e. lens epithelium-derived growth factor (LEDGF/p75) (see [29] for a review) and bromodomain and extraterminal domain (BET) proteins [30,31], respectively – that recognize defined transcription-associated histone modifications. On the other hand, cellular data obtained from a murine LEDGF/p75 knock-out (KO) model have shown that LEDGF/p75 was not involved in the local target DNA sequence preference associated with HIV-1 integration [32-34]. Thus, despite its ability to bind histone tails through its PWWP domain [35], LEDGF/ p75 is unlikely the sole protein responsible for targeting integration into nucleosomal DNA which may require additional intasome/nucleosome interactions and/or chromatinremodeling activities [36]. Recently it has been shown that dissociating the interaction between MLV integrase and BET proteins did not change the local integration site sequence selection [37]. Furthermore, in the lack of LEDGF/p75, the local HIV-1 integration sequence selectivity was also shown unchanged [38,39]. Taken together all these data suggest that integrase protein plays a role in the local targeting to the nucleosomal locus after targeting of the intasome into suitable regions of the chromatin thanks to its intera.