Retroviruses and retroelements in diseases and in gene therapy: 15 years later

Having an insight into the molecular events governing the central process of retrovirus replication cycle represented by reverse transcription, the question of site specificity of retrovirus DNA integration became the focus of interest. In order to introduce the process of retrovirus integration the main steps involved in its realization are briefly summarized (see Figure 1) Viral DNA synthesized by reverse transcription is recessed at both ends constituted of long terminal repeats (LTR). Such cleavage leads to the formation of CA dinucleotide overhangs. The next step is accomplished by staggered nick on host DNA and joining 3' recessed ends of viral DNA with 5' end nucleotides of host cell DNA. The non-complementary dinucleotides AA from the 5' ends of viral DNA are then removed and the gaps between protruding 5' ends of cleaved host cell DNA are filled by DNA repair leading to formation of several nucleotide repeats flanking the integrated provirus [1].At present, new knowledge about the interaction of viral integrase with viral DNA has been obtained using protein crystallography (for references see Li et al., 2011)[2]. Integrase acts as a tetramer and engages both viral DNA ends. It triggers formation of recessed end joining of 3' end of viral with 5' end of cell DNA. These activities depend on a series of cellular factors; one of them, the lens epithelium-derived growth factor (LEDGF), targets HIV DNA, preferentially at active transcription units. LEGDF acts as an adaptor equipped with integrase and chromatin-binding domains. The latter can be substituted with sequences binding other proteins which lead to preferential provirus targeting to selected genome regions [3]. Further knowledge of processes deciding about provirus positioning in the cell genome will undoubtedly contribute to designing of safe retroviral vectors.There are clear differences in the affinity of retroviruses to certain cell genomic regions. ALU/ASV tend to integrate in GC-rich, preferentiall