{'fraction_non_alphanumeric': 0.026277372262773723, 'fraction_numerical': 0.006812652068126521, 'mean_word_length': 5.249240121580547, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
The ups and downs of gene expression and retroviral DNA integration.

Unique among animal viruses, retroviral replication proceeds through an obligate recombination step with host cell DNA. Although this step makes it extremely difficult to eradicate a retrovirus from a cell, it also confers a desirable trait to gene therapy vectors. Yet stable integration can yield unwanted side effects, as highlighted in a recent gene therapy trial in which 2 of 11 patients developed leukemia-like illness because of the integration of a murine leukemia virus (MLV)-based vector in the vicinity of the LMO2 protooncogene (1). Deciphering the mechanism(s) of integration site selection not only will shed light on a basic step(s) in retroviral biology but also holds promise for the design of more effective vectors. Although different cloning strategies have indicated an overall preference for transcription units, the mechanism of retroviral integration site selection is for the most part unknown. In this issue of PNAS, Maxfield et al . (2) assayed RAV-1 (a subgroup A Alpharetrovirus ) integration into the quail metallothionein (MT) gene with and without transcriptional activation. A 100-fold increase in gene expression reduced integration 6-fold. Taken alongside a previous study that demonstrated that more modest levels of induction also inhibited integration (3), the active transcription complex appears unlikely to help guide retroviruses to their sites of integration.

Retroviruses encode their own integrase (IN) protein that is carried into the cell as part of the virus. After reverse transcription the viral cDNA, IN and other proteins comprise an integration-competent nucleoprotein complex known as the preintegration complex (PIC) (reviewed in ref. 4). Early studies indicated that transcriptionally active and/or DNase I-hypersensitive regions were preferred sites, but it was unclear to what extent relatively small sample size and the selective outgrowth of certain integrants before cloning may have influenced those results (see ref. 5 …