A role for LEDGF/p75 in targeting HIV DNA integration

Abstract

HIV DNA integration is favored in active genes, but the underlying mechanism is unclear. Cellular lens epithelium-derived growth factor (LEDGF/p75) binds both chromosomal DNA and HIV integrase, and might therefore direct integration by a tethering interaction. We analyzed HIV integration in cells depleted for LEDGF/p75, and found that integration was (i) less frequent in transcription units, (ii) less frequent in genes regulated by LEDGF/p75 and (iii) more frequent in GC-rich DNA. LEDGF is thus the first example of a cellular protein controlling the location of HIV integration in human cells.

Integrase, LEDGF/p75 and HIV replication

“…This functional assignment remains provisional since little subsequent work on the transcriptional role of either protein has followed. Transcriptional profiling in p75-deficient human cells revealed significant global changes (approximately 1000 mRNAs changed significantly in each direction) but Gene Ontology annotation did not suggest regulation of a coherent developmental or physiological program [85]. In −/− mouse embryonic fibroblasts (MEFs) fewer genes were up-or down-regulated (< 200) and, again, a particular transcriptional network was not identified [101].…”

“…Studies focused on other biological questions have implicated p75 in modulating apoptosis and other cellular responses to stress and have suggested a role as an auto-antigen in certain disease states [66][67][68][70][71][72]84,107]. However, p75 depletion does not disproportionately alter stress-responsive gene transcription, nor does HIV appear to preferentially target such genes [85,101,110].…”

“…Knockout mice feed poorly in the perinatal period, leading to some mortality, but survivors display mild skeletal and neurobehavioral abnormalities and the derived MEFs grow normally [94]. In addition, stable knockdown is well tolerated in human cell lines, so far producing no discernible differences in growth rates, morphology or phenotypes other than lentivirus susceptibility [75,80,85,95,96,110].…”

“…The interaction between p75 and IN is direct [73] and it is confined to only one of the seven retroviral genera, lentivirinae [75,87,100]. A number of laboratories established the role of p75 in chromatin tethering, mapped relevant functional domains, and worked to answer the question of virological relevance [74][75][76][77][78][79][80][81][82][85][86][87][88][89][90][91]93,[95][96][97][100][101][102][103][104][105][108][109][110]. The first indication of the protein's significance was the clarification it provided about the vexing issue of the intracellular trafficking of retroviral integrase proteins.…”

“…Lentiviral integration sites have an average G/C content significantly lower than other retroviruses, an observation that stands in intriguing paradox to the overall tendency to integrate into transcription units, which are in general G/C-rich [136]. It can be reasonably speculated that the p75 AT hook pair participates in this relative A/T targeting, since an increase in HIV integration into G/C-rich regions of chromatin has been seen repeatedly in p75-deficient cells [85,101,110].…”