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Targeting HIV-1 DNA integration by swapping tethers

Retroviruses replicate by integrating a DNA copy of their genome into cellular DNA (1). The integrated DNA is replicated along with cellular DNA during each cell-division cycle and is the template for transcription of RNAs required for production of progeny virus. DNA integration is mediated by the virally encoded integrase enzyme and occurs at essentially any location in the host DNA, but each group of retroviruses exhibits distinct regional preferences (2). For example, HIV-1 and closely related retroviruses called lentiviruses preferentially integrate in active transcription units. The mechanistic basis of the target-site preference of HIV-1 DNA integration is not well understood, but studies suggest that a cellular protein called lens epithelium-derived growth factor (LEDGF) plays a key role (3). LEDGF binds to both HIV-1 integrase and chromatin, and in a popular model, it tethers the viral integration machinery to chromatin (4). In this issue of PNAS, Ferris et al. (5) provide strong support for this model and show that the targeting preference of HIV-1 can be changed simply by swapping the chromatin-binding domain (CBD) of LEDGF.