IP6 is an HIV pocket factor that prevents capsid collapse and promotes DNA synthesis

The HIV capsid is semipermeable and covered in electropositive pores that are essential for viral DNA synthesis and infection. Here, we show that these pores bind the abundant cellular polyanion IP₆, transforming viral stability from minutes to hours and allowing newly synthesised DNA to accumulate inside the capsid. An arginine ring within the pore coordinates IP₆, which strengthens capsid hexamers by almost 10°C. Single molecule measurements demonstrate that this renders native HIV capsids highly stable and protected from spontaneous collapse. Moreover, encapsidated reverse transcription assays reveal that, once stabilised by IP₆, the accumulation of new viral DNA inside the capsid increases >100 fold. Remarkably, isotopic labelling of inositol in virus-producing cells reveals that HIV selectively packages over 300 IP₆ molecules per infectious virion. We propose that HIV recruits IP₆ to regulate capsid stability and uncoating, analogous to picornavirus pocket factors. HIV-1/IP₆/capsid/co-factor/reverse transcription.