Abstract
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.
Highlights
Despite a wealth of assays and data, HIV post-entry biology remains poorly understood
Before the virus can integrate its genes into the host genome, it must reverse transcribe its RNA into DNA, travel to the nucleus, remove its protective capsid and target actively transcribing chromatin
We have shown that HIV virions package IP6 when they bud from a producer cell, that IP6 coordinates the electrostatic pores in HIV hexamers and that IP6 dramatically increases capsid stability both intrinsically and during Encapsidated reverse transcription (ERT)
Summary
Despite a wealth of assays and data, HIV post-entry biology remains poorly understood. Before the virus can integrate its genes into the host genome, it must reverse transcribe its RNA into DNA, travel to the nucleus, remove its protective capsid (uncoating) and target actively transcribing chromatin. Reverse transcription (RT) is the first enzymatic step in infection and likely occurs as soon as the viral capsid enters the cytosol. Evidence suggests that it precedes all other processes including uncoating and nuclear import. Depletion of dynein (Fernandez et al, 2015) and kinesin one heavy chain (KIF5B) (Lukic et al, 2014), required for mechanical transport of viral cores to the nucleus, delays uncoating and nuclear entry but does not affect RT. Capsid mutants at cofactor interfaces largely phenocopy cofactor dependence, reinforcing this notion.
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