Poster Presentation The 43rd Lorne Conference on Protein Structure and Function 2018

The inositol phosphate IP6 coordinates electrostatic pores to stabilise the HIV capsid and promote encapsidated DNA synthesis (#182)

Donna L Mallery 1 , Chantal L Marquez 2 , William A McEwan 1 , Claire F Dickson 1 , David A Jacques 2 , Greg J Towers 3 , Adolfo Saiardi 4 , Till Boecking 2 , Leo C James 1
  1. MRC Laboratory of Molecular Biology, Cambridge, CAMBRIDGESHIRE, United Kingdom
  2. University of New South Wales, Sydney, NSW, Australia
  3. University College, London, London, United Kingdom
  4. MRC Laboratory of Molecular Cell Biology, London, United Kingdom

The HIV capsid is semi-permeable and covered in electropositive pores that are essential for infection. We have shown that cellular polyanions bind these pores, increasing viral stability from minutes to hours and allowing the accumulation of newly synthesised DNA inside the capsid. An arginine ring inside the pore attracts polyanions and does not discriminate between ribo and deoxyribo nucleotides. However, excess ATP does not inhibit encapsidated DNA synthesis but promotes it by stabilising the capsid. Maximal capsid stabilisation and encapsidated DNA accumulation is achieved by the immature lattice assembly ligand inositol hexakisphosphate (IP6), which is > 100-fold more potent than ATP. Single molecule measurements demonstrate that IP6 is sufficient to prevent HIV virions from rapidly and spontaneously uncoating. We have also shown that IP6 is specifically incorporated into newly synthesised virions, suggesting that IP6 could serve as a ‘pocket factor’ analogous to picornaviruses, allowing HIV to regulate capsid uncoating and promote infection.