Fig. 4. Pandemic-associated adaptation of HIV capsid at position 50.
a, Replication of HIV-1(M) NL4.3 (BalEnv) bearing HIV-2 ROD10 (top) or (O) MVP5180 (bottom) capsid in MDM in the presence of IFNα/β-R or CAb. Data show mean + s.d. n = 3 donors. Two-way ANOVA vs CAb, HIV-1(HIV-2 CA) P = 0.02, HIV-1(O CA) P = 0.002. b, HIV-1(M) CA hexamer highlighting β-hairpin (BHP) position in a closed (green) (PDB ID:5HGN) or open conformation (wheat) (PDB ID:5HGL). Lower panel details residues in hinge region that close BHP by coordinating water and increasing distance between His12 and Asp51. c, Maximum-likelihood phylogenetic tree of primate lentiviral capsid genes coloured by chromaclade to illustrate the residues equivalent to CA Q50 in HIV-1(M). d, SIVcpz CA hexamer (PDB ID:7T15) with the BHP position in a closed (green) conformation. Lower panel details residues in hinge region that close BHP by coordinating water and increasing distance between His12 and Asp51. e,f, HIV-1(O) (PDB ID: 7T12) and SIVmac (PDB ID:7T14) hexamers with open BHP (wheat) and key Gln at position 50 substituted for Tyr (Y), preventing water coordination and channel closure. Lower panels show the BHP hinge region in detail. g, A modelled hexamer built from the HIV-2 N-terminal CA domain (PDB ID:2 × 82) is shown for comparison with HIV-1(M) and (O). The HIV-2 BHP (wheat) is open. Note that HIV-2 position 49 is Tyr (Y). h, Crystal structure of HIV-1(M) Q50Y (PDB ID:7T13) highlighting BHP position in an open conformation (wheat). R18 is shown at the centre of the hexamers. Lower panels show the BHP hinge region in detail. i, WT and CA Q50Y capsid survival curves obtained from TIRF in vitro uncoating experiments. In the absence of IP6, HIV-1 Q50Y capsids are metastable and disassemble spontaneously with similar half-life to WT. Most capsids are stabilized in the presence of 100 μM IP6. Survival curves were generated from single-virion uncoating traces (N = 326 for WT, 326 for WT + 100 μM IP6, 326 for Q50Y, 326 for Q50Y + 100 μM IP6) from one representative uncoating experiment (see Extended Data Fig. 5 for additional Q50Y data).