MxB restricts HIV-1 by targeting the tri-hexamer interface of the viral capsid

Sarah Sierra Smaga; Chaoyi Xu; Brady James Summers; Katherine Marie Digianantonio; Juan Roberto Perilla; Yong Xiong

Though our mutant CA tubes are similar in morphology to that of wild-type CA, many of 311 these mutations have deleterious effects in the virus, which may explain why MxB escape 312 mutations are not commonly seen. Notably, it has been reported that the mutation E213A leads to 313 decreased infectivity in cellular assays, and while Gag processing and viral cores appear normal, 314 the core remains stable longer than wild-type upon entry into the target cell [31]. This is 315 consistent with our observation during protein purification that E213A appeared to produce more 316 stable CA assemblies and prone to precipitation. Viruses containing the CA mutations E71A and 317 E180A had reduced infectivity relative to wild-type [32, 33] . The latter suggests that these two 318 mutations are not tolerated well by the virus, and perhaps coping with MxB restriction is a lower-319 cost measure than evolving resistance. 320 Our all-atom molecular dynamics simulations identified the same important tri-hexamer 321 interface independent of the experimental biochemistry. In the simulation, the bound MxB 322 peptide interacts with many CA residues that were tested biochemically to be critical for MxB 323 interaction (E71, E75, E212 and E213) and shown to be functionally important for MxB 324 sensitivity (P207, G208, and T210). The extensive contacts between the MxB peptide and CA 325 residues illustrate where and how MxB targets the CA lattice. Moreover, the glutamates in the tri-326 hexamer region, i.e. E213, create inter-hexamer repulsion and undermine the tri-hexamer