UNASSIGNED: Entry-inhibitors represent a potent class of antiretroviral drugs that target a host cell protein, @entity5075 , an @entity2858 entry coreceptor, and not viral protein. Lack of sensitivity can occur due to pre-existing virus that uses the @entity436 coreceptor, while true resistance occurs through viral adaptation to use drug-bound @entity5075 coreceptor. To understand this R5-resistance pathway we analysed >500 envelope protein sequences and phenotypes from viruses of 20 @entity1 from the clinical trials MOTIVATE 1 and 2 in which treatment experienced @entity1 received maraviroc plus optimised background therapy. The resistant viral population was phylogenetically distinct and associated with a genetic bottleneck in each @entity1 , consistent with de novo emergence of resistance. Recombination analysis shows the C2-V3-C3 region tends to genotypically correspond to the recombinant's phenotype, indicating its primary importance in conferring resistance. Between @entity1 , there is a notable lack of commonality in the specific sites conferring resistance confirming the unusual nature of R5-tropic resistance. We use coevolutionary and positive selection analysis to characterise the genotypic determinants of resistance and find: (1) complicated covariation networks indicating frequent coevolutionary/compensatory changes in the context of protein structure; (2) covarying sites under positive selection are enriched in resistant viruses; (3) @entity404 binding sites form part of a unique covariation network independent of the V3 loop; (4) the covariation network formed between the V3 loop, and other regions of @entity7957 and gp41 intersects with sites involved in glycosylation and protein secretion. These results demonstrate that while envelope sequence mutations are the key to conferring maraviroc resistance, the specific changes involved are context-dependent and thus inherently unpredictable. IMPORTANCE: The entry-inhibitor drug maraviroc makes the cell coreceptor @entity5075 unavailable for use by @entity2858 and is now used in combination antiretroviral therapy. Treatment failure with drug resistant virus is particularly interesting because it tends to be rare with lack of sensitivity usually associated with the presence of @entity436 -using virus (the main alternative coreceptor @entity2858 uses in addition to @entity404 ). We analysed envelope sequences from @entity2858 obtained from 20 @entity1 who enrolled in maraviroc clinical trials and experienced treatment failure without detection of @entity436 -using virus. Evolutionary analysis was employed to identify molecular changes that confer maraviroc resistance. We find that in these individuals, resistant viral populations form a distinct population that evolved once and were successful as a result of the drug pressure. Further evolutionary analysis places the complex network of inter-dependent mutational changes into functional groups that help explain the impediments to the emergence of maraviroc-associated R5 drug resistance.

Characterising the diverse mutational pathways associated with R5-tropic maraviroc resistance: @entity2858 that uses the drug-bound XXXX coreceptor.

@entity1 :: ('9606', 'Species') :: ['patients', 'patient'] @entity404 :: ('920', 'Gene') :: ['CD4'] @entity2858 :: ('11676', 'Species') :: ['HIV-1'] @entity5075 :: ('1234', 'Gene') :: ['CCR5'] @entity7957 :: ('3700', 'Gene') :: ['gp120'] @entity436 :: ('7852', 'Gene') :: ['CXCR4']
@entity5075 :: (1234,Gene) :: ['CCR5']
