Yes / ABSTRACT
Entry inhibitors represent a potent class of antiretroviral drugs that target a host cell protein, CCR5, an HIV-1 entry coreceptor, and
not viral protein. Lack of sensitivity can occur due to preexisting virus that uses the CXCR4 coreceptor, while true resistance occurs
through viral adaptation to use a drug-bound CCR5 coreceptor. To understand this R5 resistance pathway, we analyzed >500 envelope
protein sequences and phenotypes from viruses of 20 patients from the clinical trials MOTIVATE 1 and 2, in which treatment-experienced patients received maraviroc plus optimized background therapy. The resistant viral population was phylogenetically distinct and
associated with a genetic bottleneck in each patient, consistent with de novo emergence of resistance. Recombination analysis showed
that the C2-V3-C3 region tends to genotypically correspond to the recombinant’s phenotype, indicating its primary importance in conferring resistance. Between patients, there was a notable lack of commonality in the specific sites conferring resistance, confirming the
unusual nature of R5-tropic resistance. We used coevolutionary and positive-selection analyses to characterize the genotypic determinants of resistance and found that (i) there are complicated covariation networks, indicating frequent coevolutionary/compensatory
changes in the context of protein structure; (ii) covarying sites under positive selection are enriched in resistant viruses; (iii) CD4 binding sites form part of a unique covariation network independent of the V3 loop; and (iv) the covariation network formed between the
V3 loop and other regions of gp120 and gp41 intersects 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 CCR5 unavailable for use by HIV-1 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 CXCR4-using virus (CXCR4 is the main alternative coreceptor HIV-1 uses, in addition to
CD4). We analyzed envelope sequences from HIV-1, obtained from 20 patients who enrolled in maraviroc clinical trials and experienced treatment failure, without detection of CXCR4-using virus. Evolutionary analysis was employed to identify molecular changes
that confer maraviroc resistance. We found that in these individuals, resistant viruses form a distinct population that evolved once and
was successful as a result of drug pressure. Further evolutionary analysis placed the complex network of interdependent mutational
changes into functional groups that help explain the impediments to the emergence of maraviroc-associated R5 drug resistance. / X.J. was supported by Medical Research Council (G1001806/1) and Wellcome Trust (097820/Z/11/A) funding and F.F. by a Biotechnology and Biological Sciences Research Council studentship to D.L.R.
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/17292 |
| Date | 24 September 2019 |
| Creators | Jiang, X., Feyertag, F., Meehan, Conor J., McCormack, G.P., Travers, S.A., Craig, C., Westby, M., Lewis, M., Robertson, D.L. |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Article, Published version |
| Rights | © 2015, Jiang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 3.0 Unported license. http://creativecommons.org/licenses/by/3.0/., CC-BY |
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