title: SHIV-162P3 infection of rhesus macaques given maraviroc gel vaginally does not involve resistant viruses.
abstract: Maraviroc (MVC) gels are effective at protecting rhesus macaques from vaginal SHIV transmission, but breakthrough infections can occur. To determine the effects of a vaginal MVC gel on infecting SHIV populations in a macaque model, we analyzed plasma samples from three rhesus macaques that received a MVC vaginal gel (day 0) but became infected after high-dose SHIV-162P3 vaginal challenge. Two infected macaques that received a placebo gel served as controls. The infecting SHIV-162P3 stock had an overall mean genetic distance of 0.294±0.027%; limited entropy changes were noted across the envelope (gp160). No envelope mutations were observed consistently in viruses isolated from infected macaques at days 14-21, the time of first detectable viremia, nor selected at later time points, days 42-70. No statistically significant differences in MVC susceptibilities were observed between the SHIV inoculum (50% inhibitory concentration [IC(50)] 1.87 nM) and virus isolated from the three MVC-treated macaques (MVC IC(50) 1.18 nM, 1.69 nM, and 1.53 nM, respectively). Highlighter plot analyses suggested that infection was established in each MVC-treated animal by one founder virus genotype. The expected Poisson distribution of pairwise Hamming Distance frequency counts was observed and a phylogenetic analysis did not identify infections with distinct lineages from the challenge stock. These data suggest that breakthrough infections most likely result from incomplete viral inhibition and not the selection of MVC-resistant variants.
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, United States of America. atsibris@partners.org
authors.forename: Athe M N
authors.initials: AM
authors.lastname: Tsibris
authors.forename: Urboshi
authors.initials: U
authors.lastname: Pal
authors.forename: Allison L
authors.initials: AL
authors.lastname: Schure
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Veazey
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Kunstman
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Henrich
authors.forename: P J
authors.initials: PJ
authors.lastname: Klasse
authors.forename: Steven M
authors.initials: SM
authors.lastname: Wolinsky
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Kuritzkes
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D002460:Cell Line; D003510:Cyclohexanes / Q000737:chemistry*; D024882:Drug Resistance, Viral; D019277:Entropy; D005260:Female; D016679:Genome, Viral; D006801:Humans; D008253:Macaca mulatta; D000077592:Maraviroc; D008562:Membrane Glycoproteins; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D015203:Reproducibility of Results; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism*; D014230:Triazoles / Q000737:chemistry*; D014622:Vaginal Creams, Foams, and Jellies / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000235:genetics; D019562:Viral Load; D014764:Viral Proteins / Q000737:chemistry
chemical_list: D003510:Cyclohexanes; D008562:Membrane Glycoproteins; D014230:Triazoles; D014622:Vaginal Creams, Foams, and Jellies; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C069623:gp120 protein, Simian immunodeficiency virus; D000077592:Maraviroc