title: Maraviroc and other HIV-1 entry inhibitors exhibit a class-specific redistribution effect that results in increased extracellular viral load.
abstract: HIV entry inhibitors, such as maraviroc (MVC), prevent cell-free viruses from entering the cells. In clinical trials, patients who were treated with MVC often displayed viral loads that were above the limit of conventional viral load detection compared to efavirenz-based regimens. We hypothesize that viruses blocked by entry inhibitors may be redistributed to plasma, where they artificially increase viral load measurements compared to those with the use of antiretroviral drugs (ARVs) that act intracellularly. We infected PM-1 cells with CCR5-tropic HIV-1 BaL or CXCR4-tropic HIV-1 NL4-3 in the presence of inhibitory concentrations of efavirenz, raltegravir, enfuvirtide, maraviroc, and AMD3100, the latter three being entry inhibitors. Supernatant viral load, reverse transcriptase enzyme activity, and intracellular nucleic acid levels were measured at times up to 24 h postinfection. Infectivity of redistributed dual-tropic HIV-1 was assessed using TZM-bl cells. Extracellular viral load analysis revealed that entry inhibitor-treated cells had higher levels of virus in the supernatant than the cells treated with other ARVs at 8 h postinfection. By 24 h, the supernatant viral load was still higher for entry inhibitors than other ARVs. We observed a correlation between viral load and the step of entry inhibition. Dual-tropic virus infectivity was undiminished utilizing the CCR5 coreceptor following redistribution by CXCR4 entry inhibition. This in vitro model indicates that entry inhibitors exhibit a redistribution effect unseen with intracellular ARV drugs. Based on these results, the effectiveness of some entry inhibitors may be underestimated if plasma viral load is used as a sole indicator of clinical success.
authors.affiliation: McGill AIDS Centre, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Victor G
authors.initials: VG
authors.lastname: Kramer
authors.forename: Susan M
authors.initials: SM
authors.lastname: Schader
authors.forename: Maureen
authors.initials: M
authors.lastname: Oliveira
authors.forename: Susan P
authors.initials: SP
authors.lastname: Colby-Germinario
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Donahue
authors.forename: Diane N
authors.initials: DN
authors.lastname: Singhroy
authors.forename: Randy
authors.initials: R
authors.lastname: Tressler
authors.forename: Richard D
authors.initials: RD
authors.lastname: Sloan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D001596:Benzylamines; D002460:Cell Line; D000080027:Cyclams; D003510:Cyclohexanes / Q000494:pharmacology*; D003521:Cyclopropanes; D004279:DNA, Viral / Q000032:analysis; D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000032:analysis; D015497:HIV-1 / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D000077592:Maraviroc; D010446:Peptide Fragments / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D012367:RNA, Viral / Q000032:analysis; D000068898:Raltegravir Potassium; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D019562:Viral Load / Q000187:drug effects*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D003510:Cyclohexanes; D003521:Cyclopropanes; D004279:DNA, Viral; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D006571:Heterocyclic Compounds; D010446:Peptide Fragments; D011760:Pyrrolidinones; D012367:RNA, Viral; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D014230:Triazoles; D000077560:Enfuvirtide; D000068898:Raltegravir Potassium; D054303:HIV Reverse Transcriptase; C098320:efavirenz; D000077592:Maraviroc; C088327:plerixafor