title: Pharmacovirological impact of an integrase inhibitor on human immunodeficiency virus type 1 cDNA species in vivo.
abstract: Clinical trials of the first approved integrase inhibitor (INI), raltegravir, have demonstrated a drop in the human immunodeficiency virus type 1 (HIV-1) RNA loads of infected patients that was unexpectedly more rapid than that with a potent reverse transcriptase inhibitor, and apparently dose independent. These clinical outcomes are not understood. In tissue culture, although their inhibition of integration is well documented, the effects of INIs on levels of unintegrated HIV-1 cDNAs have been variable. Furthermore, there has been no report to date on an INI's effect on these episomal species in vivo. Here, we show that prophylactic treatment of transgenic rats with the strand transfer INI GSK501015 reduced levels of viral integrants in the spleen by up to 99.7%. Episomal two-long-terminal-repeat (LTR) circles accumulated up to sevenfold in this secondary lymphoid organ, and this inversely correlated with the impact on the proviral burden. Contrasting raltegravir's dose-ranging study with HIV patients, titration of GSK501015 in HIV-infected animals demonstrated dependence of the INI's antiviral effect on its serum concentration. Furthermore, the in vivo 50% effective concentration calculated from these data best matched GSK501015's in vitro potency when serum protein binding was accounted for. Collectively, this study demonstrates a titratable, antipodal impact of an INI on integrated and episomal HIV-1 cDNAs in vivo. Based on these findings and known biological characteristics of viral episomes, we discuss how integrase inhibition may result in additional indirect antiviral effects that contribute to more rapid HIV-1 decay in HIV/AIDS patients.
authors.affiliation: Department of Virology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Goffinet
authors.forename: Ina
authors.initials: I
authors.lastname: Allespach
authors.forename: Lena
authors.initials: L
authors.lastname: Oberbremer
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Golden
authors.forename: Scott A
authors.initials: SA
authors.lastname: Foster
authors.forename: Brian A
authors.initials: BA
authors.lastname: Johns
authors.forename: Jason G
authors.initials: JG
authors.lastname: Weatherhead
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Novick
authors.forename: Karen E
authors.initials: KE
authors.lastname: Chiswell
authors.forename: Edward P
authors.initials: EP
authors.lastname: Garvey
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Keppler
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019428:HIV Integrase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D011753:Pyrones / Q000493:pharmacokinetics / Q000494:pharmacology; D011760:Pyrrolidinones / Q000493:pharmacokinetics / Q000494:pharmacology; D000068898:Raltegravir Potassium; D051381:Rats; D055647:Rats, Transgenic; D016662:Virus Integration / Q000187:drug effects
chemical_list: D018076:DNA, Complementary; D004279:DNA, Viral; C542914:GSK 501015; D019428:HIV Integrase Inhibitors; D011753:Pyrones; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium