Pharmacovirological Impact of an Integrase Inhibitor on HIV-1 cDNA Species in vivo. - Related Articles
Pharmacovirological Impact of an Integrase Inhibitor on HIV-1 cDNA Species in vivo.
J Virol. 2009 May 20;
Authors: Goffinet C, Allespach I, Oberbremer L, Golden PL, Foster SA, Johns BA, Weatherhead JG, Novick SJ, Chiswell KE, Garvey EP, Keppler OT
Clinical trials of the first approved integrase inhibitor (INI), raltegravir, have demonstrated a drop in the HIV-1 RNA load of infected patients that was unexpectedly more rapid than 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 measuring 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 2-LTR circles accumulated up to 7-fold in this secondary lymphoid organ and this inversely correlated with the impact on proviral burden. Contrasting raltegravir's dose-ranging study in HIV patients, titration of GSK501015 in HIV-infected animals demonstrated a dependence of the INI's antiviral effect on its serum concentration. Furthermore, the in vivo EC50 value 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 2-LTR circles, we discuss how integrase inhibition may result in additional indirect antiviral effects that contribute to more rapid HIV-1 decay in HIV/AIDS patients.
PMID: 19458008 [PubMed - as supplied by publisher] [PubMed-HIV]