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.

Comparative antiviral activity of integrase inhibitors in human monocyte-derived macrophages and lymphocytes

“…RAL is a new drug belonging to a new class of antiretrovirals (INIs), which has demonstrated an exquisite potency, a clean safety profile also at once-daily dosing of 800 mg/day, and to not accumulate in PBMCs, with intracellular concentrations being about 1/10 of the concentrations in plasma (Goffinet et al, 2009;Moltó et al, 2011;Murray et al, 2007;Steigbigel et al, 2008;Summa et al, 2008).…”

“…For instance, one of the most exciting recent advances in HIV-1 pharmacotherapy has been the approval in the October 2007 by Food and Drug Administration (FDA) of the first INI, the new pyrimidone carboxamide raltegravir (RAL) provided with a high potency and generally well tolerability (Cocohoba and Dong, 2008;Goffinet et al, 2009;Moltò et al, 2011;Steigbigel et al, 2008;Summa et al, 2008).…”

Stage-Dependent Inhibition of HIV-1 Replication by Antiretroviral Drugs in Cell Culture

“…This is in contrast to the parameter choices concerning cells latently infected preintegration used previously (26), which are in conflict with the known properties of this viral reservoir. Others have suggested that the greater decay observed with RAL could be a result of the gene expression from or the apoptosis triggered by unintegrated DNA that accumulates following the use of an IN inhibitor (15). However, these effects would occur in cells that are unable to produce virus (since productive infection has been blocked by the IN inhibitor) and therefore would not be expected to contribute to the viral load, although the possibility that these effects play a role in superinfected cells cannot be excluded.…”

“…They include differences in the time until drug bioavailability, differences in drug potency, a role for cells latently infected preintegration, the greater penetration of certain drugs into sanctuary sites, the stage of viral replication targeted, and the IN inhibitor-induced accumulation of unintegrated viral DNA (15,23,26,33,34). On the basis of the mathematical modeling of viral load decay, it has been proposed that the clinical observations can be explained by the effect of RAL on cells latently infected preintegration (26).…”

High Natural Permissivity of Primary Rabbit Cells for HIV-1, with a Virion Infectivity Defect in Macrophages as the Final Replication Barrier

“…Our parallel efforts in the rat species have markedly increased in vivo susceptibility to systemic HIV-1 challenge. The human-CD4 (hCD4)/hCCR5-transgenic rat model has facilitated preclinical evaluation of antiviral drugs targeting entry, reverse transcriptase, and integrase (29,30) and has contributed to aspects of viral pathogenesis (53,59) and testing of a vaccine candidate (14). Despite a high proviral load in lymphatic organs, the current transgenic rat model still has limitations, including low and transient viremia and lack of HIV disease.…”