Polymorphism in Gag Gene Cleavage Sites of HIV-1 Non-B Subtype and Virological Outcome of a First-Line Lopinavir/Ritonavir Single Drug Regimen

Jade Ghosn,Constance Delaugerre,Christine Rouzioux,Philippe Flandre,François Raffi,Julie Galimand,Isabelle Cohen-Codar,Jean-François Delfraissy,Marie-Laure Chaix,Fabrizio Mammano

doi:10.1371/journal.pone.0024798

Abstract

Virological failure on a boosted-protease inhibitor (PI/r) first-line triple combination is usually not associated with the detection of resistance mutations in the protease gene. Thus, other resistance pathways are being investigated. First-line PI/r monotherapy is the best model to investigate in vivo if the presence of mutations in the cleavage sites (CS) of gag gene prior to any antiretroviral treatment might influence PI/r efficacy. 83 patients were assigned to initiate antiretroviral treatment with first-line lopinavir/r monotherapy in the randomised Monark trial. We compared baseline sequence of gag CS between patients harbouring B or non-B HIV-1 subtype, and between those who achieved viral suppression and those who experienced virological failure while on LPV/r monotherapy up to Week 96. Baseline sequence of gag CS was available for 82/83 isolates; 81/82 carried at least one substitution in gag CS compared to HXB2 sequence. At baseline, non-B subtype isolates were significantly more likely to harbour mutations in gag CS than B subtype isolates (p<0.0001). Twenty-three patients experienced virological failure while on lopinavir/r monotherapy. The presence of more than two substitutions in p2/NC site at baseline significantly predicted virological failure (p = 0.0479), non-B subtype isolates being more likely to harbour more than two substitutions in this specific site. In conclusion, gag cleavage site was highly polymorphic in antiretroviral-naive patients harbouring a non-B HIV-1 strain. We show that pre-therapy mutations in gag cleavage site sequence were significantly associated with the virological outcome of a first-line LPV/r single drug regimen in the Monark trial.

Highlights

Complete viral suppression may be achieved in 64 to 84% of antiretroviral-naıve HIV-infected patients starting a ritonavirboosted protease inhibitor based first-line combination [1,2,3,4]
The major result of the MONARK trial was that LPV/r monotherapy demonstrated lower rates of virological suppression when compared to LPV/r triple therapy [24]
In most patients experiencing virological failure, this was not explained by the emergence of resistance mutations in the protease gene while under protease inhibitor drug-selective pressure [26]

Summary

Introduction

Complete viral suppression may be achieved in 64 to 84% of antiretroviral-naıve HIV-infected patients starting a ritonavirboosted protease inhibitor based first-line combination [1,2,3,4]. In the product of the gag open reading frame, Gag polyproteins are cleaved at five cleavage sites into p17 (MA), p24 (CA), p2 (SP1), p7 (NC), and p6gag. In the product of the gag-pol open reading frame, Gag-Pol polyproteins are cleaved at eight cleavage sites into p17 (MA), p24 (CA), p2 (SP1), p7 (NC), transframe protein (TFP), p6pol, protease, reverse transcriptase, and integrase [13,14]. Frameshifting is a rare controlled event, occurring only for 1 of 10 to 20 ribosomes It is driven by the secondary RNA structure called hairpin structure and allows for a correct Gag/Gag-Pol ratio to ensure optimal virus activity [15,16]. The RNA folding and stability of the gag-pol frameshift region can be evaluated by the measure of hairpin free energy

Methods

Results

Conclusion