To compare baseline susceptibility to protease inhibitors among HIV-1 isolates of subtypes C, F, G and CRF02_AG, and to identify polymorphisms that determine the differences in susceptibility.
Methods
A total of 42 samples of drug-naive patients infected with subtypes G (n=19), CRF02_AG (n=10), F (n=6) and C (n=7) were phenotyped and genotyped with the Antivirogram and the ViroSeq 2.0 genotyping system, respectively. A Bayesian network approach was used for a preliminary analysis of the collected data and the dependencies indicated by the network were statistically confirmed.
Results
CRF02_AG samples were found to be more susceptible to nelfinavir and ritonavir than other subtypes. Hypersusceptibility to these drugs was associated with the 70R polymorphism. 37D/S/T was associated with reduced susceptibility to indinavir and 89M with reduced susceptibility to lopinavir. Susceptibility to tipranavir was the lowest among the subtype F samples and the highest for subtype G samples, with samples carrying 57R being more susceptible than samples carrying 57K.
Conclusions
Our study suggests that there are baseline susceptibility differences between subtypes and these differences are due to naturally occurring polymorphisms in these subtypes. The predictive value for phenotype of these polymorphisms was even valid in subtypes where these polymorphisms are less prevalent. Taking into account such polymorphisms should improve current algorithms for interpretation of genotyping results in a subtype-independent way.
FraterA.J., BeardallA., AriyoshiK.Impact of baseline polymorphisms in RT and protease on outcome of highly active antiretroviral therapy in HIV-1-infected African patients.AIDS2001; 15: 1493–1502.
3.
FraterA.J., DunnD.T., BeardallA.J.Comparative response of African HIV-1-infected individuals to highly active antiretroviral therapy.AIDS2002; 16: 1139–1146.
4.
DescampsD., ApetreiC., CollinG., DamondF., SimonF., Brun-VezinetF.Naturally occurring decreased susceptibility of HIV-1 subtype G to protease inhibitors.AIDS1998; 12: 1109–1111.
5.
KantorR., KatzensteinD.Drug resistance in non-subtype B HIV-1.J Clin Virol2004; 29: 152–159.
6.
KantorR., KatzensteinD.A., EfronB.Impact of HIV-1 subtype and antiretroviral therapy on protease and reverse transcriptase genotype: results of a global collaboration.PLoS Med2005; 2: e112.
7.
KohlbrennerV., HallD., SchapiroJ.Development of a tipranavir mutation score: analysis of protease mutations associated with phenotypic drug susceptibility and antiviral response in Phase II clinical trials.13th International HIV Drug Resistance Workshop. 8–12 June 2004, Canary Islands, Spain. Abstract 19.
8.
VandammeA-M, DeforcheK., Van LaethemK., CamachoR.HIV-1 subtype A1, C, F and G strains have a higher mutation score than subtype B strains.14th International Drug Resistance Workshop. 7–11 June 2005, Quebec, Canada. Abstract 139.
9.
DerooS., RobertI., FontaineE.HIV-1 subtypes in Luxembourg, 1983–2000.AIDS2002; 16: 2461–2467.
10.
SnoeckJ., Van LaethemK., HermansP.Rising prevalence of HIV-1 non-B subtypes in Belgium: 1983–2001.J Acquir Immune Defic Syndr2004; 35: 279–285.
11.
KinomotoM., Appiah-OpongR., BrandfulJ.A.HIV-1 proteases from drug-naive West African patients are differentially less susceptible to protease inhibitors.Clin Infect Dis2005; 41: 243–251.
12.
Leigh BrownA.J., FrostS.D., GoodB.Genetic basis of hypersusceptibility to protease inhibitors and low replicative capacity of human immunodeficiency virus type 1 strains in primary infection.J Virol2004; 78: 2242–2246.
13.
DeforcheK., LaethemK.V., AbecasisA.Bayesian Network reveals linkage for mutations at position 89 of HIV-1 protease to other protease codons and therapy with protease inhibitors.2nd European HIV Drug Resistance Workshop. 11–13 March 2004, Rome, Italy. Abstract 7.11.
14.
AbecasisA.B., DeforcheK., SnoeckJ.Protease mutation M89I/V is linked to therapy failure in patients infected with the HIV-1 non-B subtypes C, F or G.AIDS2005; 19: 1799–1806.
15.
DeforcheK., CamachoR., GrossmanZ.Applying Bayesian networks to study nelfinavir resistance pathways in subtypes A, B, C, F and G.3rd European HIV Drug Resistance Workshop. March 30–April 1 2005, Athens, Greece. Abstract 1.6.
16.
HertogsK., ConantM., SchelP., Van CauwenbergeA., de BéthuneP., PauwelsR.The RT-Antivirogram™: a rapid and accurate method to determine phenotype (multi-)drug resistance in plasma of patients treated with various HIV-1 RT inhibitors.Antivir Ther1996; 1: 40.
17.
HertogsK., de BethuneM.P., MillerV.A rapid method for simultaneous detection of phenotypic resistance to inhibitors of protease and reverse transcriptase in recombinant human immunodeficiency virus type 1 isolates from patients treated with antiretroviral drugs.Antimicrob Agents Chemother1998; 42: 269–276.
18.
WegnerS.A., De VroeyV., Van Den EyndeC., HertogsK., LarderB.The Antivirogram recombinant virus assay is able to detect phenotypic resistance in low viral load samples of non-subtype B isolates.4th International Workshop on HIV Drug Resistance & Treatment Strategies. 12–16 June 2000, Sitges, Spain. Abstract 80.
19.
HolguinA., HertogsK., SorianoV.Performance of the Virco drug resistance assays testing HIV-1 non-B subtypes.8th Conference on Retroviruses & Opportunistic Infections. 4–8 February 2001, Chicago IL, USA. Abstract 458.
20.
SnoeckJ., Van DoorenS., Van LaethemK.Prevalence and origin of HIV-1 group M subtypes among patients attending a Belgian hospital in 1999.Virus Res2002; 85: 95–107.
21.
HeckermanD.A tutorial on learning with Bayesian networks. In Learning in graphical models, 1999; pp. 301–354. Edited by JordanM.. Massachusetts: MIT Press.
22.
MyllymäkiP., SilanderT., TirriH., UronenP.B-Course: a web-based tool for Bayesian and causal data analysis.International Journal on Artificial Intelligence Tools2002; 11: 369–387.
23.
B-Course [homepage on the internet].Helsinki, Finland: Complex Systems Computation Group [updated 2002]. Available from http://b-course.hiit.fi.
24.
DanielW.W.The Kruskal-Wallis one-way analysis of variance by ranks. In Biostatistics: a foundation for analysis in the health sciences, 1999; pp 691–700. Edited by WileyB.II. New York: John Wiley and Sons.
25.
R Core Development Team.R: a language and environment for statistical computing. Vienna, Austria: R foundation for Statistical Computing; 2004.
26.
PalmaA.C., AbecasisA., CarvalhoA.P., CabanasJ., GomesP., CamachoR.Amino acid substitutions under therapy on HIV-1 subtype G protease sites not associated so far with antiretroviral resistance.10th European AIDS Conference/EACS. 17–20 November 2005, Dublin, Ireland. Abstract 3.2/2.
27.
HolguinA., PaxinosE., HertogsK., WomacC., SorianoV.Impact of frequent natural polymorphisms at the protease gene on the in vitro susceptibility to protease inhibitors in HIV-1 non-B subtypes.J Clin Virol2004; 31: 215–220.
28.
TurnerD., BrennerB., MoisiD.Nucleotide and amino acid polymorphisms at drug resistance sites in non-B-subtype variants of human immunodeficiency virus type 1.Antimicrob Agents Chemother2004; 48: 2993–2998.
29.
ParkinN.T., ChappeyC.Protease mutations associated with higher or lower than expected tipranavir susceptibility based on the TPV mutation score.13th Conference on Retroviruses & Opportunistic Infections. 5–8 February 2006, Denver, Colorado, USA. Abstract 637.
