<i>In Vitro</i>Phenotypic Susceptibility of HIV-2 Clinical Isolates to CCR5 Inhibitors

Visseaux, Benoît; Charpentier, Charlotte; Hurtado-Nédelec, Margarita; Storto, Alexandre; Antoine, Romain; Peytavin, Gilles; Damond, Florence; Matheron, Sophie; Brun‐Vézinet, Françoise; Descamps, Diane

doi:10.1128/aac.05313-11

Cited by 22 publications

(16 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ingenol 3,5,20-triacetate (ITA), for instance, was shown to inhibit HIV replication in MT-4 cells at concentrations as low as 0.05 µM [41]. The novel ISD here evaluated, while maintaining low toxicity, exhibited even lower effective concentrations than ITA when used in MT-4 cells, and were comparable to many antiretroviral compounds currently in use, including entry inhibitors, such as enfuvirtide and maraviroc [64], [65]. In addition, ING-B EC 50 and TI values are close to classical antiretroviral compounds including ritonavir, nevirapine, delavirdine, nelfinavir and ddC [66]–[68].…”

Section: Discussionmentioning

confidence: 91%

Dual Role of Novel Ingenol Derivatives from Euphorbia tirucalli in HIV Replication: Inhibition of De Novo Infection and Activation of Viral LTR

et al. 2014

View full text Add to dashboard Cite

HIV infection is not cleared by antiretroviral drugs due to the presence of latently infected cells that are not eliminated with current therapies and persist in the blood and organs of infected patients. New compounds to activate these latent reservoirs have been evaluated so that, along with HAART, they can be used to activate latent virus and eliminate the latently infected cells resulting in eradication of viral infection. Here we describe three novel diterpenes isolated from the sap of Euphorbia tirucalli, a tropical shrub. These molecules, identified as ingenols, were modified at carbon 3 and termed ingenol synthetic derivatives (ISD). They activated the HIV-LTR in reporter cell lines and human PBMCs with latent virus in concentrations as low as 10 nM. ISDs were also able to inhibit the replication of HIV-1 subtype B and C in MT-4 cells and human PBMCs at concentrations of EC50 0.02 and 0.09 µM respectively, which are comparable to the EC50 of some antiretroviral currently used in AIDS treatment. Control of viral replication may be caused by downregulation of surface CD4, CCR5 and CXCR4 observed after ISD treatment in vitro. These compounds appear to be less cytotoxic than other diterpenes such as PMA and prostratin, with effective dose versus toxic dose TI>400. Although the mechanisms of action of the three ISDs are primarily attributed to the PKC pathway, downregulation of surface receptors and stimulation of the viral LTR might be differentially modulated by different PKC isoforms.

show abstract

Section: Discussionmentioning

confidence: 91%

Dual Role of Novel Ingenol Derivatives from Euphorbia tirucalli in HIV Replication: Inhibition of De Novo Infection and Activation of Viral LTR

et al. 2014

View full text Add to dashboard Cite

show abstract

“…With regard to the HIV-2 therapeutic arsenal, in cases of NRTI and protease inhibitor resistance, the only active drug class is integrase inhibitors [20, 30], and possibly the CCR5 inhibitor maraviroc [31]. However, the use of integrase inhibitors may be limited in pretreated patients who harbor NRTI-resistant viruses because of the low genetic barrier to resistance of this drug class, and who require a combination with fully active drugs.…”

Section: Discussionmentioning

confidence: 99%

Genotypic resistance profiles of HIV-2-treated patients in West Africa

Charpentier

Eholié

Anglaret

et al. 2014

Aids

Self Cite

View full text Add to dashboard Cite

Objective To assess the virological response, genotypic resistance profiles, and antiretroviral plasma concentrations in HIV-2 antiretroviral-treated (antiretroviral therapy, ART) patients in Côte d‘Ivoire. Methods A cross-sectional survey was conducted among HIV-2 patients receiving ART. Plasma HIV-2 viral load was performed using the Agence Nationale de Recherche sur le SIDA et les hépatites virales (ANRS) assay. Protease and reverse transcriptase sequencing was performed using in-house methods and antiretroviral plasma concentrations were assessed using ultra performance liquid chromatography combined with tandem mass spectrometry. Results One hundred and forty-five HIV-2-treated patients were enrolled with a median CD4+ cell count of 360 cells/µl (interquartile range, IQR = 215–528). Median duration of ART was 4 years (IQR = 2–7) and 74% of patients displayed viral load less than 50 copies/ml. Median plasma HIV-2 RNA among patients with viral load more than 50 copies/ml was 3016 copies/ml (IQR = 436–5156). Most patients (84%) received a lopinavir/ritonavir-based regimen. HIV-2 resistance mutations to nucleoside reverse transcriptase inhibitors and protease inhibitors were detected in 21 of 25 (84%) and 20 of 29 (69%) samples, respectively. The most prevalent nucleoside reverse transcriptase inhibitor resistance mutations were M184I/V (90%), Q151M (24%), and S215F/Y (24%). The most prevalent protease inhibitor resistance mutations were V47A (60%) and I54M (30%). Median CD4+ cell counts were 434 cells/µl (292–573) and 204 cells/µl (122–281) in patients with viral load less than 50 copies/ml and those exhibiting virological failure (P < 0.0001), respectively. The proportions of patients with adequate antiretroviral plasma concentrations were 81 and 93% in patients displaying virological failure and in those with viral load less than 50 copies/ml, respectively (P = 0.046), suggesting good treatment adherence. Conclusion We observed adequate drug plasma concentrations and virological suppression in a high proportion of HIV-2-infected patients. However, in cases of virological failure, the limited HIV-2 therapeutic arsenal and cross-resistance dramatically reduced treatment options.

show abstract

“…The first type of data is a numeric input matrix , where N gives the number of observations and p gives the number of features. Due to the established association between the V3 loop and HIV-2 coreceptor usage [17, 27, 29, 30], we used the amino acids of the V3 loop as features (N = 126). The input matrix was constructed such that each row contains the aligned, binary-encoded V3 amino-acid sequence of sample .…”

Section: Methodsmentioning

confidence: 99%

A genotypic method for determining HIV-2 coreceptor usage enables epidemiological studies and clinical decision support

et al. 2016

View full text Add to dashboard Cite

BackgroundCCR5-coreceptor antagonists can be used for treating HIV-2 infected individuals. Before initiating treatment with coreceptor antagonists, viral coreceptor usage should be determined to ensure that the virus can use only the CCR5 coreceptor (R5) and cannot evade the drug by using the CXCR4 coreceptor (X4-capable). However, until now, no online tool for the genotypic identification of HIV-2 coreceptor usage had been available. Furthermore, there is a lack of knowledge on the determinants of HIV-2 coreceptor usage. Therefore, we developed a data-driven web service for the prediction of HIV-2 coreceptor usage from the V3 loop of the HIV-2 glycoprotein and used the tool to identify novel discriminatory features of X4-capable variants.ResultsUsing 10 runs of tenfold cross validation, we selected a linear support vector machine (SVM) as the model for geno2pheno[coreceptor-hiv2], because it outperformed the other SVMs with an area under the ROC curve (AUC) of 0.95. We found that SVMs were highly accurate in identifying HIV-2 coreceptor usage, attaining sensitivities of 73.5% and specificities of 96% during tenfold nested cross validation. The predictive performance of SVMs was not significantly different (p value 0.37) from an existing rules-based approach. Moreover, geno2pheno[coreceptor-hiv2] achieved a predictive accuracy of 100% and outperformed the existing approach on an independent data set containing nine new isolates with corresponding phenotypic measurements of coreceptor usage. geno2pheno[coreceptor-hiv2] could not only reproduce the established markers of CXCR4-usage, but also revealed novel markers: the substitutions 27K, 15G, and 8S were significantly predictive of CXCR4 usage. Furthermore, SVMs trained on the amino-acid sequences of the V1 and V2 loops were also quite accurate in predicting coreceptor usage (AUCs of 0.84 and 0.65, respectively).ConclusionsIn this study, we developed geno2pheno[coreceptor-hiv2], the first online tool for the prediction of HIV-2 coreceptor usage from the V3 loop. Using our method, we identified novel amino-acid markers of X4-capable variants in the V3 loop and found that HIV-2 coreceptor usage is also influenced by the V1/V2 region. The tool can aid clinicians in deciding whether coreceptor antagonists such as maraviroc are a treatment option and enables epidemiological studies investigating HIV-2 coreceptor usage. geno2pheno[coreceptor-hiv2] is freely available at http://coreceptor-hiv2.geno2pheno.org.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0320-7) contains supplementary material, which is available to authorized users.

show abstract

In VitroPhenotypic Susceptibility of HIV-2 Clinical Isolates to CCR5 Inhibitors

Cited by 22 publications

References 20 publications

Dual Role of Novel Ingenol Derivatives from Euphorbia tirucalli in HIV Replication: Inhibition of De Novo Infection and Activation of Viral LTR

Dual Role of Novel Ingenol Derivatives from Euphorbia tirucalli in HIV Replication: Inhibition of De Novo Infection and Activation of Viral LTR

Genotypic resistance profiles of HIV-2-treated patients in West Africa

A genotypic method for determining HIV-2 coreceptor usage enables epidemiological studies and clinical decision support

Contact Info

Product

Resources

About