Prevalence of X4 tropic viruses in patients recently infected with HIV-1 and lack of association with transmission of drug resistance

Mendoza, Carmen de; Rodrı́guez, Carmen; García, Féderico; Eirós, José María; Ruiz, Lı́dia; Caballero, Estrella; Aguilera, Antonio; Leiva, Pilar; Colomina, Javier; Gutiérrez, Félix; Romero, Jorge del; Agüero, Jesús; Soriano, Vincent

doi:10.1093/jac/dkm012

Cited by 73 publications

(61 citation statements)

References 37 publications

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“…The resistance mechanism that HIV utilizes to evade CCR5 antagonists is likely to depend in part on the disease stage of the patient. Patients with more advanced disease have a greater likelihood of harboring X4-utilizing viruses [52][53][54] and have R5-tropic viruses with reduced sensitivity to RANTES and the CCR5 antagonists TAK779 and AD101 compared with patients at earlier disease stages. [55][56][57][58] As a consequence, these patients may fail R5 antagonist therapy via either outgrowth of minor preexisting X4-utilizing populations or the continued use of CCR5 in the presence of drug.…”

Section: Discussionmentioning

confidence: 99%

HIV Type 1 from a Patient with Baseline Resistance to CCR5 Antagonists Uses Drug-Bound Receptor for Entry

Tilton

Amrine-Madsen

Miamidian

et al. 2010

AIDS Research and Human Retroviruses

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CCR5 antagonists are a new class of antiretroviral drugs that block viral entry by disrupting interactions between the viral envelope (Env) glycoprotein and coreceptor. During the CCR100136 (EPIC) Phase IIb study of the CCR5 antagonist aplaviroc (APL) in treatment-naive individuals, a patient was identified who harbored virus strains that exhibited partial resistance to APL at the time of virologic failure. Retrospectively, it was found that APL resistance was present at baseline as well. To investigate the mechanism of APL resistance in this patient, we cloned HIV-1 env genes from plasma obtained at baseline and after virologic failure. Approximately 85% of cloned Envs were functional, and all exhibited partial resistance to APL. All Envs were R5-tropic, were partially resistant to other CCR5 antagonists including maraviroc on cells with high CCR5 expression, but remained sensitive to the fusion inhibitor enfuvirtide. Competition studies with natural CCR5 ligands revealed that the mechanism of drug resistance entailed the use of the drug-bound conformation of CCR5 by the Env proteins obtained from this individual. The degree of drug resistance varied between Env clones, and also varied depending on the cell line used or the donor from whom the primary T cells were obtained. Thus, both virus and host factors contribute to CCR5 antagonist resistance. This study shows that R5 HIV-1 strains resistant to CCR5 inhibitors can arise in patients, confirming a mechanism of resistance previously characterized in vitro. In addition, some patients can harbor CCR5 antagonist-resistant viruses prior to treatment, which may have implications for the clinical use of this new class of antiretrovirals.

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Section: Discussionmentioning

confidence: 99%

HIV Type 1 from a Patient with Baseline Resistance to CCR5 Antagonists Uses Drug-Bound Receptor for Entry

Tilton

Amrine-Madsen

Miamidian

et al. 2010

AIDS Research and Human Retroviruses

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“…V3 sequences were amplified by nested PCR using E80 and E105 as outer primers and ES7 and E125 as inner primers; primers and PCR conditions were previously described (7,26). Sequences were edited with SeqScape v2.5 (Applied Biosystems).…”

Section: Methodsmentioning

confidence: 99%

Evaluation of Eight Different Bioinformatics Tools To Predict Viral Tropism in Different Human Immunodeficiency Virus Type 1 Subtypes

et al. 2008

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Human immunodeficiency virus type 1 (HIV-1) tropism can be assessed using phenotypic assays, but this is quite laborious, expensive, and time-consuming and can be made only in sophisticated laboratories. More accessible albeit reliable tools for testing of HIV-1 tropism are needed in view of the prompt introduction of CCR5 antagonists in clinical practice. Bioinformatics tools based on V3 sequences might help to predict HIV-1 tropism; however, most of these methods have been designed by taking only genetic information derived from HIV-1 subtype B into consideration. The aim of this study was to evaluate the performances of several genotypic tools to predict HIV-1 tropism in non-B subtypes, as data on this issue are scarce. Plasma samples were tested using a new phenotypic tropism assay (Phenoscript-tropism; Eurofins), and results were compared with estimates of coreceptor usage using eight different genotypic predictor softwares (Support Vector Machine [SVM], C4.5, C4.5 with positions 8 to 12 only, PART, Charge Rule, geno2pheno coreceptor, Position-Specific Scoring Matrix X4R5 [PSSM X4R5 ], and PSSM sinsi ). A total of 150 samples were tested, with 115 belonging to patients infected with non-B subtypes and 35 drawn from subtype B-infected patients, which were taken as controls. When non-B subtypes were tested, the concordances between the results obtained using the phenotypic assay and distinct genotypic tools were as follows: 78.8% for SVM, 77.5% for C4.5, 82.5% for C4.5 with positions 8 to 12 only, 82.5% for PART, 82.5% for Charge Rule, 82.5% for PSSM X4R5 , 83.8% for PSSM sinsi , and 71.3% for geno2pheno. When clade B viruses were tested, the best concordances were seen for PSSM X4R5 (91.4%), PSSM sinsi (88.6%), and geno2pheno (88.6%). The sensitivity for detecting X4 variants was lower for non-B than for B viruses, especially in the case of PSSM sinsi (38.4% versus 100%, respectively), SVM wetcat (46% versus 100%, respectively), and PART (30% versus 90%, respectively). In summary, while inferences of HIV-1 coreceptor usage using genotypic tools seem to be reliable for clade B viruses, their performances are poor for non-B subtypes, in which they particularly fail to detect X4 variants.

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“…Firstly, X4 viruses transmission seems not to be associated with transmission of drug resistance, as reported by de Mendoza et al [21].…”

Section: Acute Patientsmentioning

confidence: 75%

“…As well described in the review of Verhofstede et al [16] the prevalence of X4 or dual mixed tropic (DM) viruses among different cohorts of recent infection varies from 2% to 19% (as discussed elsewhere [17][18][19][20][21][22]). …”

Section: Acute Patientsmentioning

confidence: 90%

HIV-1 Tropism Test Evaluation: Assessment and Clinical Implications

et al. 2014

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CCR5 and CXCR4 chemokines receptors are critical coreceptors for the binding of HIV to specific host cells. Guidelines recommend its assessment in case of virological failure or before prescription of CCR5 inhibitors. Strategies to assess viral tropism may be divided into phenotypic and genotypic assays; registrative trials of CCR5 inhibitors used phenotypic assay, but recently genotypic ones have been used in clinical practice. The presence of CXCR4 is increasing in naïve patients, with both acute and chronic HIV-1 infections; this coreceptor usage is associated with CD4 depletion. The assessment of viral tropism should be considered in every stage of HIV-1 infection.

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Prevalence of X4 tropic viruses in patients recently infected with HIV-1 and lack of association with transmission of drug resistance

Abstract: A significant proportion of recent HIV-1 seroconverters harbour X4 viruses (17.2%), without any evidence of association between co-receptor usage, transmission of drug-resistant viruses and HIV subtype.

Cited by 73 publications

References 37 publications

HIV Type 1 from a Patient with Baseline Resistance to CCR5 Antagonists Uses Drug-Bound Receptor for Entry

HIV Type 1 from a Patient with Baseline Resistance to CCR5 Antagonists Uses Drug-Bound Receptor for Entry

Evaluation of Eight Different Bioinformatics Tools To Predict Viral Tropism in Different Human Immunodeficiency Virus Type 1 Subtypes

HIV-1 Tropism Test Evaluation: Assessment and Clinical Implications

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