CXCR4-Using HIV Type 1 Variants Are More Commonly Found in Peripheral Blood Mononuclear Cell DNA Than in Plasma RNA

Verhofstede, Chris; Vandekerckhove, Linos; Eygen, Veerle Van; Demecheleer, Els; Vandenbroucke, Ina; Winters, Bart; Plum, Jean; Vogelaers, Dirk; Stuyver, Lieven

doi:10.1097/qai.0b013e31819118fa

Cited by 48 publications

(27 citation statements)

References 41 publications

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“…On the other hand, correlations found between Trofile (ES) and bioinformatics algorithms in our study are similar to those found in other studies (6,16,18,19). In 8/10 (80%) patients genotyped from serum, proviral DNA, and virus isolates, the same tropism was predicted, supporting the absence of differences in the tropism among different viral sources (26). One of the discordant result sets was that for patient 2, for which genotypic approaches reported a D/M result in the virus isolate; however, the TROCAI result was clearly R5 (0% X4 and 100% R5) ( Table 2).…”

Section: Discussionsupporting

confidence: 79%

TROCAI (Tropism Coreceptor Assay Information): a New Phenotypic Tropism Test and Its Correlation with Trofile Enhanced Sensitivity and Genotypic Approaches

et al. 2010

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The only clinically validated assay available to determine HIV tropism is Trofile, an assay that possesses some limitations. Our first aim was to develop a new phenotypic tropism test (TROCAI [tropism coreceptor assay information]) and to categorize results generated by this test according to the virological response to a short-term exposure to the CCR5 receptor antagonist maraviroc (maraviroc clinical test). Our second aim was to compare TROCAI results to those obtained by Trofile enhanced sensitivity (ES) and to different genotypic algorithms. TROCAI assayed HIV tropism in 33 HIV-infected patient viral isolates obtained from a modified coculture, followed by multiple infection cycles of indicator cells. TROCAI obtained a reportable result in all patients with viral loads of >500 HIV RNA copies/ml and in 3/6 patients with <500 HIV RNA copies/ml (30/33 patients, 91.9%). Patients who responded to maraviroc had an X4-using virus proportion in indicator cell supernatant of 0 to 0.41%. Hence, we used the threshold of 0.5% to categorize TROCAI results as R5 (<0.5%) or dual/mixed (>0.5%). The concordance between TROCAI and Trofile (ES) was 22/24 (91.6%), and with genotypic approaches it was 22/26 (84.6%). TROCAI results, which were categorized in this study by the maraviroc clinical test, could be used as a test in addition to those currently used to select patients for treatment with CCR5 antagonists.

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Section: Discussionsupporting

confidence: 79%

TROCAI (Tropism Coreceptor Assay Information): a New Phenotypic Tropism Test and Its Correlation with Trofile Enhanced Sensitivity and Genotypic Approaches

et al. 2010

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“…The detection of the R5 variant in plasma and the X4 strain in PBMCs in the chronic phase of infection could represent the emergence of the most fit virus. A recent study suggested that CXCR4-using viruses were more frequent in PBMCs than in plasma samples from patients with advanced disease (49). However, the virus population during the first few months of HIV-1 infection is more homogenous than later in the disease evolution.…”

Section: Discussionmentioning

confidence: 99%

HIV Coreceptor Tropism in Paired Plasma, Peripheral Blood Mononuclear Cell, and Cerebrospinal Fluid Isolates from Antiretroviral-Naïve Subjects

et al. 2011

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A survey of HIV coreceptor usage in cerebrospinal fluid (CSF) samples, peripheral blood mononuclear cells (PBMCs), and plasma samples from naïve seropositive patients was conducted. One hundred patients were enrolled in this study. Of the 100 patients, 36 had a primary or recent infection (P-RI), 31 had an early chronic infection (>350 CD4 cells) (ECI), and 33 had a late chronic infection (LCI). All 3 compartments were sampled in a subset of 33 participants, while the remaining 67 patients provided plasma samples and PBMCs only. Seventy-seven patients harbored the R5 virus in plasma samples and had a significantly higher median and percentage of CD4 ؉ T cells than patients with X4 virus (437 and 281 cells/l, respectively; P ‫؍‬ 0.0086; 20.6% and 18.6%, respectively). The X4 strain was detected more frequently in patients with LCI than in patients with P-RI or ECI (39.3%, 19.4%, and 9.6%, respectively; P ‫؍‬ 0.0063). PBMC and plasma tropism was concordant in 90 patients, and 73 had the R5 strain. Among patients with discordant results, 4 had the R5 virus in their plasma and the X4 virus in PBMCs; 6 showed the opposite profile. Plasma, PBMC, and CSF tropism determinations were concordant in 26/33 patients (21 patients had R5, and 5 had X4). The tropism was discordant in 5/33 patients, with the X4 virus in plasma and R5 in CSF; the HIV tropism in PBMCs was X4 in 3 patients. The remaining 2/33 patients had the R5 virus in plasma and PBMCs and the X4 virus in CSF; one of these patients had a P-RI. The discordant tropism in CSF and blood may have implications for chemokine (C-C motif) receptor 5 (CCR5) antagonist use in patients with limited response to antiretroviral therapy (ART) or in responding patients evaluated for simplification of treatment.

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Section: Introductionmentioning

confidence: 99%

“…Proviral DNA may be considered a potential alternative source of viral genetic material for tropism testing in patients with low or undetectable viral load. Cellular proviral DNA contains the reservoir of archived viruses, and it has been shown that V3 sequences predicted to derive from X4 viruses are present and even enriched in this reservoir [10][11][12].The aim of this study was to evaluate GTT on plasma RNA and proviral DNA for two groups of patients. The first group comprised treated and untreated patients with a viral load of 4500 copies/mL who underwent parallel testing of plasma RNA and proviral DNA.…”

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Concordance between HIV-1 genotypic coreceptor tropism predictions based on plasma RNA and proviral DNA

et al. 2011

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ObjectiveThe aim of the study was to evaluate the use of proviral DNA as a source of viral genetic material for genotypic coreceptor tropism testing (GTT). MethodsGTT consisted of bulk V3 sequencing followed by geno2pheno interpretation with the interpretative cut-off [false positive rate (FPR)] set at 5 and 10%. GTT was performed for 165 patients with a viral load of 4500 HIV-1 RNA copies/mL on simultaneously collected plasma RNA and proviral DNA, and for 126 patients with a viral load of o500 copies/mL on current proviral DNA and pretreatment plasma RNA. Phenotypic tropism testing (PTT) results were available for 142 samples. ResultsIn the simultaneous RNA/DNA comparison, concordance in prediction was 95.2% (at FPR 10%) and 96.4% (at FPR 5%). Six RNA-R5/DNA-X4 and two RNA-X4/DNA-R5 discordances were observed at an FPR of 10%, and six RNA-R5/DNA-X4 discordances were observed at an FPR of 5%. In the longitudinal RNA/DNA comparison, concordance was 88.1% (at FPR 10%) and 90.5% (at FPR 5%). Eight RNA-X4/DNA-R5 and seven RNA-R5/DNA-X4 discordances were seen at an FPR of 10%, and 10 RNA-R5/DNA-X4 and two RNA-X4/DNA-R5 discordances at an FPR of 5%. The overall concordance of RNA GTT with PTT was 82% (at FPR 10%) and 83% (at FPR 5%). The overall concordance of DNA GTT with PTT was 85% (at both 10 and 5% FPRs). ConclusionsGTT produced highly concordant tropism predictions for proviral DNA and plasma RNA. GTT on proviral DNA offers a promising approach for tropism prediction in clinical practice, particularly for the assessment of treated patients with low or suppressed viraemia.Keywords: chemokine (C-C motif) receptor 5 (CCR5) inhibitors, genotypic tropism testing, HIV-1 coreceptor, HIV-1 proviral DNA Accepted 25 January 2011Introduction Chemokine (C-C motif) receptor 5 (CCR5) antagonists, members of the class of HIV-1 entry inhibitors, selectively inhibit the replication of CCR5-using (R5) viral strains. Before introducing a CCR5 antagonist as a component of antiretroviral therapy (ART), coreceptor usage, or viral tropism, must be determined to exclude the possibility of the presence of chemokine (C-X-C motif) receptor 4 (CXCR4)-using (X4) strains, as these are associated with poor virological response to the drug [1]. The output of the earliest HIV-1 phenotypic tropism testing (PTT) assay was the formation of syncytia in cultured MT2 cells after virus inoculation. This assay is less well suited for use in routine clinical practice because of inherent difficulties with Correspondence: Prof. Chris Verhofstede, AIDS Reference Laboratory, University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. Tel: 1 32 9 332 51 61; fax: 1 32 9 332 38 41; e-mail: Chris.verhofstede@ugent.be DOI: 10.1111/j.1468-1293.2011.00922.x HIV Medicine (2011 GTT is based on analysis of the V3-loop sequence of the HIV-1 envelope (env) gene using bioinformatic prediction models to deduce coreceptor usage. GTT has the advantage of being less technically demanding, more rapid and less expensive than PTT, thereby meeting today's need for a fast and...

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CXCR4-Using HIV Type 1 Variants Are More Commonly Found in Peripheral Blood Mononuclear Cell DNA Than in Plasma RNA

Cited by 48 publications

References 41 publications

TROCAI (Tropism Coreceptor Assay Information): a New Phenotypic Tropism Test and Its Correlation with Trofile Enhanced Sensitivity and Genotypic Approaches

TROCAI (Tropism Coreceptor Assay Information): a New Phenotypic Tropism Test and Its Correlation with Trofile Enhanced Sensitivity and Genotypic Approaches

HIV Coreceptor Tropism in Paired Plasma, Peripheral Blood Mononuclear Cell, and Cerebrospinal Fluid Isolates from Antiretroviral-Naïve Subjects

Concordance between HIV-1 genotypic coreceptor tropism predictions based on plasma RNA and proviral DNA

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