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Prolonged and substantial discordance in prevalence of raltegravir-resistant HIV-1 in plasma versus PBMC samples revealed by 454 "deep" sequencing.

ABSTRACT: The evolution of drug resistance mutations in plasma samples is relatively well-characterized. However, the viral population and diversity in other body compartments such as peripheral blood mononuclear cells (PBMC) remains poorly understood. Previous studies have mostly focused on protease and reverse transcriptase drug resistance mutations (DRMs). In this study, we used 454 "deep" sequencing technology to observe and quantify longitudinally the prevalence of resistance mutations associated with the integrase inhibitor, raltegravir, in plasma versus PBMC samples from a San Francisco-based cohort. Four heavily treatment-experienced subjects were monitored in this study over a median of 1.2 years since the initiation of raltegravir-containing regimens. We observed a consistent discordance in the prevalence of DRMs, but not resistance pathway(s), in the plasma versus PBMC viral populations. In the final paired samples that were tested while the subjects were on a raltegravir-containing regimen, DRM prevalence reached 100% in plasma but remained 1% in PBMC on day 177 post-therapy in Subject 3180 (Q148H/G140S), 100% in plasma and 36% in PBMC on day 224 in Subject 3242 (N155H), 78% in plasma and 11-12% in PBMC on day 338 in Subject 3501 (Q148H/G140S), and 100% in plasma and 0% in PBMC on day 197 in Subject 3508 (Y143R). Furthermore, absolute sequence homology comparison between the two compartments revealed that 21% - 99% of PBMC sequences had no match in plasma, whereas 14% - 100% of plasma sequences had no match in PBMC. Overall, our observations suggested that plasma and PBMC hosted drastically different HIV-1 populations even after a prolonged exposure to raltegravir selection pressure.

SUBMITTER: Lee GQ

PROVIDER: S-EPMC3458959 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Prolonged and substantial discordance in prevalence of raltegravir-resistant HIV-1 in plasma versus PBMC samples revealed by 454 "deep" sequencing.

Lee Guinevere Q GQ Swenson Luke C LC Poon Art F Y AF Martin Jeffrey N JN Hatano Hiroyu H Deeks Steven G SG Harrigan P Richard PR

PloS one 20120926 9

The evolution of drug resistance mutations in plasma samples is relatively well-characterized. However, the viral population and diversity in other body compartments such as peripheral blood mononuclear cells (PBMC) remains poorly understood. Previous studies have mostly focused on protease and reverse transcriptase drug resistance mutations (DRMs). In this study, we used 454 "deep" sequencing technology to observe and quantify longitudinally the prevalence of resistance mutations associated wit ...[more]

PMID: 23049972

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Project description:BackgroundWe aimed to investigate the tau biomarker discrepancies of Alzheimer's disease (AD) using plasma tau phosphorylated at threonine 181 (p-tau181), cerebrospinal fluid (CSF) p-tau181, and AV1451 positron emission tomography (PET).MethodsIn the Alzheimer's Disease Neuroimaging Initiative, 724 non-demented participants were categorized into plasma/CSF and plasma/PET groups. Demographic and clinical variables, amyloid-β (Aβ) burden, flortaucipir-PET binding in Braak regions of interest (ROIs), longitudinal changes in clinical outcomes, and conversion risk were compared.ResultsAcross different tau biomarker groups, the proportion of participants with a discordant profile varied (plasma+/CSF- 15.6%, plasma-/CSF+ 15.3%, plasma+/PET- 22.4%, and plasma-/PET+ 6.1%). Within the plasma/CSF categories, we found an increase from concordant-negative to discordant to concordant-positive in the frequency of Aβ pathology or cognitive impairment, rates of cognitive decline, and risk of cognitive conversion. However, the two discordant categories (plasma+/CSF- and plasma-/CSF+) showed comparable performances, resulting in similarly reduced cognitive capacities. Regarding plasma/PET categories, as expected, PET-positive individuals had increased Aβ burden, elevated flortaucipir retention in Braak ROIs, and accelerated cognitive deterioration than concordant-negative persons. Noteworthy, discordant participants with normal PET exhibited reduced flortaucipir uptake in Braak stage ROIs and slower rates of cognitive decline, relative to those PET-positive. Therefore, individuals with PET abnormality appeared to have advanced tau pathological changes and poorer cognitive function, regardless of the plasma status. Furthermore, these results were found only in individuals with Aβ pathology.ConclusionsOur results indicate that plasma and CSF p-tau181 abnormalities associated with amyloidosis occur simultaneously in the progression of AD pathogenesis and related cognitive decline, before tau-PET turns positive.

Dataset Information

Prolonged and substantial discordance in prevalence of raltegravir-resistant HIV-1 in plasma versus PBMC samples revealed by 454 "deep" sequencing.

Publications

Prolonged and substantial discordance in prevalence of raltegravir-resistant HIV-1 in plasma versus PBMC samples revealed by 454 "deep" sequencing.

Similar Datasets

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