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Search Results: 1 - 10 of 191304 matches for " Kuritzkes D "
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Progress in HIV vaccine research: an outsider's view
Kuritzkes D
Journal of the International AIDS Society , 2012, DOI: 10.7448/ias.15.6.18190
Abstract: Despite the potential for pre-exposure prophylaxis (PrEP) and treatment as prevention (TasP) to have a significant impact on HIV transmission, there is broad agreement that a safe and effective preventive vaccine remains an essential tool for ending the AIDS epidemic. To date, progress towards a vaccine has been painstaking. Nevertheless, recent progress has opened up promising new leads. Results of the STEP and RV-144 trials provide novel insights that may lead to improved design of candidate vaccines. In addition, the identification of highly potent, broadly neutralizing monoclonal antibodies from some infected patients suggests novel approaches to generating protective immunity. Refinements in our understanding of the gp120 structure and its interaction with CD4 also provide opportunities for improving immunogen design. Although the challenges remain daunting, these advances have instilled a renewed sense of optimism into the field.
Simple filter microchip for rapid separation of plasma and viruses from whole blood
Wang SQ, Sarenac D, Chen MH, Huang SH, Giguel FF, Kuritzkes DR, Demirci U
International Journal of Nanomedicine , 2012, DOI: http://dx.doi.org/10.2147/IJN.S32579
Abstract: er microchip for rapid separation of plasma and viruses from whole blood Original Research (1820) Total Article Views Authors: Wang SQ, Sarenac D, Chen MH, Huang SH, Giguel FF, Kuritzkes DR, Demirci U Published Date September 2012 Volume 2012:7 Pages 5019 - 5028 DOI: http://dx.doi.org/10.2147/IJN.S32579 Received: 03 April 2012 Accepted: 05 July 2012 Published: 17 September 2012 ShuQi Wang,1 Dusan Sarenac,1 Michael H Chen,1 Shih-Han Huang,1 Francoise F Giguel,2 Daniel R Kuritzkes,3 Utkan Demirci1,4 1Bio-acoustic MEMS in Medicine Laboratory, Department of Medicine, Division of Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; 2Infectious Diseases Unit, Massachusetts General Hospital, Boston, MA, USA; 3Section of Retroviral Therapeutics, Brigham and Women's Hospital, Boston, MA, USA; 4Harvard-MIT Health Sciences and Technology, Cambridge, MA, USA Abstract: Sample preparation is a significant challenge for detection and sensing technologies, since the presence of blood cells can interfere with the accuracy and reliability of virus detection at the nanoscale for point-of-care testing. To the best of our knowledge, there is not an existing on-chip virus isolation technology that does not use complex fluidic pumps. Here, we presented a lab-on-a-chip filter device to isolate plasma and viruses from unprocessed whole blood based on size exclusion without using a micropump. We demonstrated that viruses (eg, HIV) can be separated on a filter-based chip (2-μm pore size) from HIV-spiked whole blood at high recovery efficiencies of 89.9% ± 5.0%, 80.5% ± 4.3%, and 78.2% ± 3.8%, for viral loads of 1000, 10,000 and 100,000 copies/mL, respectively. Meanwhile, 81.7% ± 6.7% of red blood cells and 89.5% ± 2.4% of white blood cells were retained on 2 μm pore–sized filter microchips. We also tested these filter microchips with seven HIV-infected patient samples and observed recovery efficiencies ranging from 73.1% ± 8.3% to 82.5% ± 4.1%. These results are first steps towards developing disposable point-of-care diagnostics and monitoring devices for resource-constrained settings, as well as hospital and primary care settings.
Characteristics and Outcomes of Initial Virologic Suppressors during Analytic Treatment Interruption in a Therapeutic HIV-1 gag Vaccine Trial
Jonathan Z. Li, Chanson J. Brumme, Michael M. Lederman, Zabrina L. Brumme, Hongying Wang, John Spritzler, Mary Carrington, Kathleen Medvik, Bruce D. Walker, Robert T. Schooley, Daniel R. Kuritzkes, for the AIDS Clinical Trials Group A5197 Study Team
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034134
Abstract: Background In the placebo-controlled trial ACTG A5197, a trend favoring viral suppression was seen in the HIV-1-infected subjects who received a recombinant Ad5 HIV-1 gag vaccine. Objective To identify individuals with initial viral suppression (plasma HIV-1 RNA set point <3.0 log10 copies/ml) during the analytic treatment interruption (ATI) and evaluate the durability and correlates of virologic control and characteristics of HIV sequence evolution. Methods HIV-1 gag and pol RNA were amplified and sequenced from plasma obtained during the ATI. Immune responses were measured by flow cytometric analysis and intracellular cytokine expression assays. Characteristics of those with and without initial viral suppression were compared using the Wilcoxon rank sum and Fisher's exact tests. Results Eleven out of 104 participants (10.6%) were classified as initial virologic suppressors, nine of whom had received the vaccine. Initial virologic suppressors had significantly less CD4+ cell decline by ATI week 16 as compared to non-suppressors (median 7 CD4+ cell gain vs. 247 CD4+ cell loss, P = 0.04). However, of the ten initial virologic suppressors with a pVL at ATI week 49, only three maintained pVL <3.0 log10 copies/ml. HIV-1 Gag-specific CD4+ interferon-γ responses were not associated with initial virologic suppression and no evidence of vaccine-driven HIV sequence evolution was detected. Participants with initial virologic suppression were found to have a lower percentage of CD4+ CTLA-4+ cells prior to treatment interruption, but a greater proportion of HIV-1 Gag-reactive CD4+ TNF-α+ cells expressing either CTLA-4 or PD-1. Conclusions Among individuals participating in a rAd5 therapeutic HIV-1 gag vaccine trial, initial viral suppression was found in a subset of patients, but this response was not sustained. The association between CTLA-4 and PD-1 expression on CD4+ T cells and virologic outcome warrants further study in trials of other therapeutic vaccines in development. Trial Registration ClinicalTrials.gov NCT00080106
Increased Risk of Virologic Rebound in Patients on Antiviral Therapy with a Detectable HIV Load <48 Copies/mL
Timothy J. Henrich, Brian R. Wood, Daniel R. Kuritzkes
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0050065
Abstract: We investigated the independent effects of HIV-1 ”target not detected” measurements versus those that were detectable but below the limit of quantification by Taqman RT-PCR assay on subsequent viral rebound as there are conflicting data regarding the clinical implications of arbitrary or isolated low-level viremia. Cox proportional hazard regression modeling was used to investigate the independent effects of the first HIV-1 load measurement after introduction of the Taqman RT-PCR assay (time-point 0 [T0]), pre-T0 viral loads, CD4 T cell count, race/ethnicity, gender, age and NNRTI use on risk of a confirmed VL >50, >200, >400 and >1000 copies/mL at 22 months follow-up in analyses of all patients and propensity-matched baseline cohorts. 778 patients had a viral load that was either not detected by RT-PCR (N = 596) or detectable, but below the limit of quantification (N = 182) at T0. Detectable viremia, lower T0 CD4 count, decreased age, and having detectable or unknown VL within a year prior to T0 were each associated with viral rebound to >50, >200 and >400 copies/mL. Overall failure rates were low and <5.5% of all patients had confirmed VL >1000 copies/mL. A majority of patients with rebound >200 copies/mL subsequently re-suppressed (28 of 53). A detectable VL <48 copies/mL was independently and significantly associated with subsequent viral rebound, and is cause for clinical concern.
Quantitative Deep Sequencing Reveals Dynamic HIV-1 Escape and Large Population Shifts during CCR5 Antagonist Therapy In Vivo
Athe M. N. Tsibris, Bette Korber, Ramy Arnaout, Carsten Russ, Chien-Chi Lo, Thomas Leitner, Brian Gaschen, James Theiler, Roger Paredes, Zhaohui Su, Michael D. Hughes, Roy M. Gulick, Wayne Greaves, Eoin Coakley, Charles Flexner, Chad Nusbaum, Daniel R. Kuritzkes
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005683
Abstract: High-throughput sequencing platforms provide an approach for detecting rare HIV-1 variants and documenting more fully quasispecies diversity. We applied this technology to the V3 loop-coding region of env in samples collected from 4 chronically HIV-infected subjects in whom CCR5 antagonist (vicriviroc [VVC]) therapy failed. Between 25,000–140,000 amplified sequences were obtained per sample. Profound baseline V3 loop sequence heterogeneity existed; predicted CXCR4-using populations were identified in a largely CCR5-using population. The V3 loop forms associated with subsequent virologic failure, either through CXCR4 use or the emergence of high-level VVC resistance, were present as minor variants at 0.8–2.8% of baseline samples. Extreme, rapid shifts in population frequencies toward these forms occurred, and deep sequencing provided a detailed view of the rapid evolutionary impact of VVC selection. Greater V3 diversity was observed post-selection. This previously unreported degree of V3 loop sequence diversity has implications for viral pathogenesis, vaccine design, and the optimal use of HIV-1 CCR5 antagonists.
Coadministration of Lopinavir/Ritonavir and Rifampicin in HIV and Tuberculosis Co-Infected Adults in South Africa
Richard A. Murphy, Vincent C. Marconi, Rajesh T. Gandhi, Daniel R. Kuritzkes, Henry Sunpath
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044793
Abstract: Background In HIV-infected patients receiving rifampicin-based treatment for tuberculosis (TB), the dosage of lopinavir/ritonavir (LPV/r) is adjusted to prevent sub-therapeutic lopinavir concentrations. In this setting, South African clinicians were advised to administer super-boosted LPV/r (400 mg/400 mg) twice daily, instead of standard dosed LPV/r (400 mg/100 mg) twice daily. We sought to determine – in routine practice – the tolerability and HIV treatment outcomes associated with super-boosted LPV/r compared to unadjusted LPV/r in combination with rifampicin-based TB treatment. Methodology/Principle Findings We conducted a retrospective review of HIV-infected patients who receiving second-line ART with a LPV/r-containing regimen who required concomitant TB treatment. We identified 29 patients; the median age was 36 years (IQR 29–40), 22 (76%) were female, the median CD4 cell count and viral load at first-line ART failure was 86 cells/mm3 (IQR 21–159) and 39,457 copies/mL (IQR 6,025–157,500), respectively. According to physician preference, 15 (52%) of 29 patients received super-boosted LPV/r (400 mg/400 mg) every 12 hours during TB treatment and 14 (48%) of 29 patients received standard dose LPV/r (400 mg/100 mg) twice daily during TB treatment. Among patients who received super-boosted LPV/r there was a trend towards a higher rate of symptomatic transaminitis (27% vs. 7%; p = 0.3), gastrointestinal toxicity (20% vs. 0%; p = 0.2) and a significantly increased need for treatment discontinuation (47% vs. 7%; p = 0.035. The durability of coadministered treatment was significantly shorter in patients who received super-boosted lopinavir/ritonavir with TB treatment compared to patients who received standard lopinavir/ritonavir dosing (log rank, P = 0.036). The rate of virologic failure was not higher in patients with unadjusted LPV/r dosing. Conclusions/Significance We observed a high rate of toxicity and need for treatment discontinuation among patients on standard rifampicin-based TB treatment who received super-boosted LPV/r.
Treatment-Mediated Alterations in HIV Fitness Preserve CD4+ T Cell Counts but Have Minimal Effects on Viral Load
Naveen K. Vaidya,Libin Rong,Vincent C. Marconi,Daniel R. Kuritzkes,Steven G. Deeks,Alan S. Perelson
PLOS Computational Biology , 2010, DOI: 10.1371/journal.pcbi.1001012
Abstract: For most HIV-infected patients, antiretroviral therapy controls viral replication. However, in some patients drug resistance can cause therapy to fail. Nonetheless, continued therapy with a failing regimen can preserve or even lead to increases in CD4+ T cell counts. To understand the biological basis of these observations, we used mathematical models to explain observations made in patients with drug-resistant HIV treated with enfuvirtide (ENF/T-20), an HIV-1 fusion inhibitor. Due to resistance emergence, ENF was removed from the drug regimen, drug-sensitive virus regrown, and ENF was re-administered. We used our model to study the dynamics of plasma-viral RNA and CD4+ T cell levels, and the competition between drug-sensitive and resistant viruses during therapy interruption and re-administration. Focusing on resistant viruses carrying the V38A mutation in gp41, we found ENF-resistant virus to be 17±3% less fit than ENF-sensitive virus in the absence of the drug, and that the loss of resistant virus during therapy interruption was primarily due to this fitness cost. Using viral dynamic parameters estimated from these patients, we show that although re-administration of ENF cannot suppress viral load, it can, in the presence of resistant virus, increase CD4+ T cell counts, which should yield clinical benefits. This study provides a framework to investigate HIV and T cell dynamics in patients who develop drug resistance to other antiretroviral agents and may help to develop more effective strategies for treatment.
Enumeration of CD4+ T-Cells Using a Portable Microchip Count Platform in Tanzanian HIV-Infected Patients
SangJun Moon,Umut Atakan Gurkan,Jeffrey Blander,Wafaie W. Fawzi,Said Aboud,Ferdinand Mugusi,Daniel R. Kuritzkes,Utkan Demirci
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0021409
Abstract: CD4+ T-lymphocyte count (CD4 count) is a standard method used to monitor HIV-infected patients during anti-retroviral therapy (ART). The World Health Organization (WHO) has pointed out or recommended that a handheld, point-of-care, reliable, and affordable CD4 count platform is urgently needed in resource-scarce settings.
Episomal Viral cDNAs Identify a Reservoir That Fuels Viral Rebound after Treatment Interruption and That Contributes to Treatment Failure
Mark Sharkey equal contributor,Dunja Z. Babic equal contributor,Thomas Greenough,Roy Gulick,Daniel R. Kuritzkes,Mario Stevenson
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1001303
Abstract: Viral reservoirs that persist in HIV-1 infected individuals on antiretroviral therapy (ART) are the major obstacle to viral eradication. The identification and definition of viral reservoirs in patients on ART is needed in order to understand viral persistence and achieve the goal of viral eradication. We examined whether analysis of episomal HIV-1 genomes provided the means to characterize virus that persists during ART and whether it could reveal the virus that contributes to treatment failure in patients on ART. For six individuals in which virus replication was highly suppressed for at least 20 months, proviral and episomal genomes present just prior to rebound were phylogenetically compared to RNA genomes of rebounding virus after therapy interruption. Episomal envelope sequences, but not proviral envelope sequences, were highly similar to sequences in rebounding virus. Since episomes are products of recent infections, the phylogenetic relationships support the conclusion that viral rebound originated from a cryptic viral reservoir. To evaluate whether the reservoir revealed by episomal sequence analysis was of clinical relevance, we examined whether episomal sequences define a viral population that contributes to virologic failure in individuals receiving the CCR5 antagonist, Vicriviroc. Episomal envelope sequences at or near baseline predicted treatment failure due to the presence of X4 or D/M (dual/mixed) viral variants. In patients that did not harbor X4 or D/M viruses, the basis for Vicriviroc treatment failure was indeterminate. Although these samples were obtained from viremic patients, the assay would be applicable to a large percentage of aviremic patients, based on previous studies. Summarily, the results support the use of episomal HIV-1 as an additional or alternative approach to traditional assays to characterize virus that is maintained during long-term, suppressive ART.
Virologic Failure of Protease Inhibitor-Based Second-Line Antiretroviral Therapy without Resistance in a Large HIV Treatment Program in South Africa
Julie H. Levison,Catherine Orrell,Sébastien Gallien,Daniel R. Kuritzkes,Naishin Fu,Elena Losina,Kenneth A. Freedberg,Robin Wood
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032144
Abstract: We investigated the prevalence of wild-type virus (no major drug resistance) and drug resistance mutations at second-line antiretroviral treatment (ART) failure in a large HIV treatment program in South Africa.
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