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Find video protocols related to scientific articles indexed in Pubmed.
Elevated Levels of Monocyte Activation Markers Are Associated with Subclinical Atherosclerosis in HIV-Infected and -Uninfected Men.
J. Infect. Dis.
PUBLISHED: 11-02-2014
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?Heightened immune activation among HIV-infected persons may contribute to atherosclerosis. We assessed associations of serologic markers of monocyte activation, soluble CD163 (sCD163) and CD14 (sCD14), and monocyte chemoattractant protein-1 (CCL2), with subclinical atherosclerosis among HIV-infected and -uninfected men in the Multicenter AIDS Cohort Study.
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Cochlear function among HIV-seropositive and HIV-seronegative men and women.
Ear Hear
PUBLISHED: 09-01-2014
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There is limited research about cochlear function in adults who are human immunodeficiency virus (HIV) positive (+). The aim of the present study was to collect measures of cochlear function in a large sample of adults with, or at risk for, HIV infection, to evaluate associations between HIV status, HIV treatment, and cochlear function.
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Prevalence and correlates of cryptococcal antigen positivity among AIDS patients--United States, 1986-2012.
MMWR Morb. Mortal. Wkly. Rep.
PUBLISHED: 07-10-2014
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Cryptococcal meningitis (CM) is one of the leading opportunistic infections associated with human immunodeficiency virus (HIV) infection. The worldwide burden of CM among persons living with HIV/acquired immunodeficiency syndrome (AIDS) was estimated in 2009 to be 957,900 cases, with approximately 624,700 deaths annually. The high burden of CM globally comes despite the fact that cryptococcal antigen (CrAg) is detectable weeks before the onset of symptoms, allowing screening for cryptococcal infection and early treatment to prevent CM and CM-related mortality (2). However, few studies have been conducted in the United States to assess the prevalence of cryptococcal infection. To quantify the prevalence of undiagnosed cryptococcal infection in HIV-infected persons in the United States during 1986-2012, stored sera from 1,872 participants in the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study with CD4 T-cell counts <100 cells/µL were screened for CrAg, using the CrAg Lateral Flow Assay (LFA) (Immy, Inc.). This report describes the results of that analysis, which indicated the overall prevalence of CrAg positivity in this population to be 2.9% (95% confidence interval [CI] = 2.2%-3.7%).
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Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy.
J. Exp. Med.
PUBLISHED: 06-16-2014
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Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in individuals below the age of 40. We recently reported that IL-17A is required for the development of DCMi. We show a novel pathway connecting IL-17A, cardiac fibroblasts (CFs), GM-CSF, and heart-infiltrating myeloid cells with the pathogenesis of DCMi. Il17ra(-/-) mice were protected from DCMi, and this was associated with significantly diminished neutrophil and Ly6Chi monocyte/macrophage (MO/M?) cardiac infiltrates. Depletion of Ly6Chi MO/M? also protected mice from DCMi. Mechanistically, IL-17A stimulated CFs to produce key chemokines and cytokines that are critical downstream effectors in the recruitment and differentiation of myeloid cells. Moreover, IL-17A directs Ly6Chi MO/M? in trans toward a more proinflammatory phenotype via CF-derived GM-CSF. Collectively, this IL-17A-fibroblast-GM-CSF-MO/M? axis could provide a novel target for the treatment of DCMi and related inflammatory cardiac diseases.
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Late-emerging strains of HIV induce T-cell homeostasis failure by promoting bystander cell death and immune exhaustion in naïve CD4 and all CD8 T-cells.
Med. Hypotheses
PUBLISHED: 04-01-2014
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The mechanisms involved in the decline of CD4 and CD8 T-cells that lead to HIV-induced immune dysregulation are not clearly understood. We hypothesize that late-emerging strains of HIV, such as CXCR4-tropic (X4) virions, induce T-cell homeostasis failure by promoting significantly more bystander cell death, and immune exhaustion in naïve CD4 and all CD8 T-cells, when compared to strain of HIV, such as CCR5-tropic (R5) virions, found early during the course of infection. In the reported study, inactivated X4 virions induced greater bystander cell death in sort-purified naïve CD4 T-cells compared to R5 virions, which was significant (p=0.013), and in memory CD8 T-cells, though the latter was not significant. A clearer understanding of the mechanisms involved in HIV-induced depletion of T-cell numbers and function could lead to therapies that prevent T-cell death and restore immune function. These therapies could improve current anti-retroviral and cure-related treatments by boosting the immune system's own ability to combat the virus.
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Heterogeneity of CD4+ and CD8+ T-cell responses to cytomegalovirus in HIV-infected and HIV-uninfected men who have sex with men.
J. Infect. Dis.
PUBLISHED: 02-14-2014
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Studies of T-cell immunity to human cytomegalovirus (CMV) primarily reflect anti-CMV pp65 or immediate early antigen 1 (IE-1) activity. We assessed responses of T cells from human immunodeficiency virus (HIV)-negative and HIV-infected men to peptide pools spanning 19 CMV open reading frames selected because they previously correlated with total CMV-specific T-cell responses in healthy donors. Cells producing cytokines in response to pp65 or IE-1 together composed <12% and <40% of the total CD4(+) and CD8(+) T-cell responses to CMV, respectively. These proportions were generally similar regardless of HIV serostatus. Thus, analyses of total CMV-specific T-cell responses should extend beyond pp65 and IE-1 regardless of HIV serostatus.
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Incorrect identification of recent HIV infection in adults in the United States using a limiting-antigen avidity assay.
AIDS
PUBLISHED: 02-12-2014
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To evaluate factors associated with misclassification by the limiting-antigen avidity (LAg-avidity) assay among individuals with long-standing HIV infection.
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NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation.
J. Clin. Invest.
PUBLISHED: 01-27-2014
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A nuclear disaster may result in exposure to potentially lethal doses of ionizing radiation (IR). Hematopoietic acute radiation syndrome (H-ARS) is characterized by severe myelosuppression, which increases the risk of infection, bleeding, and mortality. Here, we determined that activation of nuclear factor erythroid-2-related factor 2 (NRF2) signaling enhances hematopoietic stem progenitor cell (HSPC) function and mitigates IR-induced myelosuppression and mortality. Augmenting NRF2 signaling in mice, either by genetic deletion of the NRF2 inhibitor Keap1 or by pharmacological NRF2 activation with 2-trifluoromethyl-2'-methoxychalone (TMC), enhanced hematopoietic reconstitution following bone marrow transplantation (BMT). Strikingly, even 24 hours after lethal IR exposure, oral administration of TMC mitigated myelosuppression and mortality in mice. Furthermore, TMC administration to irradiated transgenic Notch reporter mice revealed activation of Notch signaling in HSPCs and enhanced HSPC expansion by increasing Jagged1 expression in BM stromal cells. Administration of a Notch inhibitor ablated the effects of TMC on hematopoietic reconstitution. Taken together, we identified a mechanism by which NRF2-mediated Notch signaling improves HSPC function and myelosuppression following IR exposure. Our data indicate that targeting this pathway may provide a countermeasure against the damaging effects of IR exposure.
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Association between systemic inflammation and obstructive sleep apnea in men with or at risk for HIV infection.
Antivir. Ther. (Lond.)
PUBLISHED: 01-21-2014
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We sought to determine whether markers of systemic inflammation are associated with the presence of moderate-to-severe obstructive sleep apnea (OSA), and whether this association differs based on HIV and HIV treatment status.
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Transmission and evolution of hepatitis C virus in HCV seroconverters in HIV infected subjects.
Virology
PUBLISHED: 01-15-2014
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HIV/HCV co-infection provides a model to determine the role of immunity on HCV transmission and evolution. In this study HCV transmission and evolution were evaluated in 6 HCV seroconverters in HIV-infected subjects with a wide range of CD4 cell count. The HCV envelope E1/E2 sequences were analyzed for transmission bottleneck, viral diversity/divergence, immune pressure, and mutations of HLA class I/II restricted epitopes. HCV infection started with transmission bottleneck in all HIV-infected individuals. During the 1.0-2.0 years of infection there was a shift of viral quasispecies in majority of the subjects from one to next visit. However, HCV diversity, divergence, mutations in HLA class I/II restricted and virus neutralizing epitopes were similar in all subjects regardless of CD4 cell count at the time of HCV infection. Our results suggest that HCV transmission and evolution in HIV-infected subjects may not be influenced by host CD4 cell count at the time of infection.
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Lower adiponectin is associated with subclinical cardiovascular disease among HIV-infected men.
AIDS
PUBLISHED: 01-10-2014
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To examine whether altered levels of adipokines, adipose-derived peptides associated with myocardial infarction in the general population, may contribute to subclinical coronary atherosclerosis in HIV-infected persons.
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Chronic CMV infection in older women: longitudinal comparisons of CMV DNA in peripheral monocytes, anti-CMV IgG titers, serum IL-6 levels, and CMV pp65 (NLV)-specific CD8(+) T-cell frequencies with twelve year follow-up.
Exp. Gerontol.
PUBLISHED: 01-02-2014
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Chronic cytomegalovirus (CMV) infection may contribute significantly to T-cell immunosenescence, chronic inflammation, and adverse health outcomes in older adults. Recent studies suggest detectable CMV DNA in peripheral monocytes as a better indicator for this persistent viral infection than anti-CMV IgG serology. Here, we conducted longitudinal comparisons of anti-CMV IgG titers, CMV DNA in the peripheral monocytes, serum IL-6 levels, and CMV pp65 (NLV)-specific CD8(+) T-cell frequencies in fifteen community-dwelling older women with twelve year follow-up. The results showed that anti-CMV IgG titers did not change over twelve years. Women with detectable CMV DNA had significantly higher IL-6 levels than those without, both at baseline (3.06±0.58 vs 1.19±0.37pg/ml, respectively, p<.001) and at the follow-up (3.23±0.66 versus 0.98±0.37pg/ml, respectively, p<.001). In addition, CMV pp65 (NLV)-specific CD8(+) T cells were detected only in women who had CMV DNA with similar frequencies at both time points. These findings indicate that anti-CMV IgG serology is neither sensitive to change nor useful for monitoring chronic CMV infection over time. They also provide a basis for further investigation into chronic CMV infection as defined by detectable CMV DNA in the peripheral monocytes and its impact on immunity and health in the elderly.
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Sleep disordered breathing, fatigue, and sleepiness in HIV-infected and -uninfected men.
PLoS ONE
PUBLISHED: 01-01-2014
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We investigated the association of HIV infection and highly active antiretroviral therapy (HAART) with sleep disordered breathing (SDB), fatigue, and sleepiness.
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A comparison of two measures of HIV diversity in multi-assay algorithms for HIV incidence estimation.
PLoS ONE
PUBLISHED: 01-01-2014
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Multi-assay algorithms (MAAs) can be used to estimate HIV incidence in cross-sectional surveys. We compared the performance of two MAAs that use HIV diversity as one of four biomarkers for analysis of HIV incidence.
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Factors affecting glomerular filtration rate, as measured by iohexol disappearance, in men with or at risk for HIV infection.
PLoS ONE
PUBLISHED: 01-01-2014
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Formulae used to estimate glomerular filtration rate (GFR) underestimate higher GFRs and have not been well-studied in HIV-infected (HIV(+)) people; we evaluated the relationships of HIV infection and known or potential risk factors for kidney disease with directly measured GFR and the presence of chronic kidney disease (CKD).
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HIV Diversity as a Biomarker for HIV Incidence Estimation: Including a High-Resolution Melting Diversity Assay in a Multiassay Algorithm.
J. Clin. Microbiol.
PUBLISHED: 10-23-2013
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Multiassay algorithms (MAAs) can be used to estimate cross-sectional HIV incidence. We previously identified a robust MAA that includes the BED capture enzyme immunoassay (BED-CEIA), the Bio-Rad Avidity assay, viral load, and CD4 cell count. In this report, we evaluated MAAs that include a high-resolution melting (HRM) diversity assay that does not require sequencing. HRM scores were determined for eight regions of the HIV genome (2 in gag, 1 in pol, and 5 in env). The MAAs that were evaluated included the BED-CEIA, the Bio-Rad Avidity assay, viral load, and the HRM diversity assay, using HRM scores from different regions and a range of region-specific HRM diversity assay cutoffs. The performance characteristics based on the proportion of samples that were classified as MAA positive by duration of infection were determined for each MAA, including the mean window period. The cross-sectional incidence estimates obtained using optimized MAAs were compared to longitudinal incidence estimates for three cohorts in the United States. The performance of the HRM-based MAA was nearly identical to that of the MAA that included CD4 cell count. The HRM-based MAA had a mean window period of 154 days and provided cross-sectional incidence estimates that were similar to those based on cohort follow-up. HIV diversity is a useful biomarker for estimating HIV incidence. MAAs that include the HRM diversity assay can provide accurate HIV incidence estimates using stored blood plasma or serum samples without a requirement for CD4 cell count data.
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Age, Comorbidities, and AIDS Predict a Frailty Phenotype in Men Who Have Sex With Men.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 10-14-2013
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Adults aging with HIV infection are at risk for age-related comorbidities and syndromes, such as frailty. The objective of this study was to evaluate the expression and predictors of the frailty phenotype (FP) among HIV-infected (HIV+) and HIV-uninfected (HIV-) men who have sex with men.
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Unique characteristics of histone deacetylase inhibitors in reactivation of latent HIV-1 in Bcl-2-transduced primary resting CD4+ T cells.
J. Antimicrob. Chemother.
PUBLISHED: 09-01-2013
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The latent reservoir for HIV-1 in resting memory CD4+ T cells is a major barrier to eradication. In vitro models involving transformed cell lines have been used to search for small molecules that reactivate latent HIV-1. Histone deacetylase (HDAC) inhibitors can reverse HIV-1 latent infection. Most studies on HDAC inhibitors have been performed in cell line models that differ in important aspects from the resting CD4+ T cells that harbour latent HIV-1 in vivo. Therefore, we evaluated the potency and kinetics of HDAC inhibitors in a primary cell model of HIV-1 latency that involves resting CD4+ T cells.
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Limited nucleotide changes in the Rev response element (RRE) during HIV-1 infection alter overall Rev-RRE activity and Rev multimerization.
J. Virol.
PUBLISHED: 08-07-2013
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HIV-1 Rev and the Rev response element (RRE) enable a critical step in the viral replication cycle by facilitating the nuclear export of intron-containing mRNAs, yet their activities have rarely been analyzed in natural infections. This study characterized their genetic and functional variation in a small cohort of HIV-infected individuals. Multiple Rev and RRE sequences were obtained using single-genome sequencing (SGS) of plasma samples collected within 6 months after seroconversion and at a later time. This allowed the identification of cognate sequences that were linked in vivo in the same viral genome and acted together as a functional unit. Phylogenetic analyses of these sequences indicated that 4/5 infections were founded by a single transmission event. Rev and RRE variants from each time point were subjected to functional analysis as both cognate pairs and as individual components. While a range of Rev-RRE activities were seen, the activity of cognate pairs from a single time point clustered to a discrete level, which was termed the set point. In 3/5 patients, this set point changed significantly over the time period studied. In all patients, RRE activity was more sensitive to sequence variation than Rev activity and acted as the primary driver of the cognate set point. Selected patient RREs were also shown to have differences in Rev multimerization using gel shift binding assays. Thus, rather than acting as a simple on-off switch or maintaining a constant level of activity throughout infection, the Rev-RRE system can fluctuate, presumably to control replication.
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Lipodystrophy and inflammation predict later grip strength in HIV-infected men: the MACS Body Composition substudy.
AIDS Res. Hum. Retroviruses
PUBLISHED: 05-02-2013
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Body fat changes in HIV-infected persons are associated with increased systemic inflammation and increased mortality. It is unknown whether lipodystrophy is also associated with declines in physical function. Between 2001 and 2003, 33 HIV-infected men with evidence of lipodystrophy (LIPO?), 23 HIV-infected men without lipodystrophy (LIPO?), and 33 seronegative men were recruited from the Multicenter AIDS Cohort Study (MACS) for the Body Composition substudy. Visceral adipose tissue (VAT) was assessed by quantitative computed tomography. Lean body mass (LBM) and extremity fat were measured by dual-energy x-ray absorptiometry. Insulin resistance was estimated by Homeostatic Model Assessment (HOMA). Serum interleukin (IL)-6, soluble tumor necrosis factor (TNF)-? receptors I and II (sTNFRI and sTNFRII), and highly sensitive C-reactive protein (hs-CRP) concentrations were quantified from archived serum samples. These measurements were correlated with grip strength measured in 2007 using linear regression. At the substudy visit, the LIPO? group had higher HOMA, sTNFRI, sTNFRII, and IL-6 levels than the LIPO? group. In 2007, the LIPO? group had lower median grip strength than the LIPO? group (34.4 vs. 42.7 kg, p=0.002). Multivariable analysis of HIV? men showed older age, lower LBM, higher sTNFRII concentrations, and LIPO? status [adjusted mean difference -4.9 kg (p=0.045)] at the substudy visit were independently associated with lower subsequent grip strength. Inflammation, lower LBM, and lipodystrophy in HIV-infected men were associated with lower subsequent grip strength. These findings suggest that inflammation may contribute to declines in functional performance, independent of age.
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A novel PCR assay for quantification of HIV-1 RNA.
J. Virol.
PUBLISHED: 03-27-2013
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Current assays for quantification of HIV-1 virions rely on real-time reverse transcriptase (RT)-PCR detection of conserved regions of HIV-1 RNA and can be limited by detection of contaminating viral or plasmid DNA. We developed a novel RT-PCR assay using a reverse primer that hybridizes with the poly(A) tail of HIV-1 mRNAs, anchored by conserved viral nucleotides at the most distal region of the transcript. This assay can detect and quantify HIV-1 RNA with high specificity and sensitivity.
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Ciprofloxacin resistance in the faecal carriage of patients undergoing transrectal ultrasound guided prostate biopsy.
BJU Int.
PUBLISHED: 03-06-2013
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WHATS KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Transrectal ultrasound guided prostate biopsies (TRUSBx) are associated with a spectrum of complications, including most significantly infection, which affects up to 5% of patients. In the most severe cases, infection leads to sepsis, a life-threatening complication. Escherichia coli is the primary responsible pathogen. Although antibiotic prophylaxis with fluoroquinolones is routinely used, there is evidence that the infection rate after TRUSBx is increasing, and this appears to be due to an increasing prevalence of ciprofloxacin-resistant rectal flora. This is the largest prospective clinical trial to date analysing the rectal flora of men undergoing prostate biopsies. We determined the microbial and antibiotic sensitivity profiles from 849 patients. Ciprofloxacin-resistant Gram-negative organisms were identified in the rectal flora of 19.0% of men. Furthermore, fluoroquinolone use within 6 months preceding a TRUSBx and the presence of a prosthetic heart valve were significant predictors of ciprofloxacin resistance on rectal swab. Determining the prevalence of rectal fluoroquinolone resistance has important implications in evaluation of the suitability of prophylactic regimens. Antimicrobial profiles derived from rectal swabs pre-biopsy may prove useful in guiding targeted antibiotic prophylaxis.
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Value of a quality assessment program in optimizing cryopreservation of peripheral blood mononuclear cells in a multicenter study.
Clin. Vaccine Immunol.
PUBLISHED: 02-13-2013
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Cryopreservation of peripheral blood mononuclear cells (PBMC) allows assays of cellular function and phenotype to be performed in batches at a later time on PBMC at a central laboratory to minimize assay variability. The Multicenter AIDS Cohort Study (MACS) is an ongoing prospective study of the natural and treated history of human immunodeficiency virus (HIV) infection that stores cryopreserved PBMC from participants two times a year at four study sites. In order to ensure consistent recovery of viable PBMC after cryopreservation, a quality assessment program was implemented and conducted in the MACS over a 6-year period. Every 4 months, recently cryopreserved PBMC from HIV-1-infected and HIV-1-uninfected participants at each MACS site were thawed and evaluated. The median recoveries of viable PBMC for HIV-1-infected and -uninfected participants were 80% and 83%, respectively. Thawed PBMC from both HIV-1-infected and -uninfected participants mounted a strong proliferative response to phytohemagglutinin, with median stimulation indices of 84 and 120, respectively. Expression of the lymphocyte surface markers CD3, CD4, and CD8 by thawed PBMC was virtually identical to what was observed on cells measured in real time using whole blood from the same participants. Furthermore, despite overall excellent performance of the four participating laboratories, problems were identified that intermittently compromised the quality of cryopreserved PBMC, which could be corrected and monitored for improvement over time. Ongoing quality assessment helps laboratories improve protocols and performance on a real-time basis to ensure optimal cryopreservation of PBMC for future studies.
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The impact of HAART on the respiratory complications of HIV infection: longitudinal trends in the MACS and WIHS cohorts.
PLoS ONE
PUBLISHED: 02-07-2013
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To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART).
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Blockade of Kv1.3 potassium channels inhibits differentiation and granzyme B secretion of human CD8+ T effector memory lymphocytes.
PLoS ONE
PUBLISHED: 01-30-2013
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Increased expression of the voltage-gated potassium channel K?1.3 on activated effector memory T cells (T(EM)) is associated with pathology in multiple sclerosis (MS). To date, most studies of K?1.3 channels in MS have focused on CD4+ T(EM) cells. Much less is known about the functional relevance of Kv1.3 on CD8+ T(EM) cells. Herein, we examined the effects of K?1.3 blockade on CD8+ T cell proliferation, differentiation into cytotoxic effector cells, and release of granzyme B (GrB), a key effector of CD8+ T cell-mediated cytotoxicity. We confirmed the expression of Kv1.3 channels on activated human CD8+ T lymphocytes by immunofluorescent staining. To test the functional relevance of the Kv1.3 channel in CD8+ T cells, we inhibited this channel via pharmacological blockers or a lentiviral-dominant negative (Kv1.xDN) approach and determined the effects of the blockade on critical pathogenic parameters of CD8+ T cells. We found that blockade of Kv1.3 with both lentivirus and pharmacologic agents effectively inhibited cytotoxic effector memory cells proliferation, secretion of GrB, and their ability to kill neural progenitor cells. Intriguingly, the KvDN transduced T cells exhibited arrested differentiation from central memory (T(CM)) to effector memory (T(EM)) states. Transduction of cells that had already differentiated into T(EM) with KvDN led to their conversion into T(CM). CD8+ T(EM) have a critical role in MS and other autoimmune diseases. Our present results indicate a critical role for Kv1.3 in the conversion of CD8+ T cells into potential pathogenic effector cells with cytotoxic function.
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Performance of a Limiting-Antigen Avidity Enzyme Immunoassay for Cross-Sectional Estimation of HIV Incidence in the United States.
PLoS ONE
PUBLISHED: 01-01-2013
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A limiting antigen avidity enzyme immunoassay (HIV-1 LAg-Avidity assay) was recently developed for cross-sectional HIV incidence estimation. We evaluated the performance of the LAg-Avidity assay alone and in multi-assay algorithms (MAAs) that included other biomarkers.
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Novel structurally related compounds reactivate latent HIV-1 in a bcl-2-transduced primary CD4+ T cell model without inducing global T cell activation.
J. Antimicrob. Chemother.
PUBLISHED: 12-07-2011
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The latent reservoir of HIV-1 in resting memory CD4+ T cells is a major barrier to curing HIV-1 infection. Eradication strategies involve reactivation of this latent reservoir; however, agents that reactivate latent HIV-1 through non-specific T cell activation are toxic.
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Factors associated with incorrect identification of recent HIV infection using the BED capture immunoassay.
AIDS Res. Hum. Retroviruses
PUBLISHED: 12-01-2011
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The BED capture enzyme immunoassay (BED-CEIA) was developed for estimating HIV incidence from cross-sectional data. This assay misclassifies some individuals with nonrecent HIV infection as recently infected, leading to overestimation of HIV incidence. We analyzed factors associated with misclassification by the BED-CEIA. We analyzed samples from 383 men who were diagnosed with HIV infection less than 1 year after a negative HIV test (Multicenter AIDS Cohort Study). Samples were collected 2-8 years after HIV seroconversion, which was defined as the midpoint between the last negative and first positive HIV test. Samples were analyzed using the BED-CEIA with a cutoff of OD-n ? 0.8 for recent infection. Logistic regression was used to identify factors associated with misclassification. Ninety-one (15.1%) of 603 samples were misclassified. In multivariate models, misclassification was independently associated with highly active antiretroviral treatment (HAART) for >2 years, HIV RNA <400 copies/ml, and CD4 cell count <50 or <200 cells/mm(3); adjusted odds ratios (OR) and 95% confidence intervals (CI) were 4.72 (1.35-16.5), 3.96 (1.53-10.3), 6.85 (2.71-17.4), and 11.5 (3.64-36.0), respectively. Among 220 men with paired samples, misclassification 2-4 years after seroconversion was significantly associated with misclassification 6-8 years after seroconversion [adjusted OR: 25.8 (95% CI: 8.17-81.5), p<0.001] after adjusting for race, CD4 cell count, HIV viral load, and HAART use. Low HIV viral load, low CD4 cell count, and >2 years of HAART were significantly associated with misclassification using the BED-CEIA. Some men were persistently misclassified as recently infected up to 8 years after HIV seroconversion.
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Functional blockade of the voltage-gated potassium channel Kv1.3 mediates reversion of T effector to central memory lymphocytes through SMAD3/p21cip1 signaling.
J. Biol. Chem.
PUBLISHED: 11-22-2011
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The maintenance of T cell memory is critical for the development of rapid recall responses to pathogens, but may also have the undesired side effect of clonal expansion of T effector memory (T(EM)) cells in chronic autoimmune diseases. The mechanisms by which lineage differentiation of T cells is controlled have been investigated, but are not completely understood. Our previous work demonstrated a role of the voltage-gated potassium channel Kv1.3 in effector T cell function in autoimmune disease. In the present study, we have identified a mechanism by which Kv1.3 regulates the conversion of T central memory cells (T(CM)) into T(EM). Using a lentiviral-dominant negative approach, we show that loss of function of Kv1.3 mediates reversion of T(EM) into T(CM), via a delay in cell cycle progression at the G2/M stage. The inhibition of Kv1.3 signaling caused an up-regulation of SMAD3 phosphorylation and induction of nuclear p21(cip1) with resulting suppression of Cdk1 and cyclin B1. These data highlight a novel role for Kv1.3 in T cell differentiation and memory responses, and provide further support for the therapeutic potential of Kv1.3 specific channel blockers in T(EM)-mediated autoimmune diseases.
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Risk factors for oral HPV infection among a high prevalence population of HIV-positive and at-risk HIV-negative adults.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 11-01-2011
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Human papillomavirus (HPV) is an important risk factor for oropharyngeal cancer. Individuals with human immunodeficiency virus (HIV) have higher oral HPV prevalence but the risk factors for oral HPV infection are not well understood for either HIV-positive or HIV-negative individuals.
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Prolonged control of replication-competent dual- tropic human immunodeficiency virus-1 following cessation of highly active antiretroviral therapy.
Retrovirology
PUBLISHED: 09-12-2011
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While initiation of highly active antiretroviral therapy (HAART) during primary HIV-1 infection occasionally results in transient control of viral replication after treatment interruption, the vast majority of patients eventually experience a rebound in plasma viremia.
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JC virus antibody and viremia as predictors of progressive multifocal leukoencephalopathy in human immunodeficiency virus-1-infected individuals.
Clin. Infect. Dis.
PUBLISHED: 08-18-2011
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We examined whether prediagnostic John Cunningham virus (JCV) antibodies and viremia are predictors of progressive multifocal leukoencephalopathy (PML) in 83 PML cases and 240 human immunodeficiency virus (HIV) disease-matched controls. JCV viremia was not predictive of PML, but some patients showed higher anti-JCV immunoglobulin G (IgG) responses 6 months prior to diagnosis.
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Identifying the early post-HIV antibody seroconversion period.
J. Infect. Dis.
PUBLISHED: 07-28-2011
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Identifying persons with recent human immunodeficiency virus (HIV) antibody seroconversion is useful for treatment, research, and prevention, but the sensitivity and specificity of tests for this purpose are uncertain.
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A frailty-related phenotype before HAART initiation as an independent risk factor for AIDS or death after HAART among HIV-infected men.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 06-30-2011
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In the general population, frailty, a late stage of the aging process, predicts mortality. We investigated whether manifesting a previously defined frailty-related phenotype (FRP) before initiating highly active antiretroviral therapy (HAART) affects the likelihood of developing clinical AIDS or mortality after HAART initiation.
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Multisite comparison of high-sensitivity multiplex cytokine assays.
Clin. Vaccine Immunol.
PUBLISHED: 06-22-2011
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The concentrations of cytokines in human serum and plasma can provide valuable information about in vivo immune status, but low concentrations often require high-sensitivity assays to permit detection. The recent development of multiplex assays, which can measure multiple cytokines in one small sample, holds great promise, especially for studies in which limited volumes of stored serum or plasma are available. Four high-sensitivity cytokine multiplex assays on a Luminex (Bio-Rad, BioSource, Linco) or electrochemiluminescence (Meso Scale Discovery) platform were evaluated for their ability to detect circulating concentrations of 13 cytokines, as well as for laboratory and lot variability. Assays were performed in six different laboratories utilizing archived serum from HIV-uninfected and -infected subjects from the Multicenter AIDS Cohort Study (MACS) and the Womens Interagency HIV Study (WIHS) and commercial plasma samples spanning initial HIV viremia. In a majority of serum samples, interleukin-6 (IL-6), IL-8, IL-10, and tumor necrosis factor alpha were detectable with at least three kits, while IL-1? was clearly detected with only one kit. No single multiplex panel detected all cytokines, and there were highly significant differences (P < 0.001) between laboratories and/or lots with all kits. Nevertheless, the kits generally detected similar patterns of cytokine perturbation during primary HIV viremia. This multisite comparison suggests that current multiplex assays vary in their ability to measure serum and/or plasma concentrations of cytokines and may not be sufficiently reproducible for repeated determinations over a long-term study or in multiple laboratories but may be useful for longitudinal studies in which relative, rather than absolute, changes in cytokines are important.
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Universal GFR determination based on two time points during plasma iohexol disappearance.
Kidney Int.
PUBLISHED: 06-08-2011
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An optimal measurement of glomerular filtration rate (GFR) should minimize the number of blood draws, and reduce procedural invasiveness and the burden to study personnel and cost, without sacrificing accuracy. Equations have been proposed to calculate GFR from the slow compartment separately for adults and children. To develop a universal equation, we used 1347 GFR measurements from two diverse groups consisting of 527 men in the Multicenter AIDS Cohort Study and 514 children in the Chronic Kidney Disease in Children cohort. Both studies used nearly identical two-compartment (fast and slow) protocols to measure GFR. To estimate the fast component from markers of body size and of the slow component, we used standard linear regression methods with the log-transformed fast area as the dependent variable. The fast area could be accurately estimated from body surface area by a simple parameter (6.4/body surface area) with no residual dependence on the slow area or other markers of body size. Our equation measures only the slow iohexol plasma disappearance curve with as few as two time points and was normalized to 1.73?m2 body surface area. It is of the form: GFR=slowGFR/[1+0.12(slowGFR/100)]. In a random sample utilizing a third of the patients for validation, there was excellent agreement between the calculated and measured GFR with low root mean square errors being 4.6 and 1.5?ml/min per 1.73?m2 for adults and children, respectively. Thus, our proposed simple equation, developed in a combined patient group with a broad range of GFRs, may be applied universally and is independent of the injected amount of iohexol.
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CD4+ T-cell counts and plasma HIV-1 RNA levels beyond 5 years of highly active antiretroviral therapy.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 05-24-2011
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The heterogeneity of CD4 T-cell counts and HIV-1 RNA at 5-12 years after the initiation of highly active antiretroviral therapy (HAART) remains largely uncharacterized.
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Serological immunity to adenovirus serotype 5 is not associated with risk of HIV infection: a case-control study.
AIDS
PUBLISHED: 05-07-2011
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adenoviruses are among the most promising vectors for the development of an HIV vaccine. The results of the phase IIB study of the adenovirus serotype 5-based Merck Trivalent HIV vaccine have raised the concern that serological immunity to adenovirus serotype 5 (Ad5) could be linked to HIV acquisition risk in high-risk individuals. We examined the association between adenovirus serostatus and the rate of incident HIV infection in populations at elevated risk of HIV acquisition.
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Multiplex measurement of proinflammatory cytokines in human serum: comparison of the Meso Scale Discovery electrochemiluminescence assay and the Cytometric Bead Array.
J. Immunol. Methods
PUBLISHED: 04-15-2011
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Serum cytokine profiling is a powerful tool to link host immune defense with disease pathogenesis. Although several multiplex assays are commercially available, none has been rigorously validated in the context of chronic infectious disease (such as HIV infection). Here we compared the measurement of proinflammatory cytokines by two multiplex platforms: the Meso Scale Discovery (MSD) electrochemiluminescence assay and the Becton Dickinson Cytometric Bead Array (CBA) flow cytometric assay, using serum samples from HIV-infected and -uninfected donors. We evaluated the ability of these assays to: a) quantify circulating levels of native cytokines (IL-6, IL-8, IL-10, TNF-?, IL-12p70, IL-1?), and b) accurately recover known amounts of recombinant cytokines added to serum samples. Based on the standard curves, the sensitivity of the MSD system was only slightly better than the CBA. However, in serum the MSD platform consistently quantified levels of endogenous IL-12p70, TNF-?, and IL-10 that were undetectable by the CBA assay. The MSD assay was also more accurate as determined by an enhanced capacity to recover known concentrations of recombinant cytokines added to serum. Both assays performed equally well in quantifying IL-6 and IL-8, while neither assay quantified IL-1? with accuracy and precision. Interestingly, HIV infection did not affect the performance of either assay. Overall, the MSD assay provided a more reliable assessment of the proinflammatory cytokines tested in the serum of healthy and HIV-infected individuals.
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Disulfiram reactivates latent HIV-1 in a Bcl-2-transduced primary CD4+ T cell model without inducing global T cell activation.
J. Virol.
PUBLISHED: 04-06-2011
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Highly active antiretroviral therapy (HAART) can reduce plasma HIV-1 levels to below the detection limit. However, due to the latent reservoir in resting CD4(+) cells, HAART is not curative. Elimination of this reservoir is critical to curing HIV-1 infection. Agents that reactivate latent HIV-1 through nonspecific T cell activation are toxic. Here we demonstrate in a primary CD4(+) T cell model that the FDA-approved drug disulfiram reactivates latent HIV-1 without global T cell activation. The extent to which disulfiram reactivates latent HIV-1 in patient cells is unclear, but the drug alone or in combination may be useful in future eradication strategies.
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Influence of host gene transcription level and orientation on HIV-1 latency in a primary-cell model.
J. Virol.
PUBLISHED: 03-23-2011
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Human immunodeficiency virus type 1 (HIV-1) establishes a latent reservoir in resting memory CD4(+) T cells. This latent reservoir is a major barrier to the eradication of HIV-1 in infected individuals and is not affected by highly active antiretroviral therapy (HAART). Reactivation of latent HIV-1 is a possible strategy for elimination of this reservoir. The mechanisms with which latency is maintained are unclear. In the analysis of the regulation of HIV-1 gene expression, it is important to consider the nature of HIV-1 integration sites. In this study, we analyzed the integration and transcription of latent HIV-1 in a primary CD4(+) T cell model of latency. The majority of integration sites in latently infected cells were in introns of transcription units. Serial analysis of gene expression (SAGE) demonstrated that more than 90% of those host genes harboring a latent integrated provirus were transcriptionally active, mostly at high levels. For latently infected cells, we observed a modest preference for integration in the same transcriptional orientation as the host gene (63.8% versus 36.2%). In contrast, this orientation preference was not observed in acutely infected or persistently infected cells. These results suggest that transcriptional interference may be one of the important factors in the establishment and maintenance of HIV-1 latency. Our findings suggest that disrupting the negative control of HIV-1 transcription by upstream host promoters could facilitate the reactivation of latent HIV-1 in some resting CD4(+) T cells.
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The dual impact of HIV-1 infection and aging on naïve CD4 T-cells: additive and distinct patterns of impairment.
PLoS ONE
PUBLISHED: 01-26-2011
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HIV-1-infected adults over the age of 50 years progress to AIDS more rapidly than adults in their twenties or thirties. In addition, HIV-1-infected individuals receiving antiretroviral therapy (ART) present with clinical diseases, such as various cancers and liver disease, more commonly seen in older uninfected adults. These observations suggest that HIV-1 infection in older persons can have detrimental immunological effects that are not completely reversed by ART. As naïve T-cells are critically important in responses to neoantigens, we first analyzed two subsets (CD45RA(+)CD31(+) and CD45RA(+)CD31(-)) within the naïve CD4(+) T-cell compartment in young (20-32 years old) and older (39-58 years old), ART-naïve, HIV-1 seropositive individuals within 1-3 years of infection and in age-matched seronegative controls. HIV-1 infection in the young cohort was associated with lower absolute numbers of, and shorter telomere lengths within, both CD45RA(+)CD31(+)CD4(+) and CD45RA(+)CD31(-)CD4(+) T-cell subsets in comparison to age-matched seronegative controls, changes that resembled seronegative individuals who were decades older. Longitudinal analysis provided evidence of thymic emigration and reconstitution of CD45RA(+)CD31(+)CD4(+) T-cells two years post-ART, but minimal reconstitution of the CD45RA(+)CD31(-)CD4(+) subset, which could impair de novo immune responses. For both ART-naïve and ART-treated HIV-1-infected adults, a renewable pool of thymic emigrants is necessary to maintain CD4(+) T-cell homeostasis. Overall, these results offer a partial explanation both for the faster disease progression of older adults and the observation that viral responders to ART present with clinical diseases associated with older adults.
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Relationship between cytomegalovirus (CMV) IgG serology, detectable CMV DNA in peripheral monocytes, and CMV pp65(495-503)-specific CD8+ T cells in older adults.
Age (Dordr)
PUBLISHED: 01-03-2011
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In immunocompetent individuals, cytomegalovirus (CMV) is thought to persist in a latent state in monocytes and myeloid progenitor cells, establishing a lifelong infection. In CMV-seropositive older adults, aging has been associated with both expansion of CMV pp65(495-503)-specific CD8(+) T cell clones and shrinkage of the T cell repertoire that characterize T cell immunosenescence. In fact it has been suggested that chronic CMV infection is a driving force in age-related T cell immunosenescence. In older adults, chronic CMV infection is conventionally diagnosed by positive IgG serology which does not distinguish between past and persistent infections. To better define the relationship between chronic CMV infection and expansion of CMV pp65(495-503)-specific CD8(+) T cells, we directly assessed CMV viral DNA in monocyte-enriched peripheral blood mononuclear cells in 16 HLA-A2-positive elderly volunteers (mean age = 83 years). While all participants had positive CMV IgG serology by enzyme-linked immunosorbent assays, only nine (56%) had detectable CMV DNA by nested polymerase chain reaction. These nine individuals had significantly higher percentages of CMV pp65(495-503) tetramer-positive CD8(+) T cells (median = 1.3%) than those without detectable CMV DNA (median = 0.1%; p < 0.001). Absolute CMV IgG antibody titers did not differ between these two groups (median = 54.6 vs 44.2 EU/ml, respectively, p = 0.4). CMV IgM titers were negative for all 16 participants, suggesting that recent primary CMV infection was unlikely. These results demonstrate a strong association between the presence of CMV DNA in peripheral monocytes and the expansion of CD8(+) T cells specific for the CMV immunodominant epitope pp65(495-503). Although the sample size in this study is relatively small, these findings provide initial evidence suggesting the heterogeneity of CMV IgG-seropositive older adult population and CMV viral DNA detection in peripheral monocytes as an informative tool to better understand the relationship between chronic CMV infection and T cell immunosenescence.
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HIV-1 Gag evolution in recently infected human leukocyte antigen-B*57 patients with low-level viremia.
AIDS
PUBLISHED: 07-31-2010
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We studied viral evolution in five human leukocyte antigen (HLA)-B*57 patients recently infected with HIV-1. Escape mutations in HLA-B*57-restricted Gag epitopes were present at study entry in all patients, but were not associated with significant increases in viremia. Conversely, no new escape mutations in HLA-B*57-restricted epitopes or known compensatory mutations were detected in patients who experienced significant increases in viremia. Thus, the development of escape mutations alone does not determine virologic outcome in recently infected HLA-B*57 patients.
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Anthropometry in the prediction of sleep disordered breathing in HIV-positive and HIV-negative men.
Antivir. Ther. (Lond.)
PUBLISHED: 07-01-2010
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Body mass index (BMI), waist circumference (WC) and neck circumference (NC) are important screening tools for sleep disordered breathing (SDB); however, the utility of anthropometry for this purpose has not been evaluated among HIV-positive patients.
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The relationship between antibody to R7V and progression of HIV type 1 infection.
AIDS Res. Hum. Retroviruses
PUBLISHED: 04-27-2010
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The presence of antibody to R7V (anti-R7VAb), a seven-amino acid sequence derived from beta(2)-microglobulin incorporated into HIV-1 virions from the surface of infected cells, has been proposed as an early marker of nonprogressive HIV-1 infection. The present study was undertaken because no prospective studies have tested this hypothesis. Stored samples collected prospectively from 361 HIV-1 seroconverting men in the Multicenter AIDS Cohort Study (0.44-1.53 years after seroconversion) were assayed for the presence or absence of anti-R7VAb, using a standardized ELISA. Using Cox proportional hazards models, crude and adjusted relative hazards (RH) were determined for the following outcomes: (a) clinically defined AIDS, (b) clinically defined AIDS or CD4 T cell count of <200 cells/microl, and (c) death. A total of 143 (39.6%) men had early anti-R7VAb and 218 (60.4%) did not; 192 (53.2%) developed AIDS. At the visit tested, men with anti-R7VAb had significantly lower CD4 T cell counts and higher plasma HIV-1 viral loads than those without antibody. After adjustment for CD4 T cell count, HIV-1 viral load, CCR5 polymorphism, and use of combined antiretroviral therapy, the presence of anti-R7VAb was associated with a higher risk of progression for all outcomes, but not significantly so. Absence of anti-R7VAb was significantly associated with expression of HLA-B*5701 and -B*2705, two alleles associated with slower progression of HIV-1 disease. The early presence of anti-R7VAb in HIV-1 seroconverters was not associated with slower progression of HIV-1 disease.
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Cytokine signaling pathway polymorphisms and AIDS-related non-Hodgkin lymphoma risk in the multicenter AIDS cohort study.
AIDS
PUBLISHED: 03-20-2010
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Cytokine stimulation of B-cell proliferation may be an important causative mechanism for acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). The Epstein-Barr virus (EBV) may be a co-factor, particularly for primary central nervous system (CNS) tumors, which are uniformly EBV-positive in the setting of AIDS. Thus, we examined associations of genetic variation in IL10 and related cytokine-signaling molecules (IL10RA, CXCL12, IL13, IL4, IL4R, CCL5 and BCL6) with AIDS-related NHL risk and evaluated differences between primary CNS and systemic tumors.
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Cancer incidence in the multicenter AIDS Cohort Study before and during the HAART era: 1984 to 2007.
Cancer
PUBLISHED: 03-02-2010
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The incidence of Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) among human immunodeficiency virus (HIV)-infected individuals declined after the introduction of highly active antiretroviral therapy (HAART) in the mid-1990s, but the cancer risk associated with HIV infection during the HAART era remains to be clarified.
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Multistage genomewide association study identifies a locus at 1q41 associated with rate of HIV-1 disease progression to clinical AIDS.
J. Infect. Dis.
PUBLISHED: 01-13-2010
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A mean of 9-10 years of human immunodeficiency virus type 1 (HIV-1) infection elapse before clinical AIDS develops in untreated persons, but this rate of disease progression varies substantially among individuals. To investigate host genetic determinants of the rate of progression to clinical AIDS, we performed a multistage genomewide association study.
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HIV-1 evolution following transmission to an HLA-B*5801-positive patient.
J. Infect. Dis.
PUBLISHED: 11-14-2009
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The human immunodeficiency virus type 1 (HIV-1)-specific immune responses of patients with the HLA-B*57/5801 alleles who spontaneously control viral replication serve as an important model for T cell-based HIV-1 vaccines. Determining the breadth of this response and the extent of virologic escape in primary infection in these patients is therefore critical. Here we document the development of mutations in 3 HLA-B*5801-restricted epitopes in gag, nef, and pol in an HLA-B*5801-positive patient who had a viral load of only 1159 copies/mL at day 167 after infection. A full genome sequence analysis was performed to determine the extent of mutations in HLA-B*5801-restricted epitopes, and longitudinal sequence data of specific genes were combined with enzyme-linked immunospot assay analysis of critical epitopes to determine the importance of escape mutations. Thus, relative control of viral replication can be maintained in spite of the rapid development of multiple escape mutations within cytotoxic T lymphocyte epitopes.
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HIV-Selectest enzyme immunoassay and rapid test: ability to detect seroconversion following HIV-1 infection.
J. Clin. Microbiol.
PUBLISHED: 11-11-2009
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HIV-Selectest is a serodiagnostic enzyme immunoassay (EIA), containing p6 and gp41 peptides, designed to differentiate between vaccine-induced antibodies and true infections. A rapid test version of the HIV-Selectest was developed. Both assays detected HIV antibodies in men and women within 2 to 4 weeks of infection, with sensitivity similar to third-generation EIAs.
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Recreational amphetamine use and risk of HIV-related non-Hodgkin lymphoma.
Cancer Causes Control
PUBLISHED: 09-16-2009
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The results of many laboratory studies suggest that amphetamine use may lead to altered immune function and cytokine expression, both of which are implicated in HIV-related lymphomagenesis. We examined the hypothesis that use of amphetamines modifies risk of non-Hodgkin lymphoma (NHL) in HIV-infected men in the Multicenter AIDS Cohort Study. Data on amphetamine use were collected every six months during the follow-up period between 1984 and 2002. A total of 171 NHL cases were diagnosed from the 19,250 person-years accrued. Multivariable Cox models were used to estimate the effects of baseline exposures, time-varying recent exposures, and three years lagged exposures on risk of NHL adjusting for potential confounders such as demographics, use of other substances, and risky sexual behaviors. We found that weekly or more frequent use of amphetamines was associated with an increased risk of NHL, with hazard ratios of 1.75 (95% CI = 0.81-3.77) for use at baseline, 4.73 (1.41-15.81) for recent use, and 3.05 (1.19-7.82) for three years prior use. Similar associations were observed when we separately examined systemic NHL and diffuse large B-cell lymphoma. Given these observations, the impact of amphetamines on lymphomagenesis among HIV-infected populations should be assessed more thoroughly.
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Cancer stem/progenitor cell active compound 8-quinolinol in combination with paclitaxel achieves an improved cure of breast cancer in the mouse model.
Breast Cancer Res. Treat.
PUBLISHED: 07-30-2009
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Increasing evidence suggests that breast cancer is caused by cancer stem cells and the cure of breast cancer requires eradication of breast cancer stem cells. In this study, we established and characterized a sphere culture model derived from side population cells from the human breast cancer cell line MCF7. The sphere culture could be maintained long term and was enriched in cells expressing known breast cancer stem cell marker CD44+CD24-. These sphere cells showed higher colony formation ability in vitro and higher tumorigenicity in vivo than MCF7 cells, suggesting the enrichment of breast cancer stem/progenitor cells. To identify compounds that preferentially inhibit the sphere cells, we performed a compound library screening. Two lead compounds, NSC24076 and NSC125034 and an analog of NSC125034, 8-quinolinol (8Q), were identified as having preferential activity against the sphere cells. 8Q showed some antitumor activity alone but had much better therapeutic effect and relapse prevention when combined with paclitaxel than either 8Q or paclitaxel alone in both MCF7 and MDA-MB-435 xenograft models. We propose that compounds selectively targeting cancer stem/progenitor cells when combined with standard chemotherapy drugs may produce an improved treatment of cancer without significant relapse.
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HLA-C cell surface expression and control of HIV/AIDS correlate with a variant upstream of HLA-C.
Nat. Genet.
PUBLISHED: 07-21-2009
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A variant 35 kb upstream of the HLA-C gene (-35C/T) was previously shown to associate with HLA-C mRNA expression level and steady-state plasma HIV RNA levels. We genotyped this variant in 1,698 patients of European ancestry with HIV. Individuals with known seroconversion dates were used for disease progression analysis and those with longitudinal viral load data were used for viral load analysis. We further tested cell surface expression of HLA-C in normal donors using an HLA-C-specific antibody. We show that the -35C allele is a proxy for high HLA-C cell surface expression, and that individuals with high-expressing HLA-C alleles progress more slowly to AIDS and control viremia significantly better than individuals with low HLA-C expressing alleles. These data strongly implicate high HLA-C expression levels in more effective control of HIV-1, potentially through better antigen presentation to cytotoxic T lymphocytes or recognition and killing of infected cells by natural killer cells.
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Common genetic variation and the control of HIV-1 in humans.
PLoS Genet.
PUBLISHED: 06-15-2009
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To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.
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Investigation of pre-diagnostic virological markers for progressive multifocal leukoencephalopathy in human immunodeficiency virus-infected patients.
J. Med. Virol.
PUBLISHED: 05-29-2009
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Progressive multifocal leukoencephalopathy (PML) is a severe neurological disorder due to JC virus (JCV) infection. Pre-diagnostic biological markers and risk factors for PML are not well understood. We conducted a case-control study nested within the Multicenter AIDS Cohort Study to examine the association between JCV viruria and viremia and serum antibody to JCV capsids, in relation to subsequent PML diagnoses, 5 months to 12 years later. Other demographic and immunologic factors were also examined. The study population included 28 incident cases of PML, 26 matched HIV-positive controls, and 50 HIV-negative controls. Prevalence of JCV viruria was 37% in cases, 42% in HIV-positive controls, and 28% in HIV-negative controls (P = 0.43). Among persons with JCV viruria, persistent viruria was more common in cases (89%) than in HIV-positive controls (33%) (P = 0.02). Presence of JCV viruria was not related to the time to PML diagnosis (OR: 1.03, 95% CI: 0.8-1.4); however, the urinary concentration of JCV DNA increased with proximity to the date of PML diagnosis in cases. JCV seropositivity did not differ between cases or controls (P = 0.42). Four cases tested JCV seronegative, including one case only 5 months prior to diagnosis with PML. JCV DNA was detected in the serum of one HIV-positive control. Smoking was the only demographic variable analyzed associated with an increased risk for PML (MOR: 9.0, 95% CI: 1.2-394.5). The results suggest that persistent JCV viruria and increasing urinary concentration of JCV DNA may be predictive of PML for some patients.
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Fat distribution and longitudinal anthropometric changes in HIV-infected men with and without clinical evidence of lipodystrophy and HIV-uninfected controls: a substudy of the Multicenter AIDS Cohort Study.
AIDS Res Ther
PUBLISHED: 05-13-2009
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Fat abnormalities are common among HIV-infected persons, but few studies have compared regional body fat distribution, including visceral fat, in HIV-infected and HIV-uninfected persons and their subsequent trajectories in body composition over time.
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A comparison of ad hoc methods to account for non-cancer AIDS and deaths as competing risks when estimating the effect of HAART on incident cancer AIDS among HIV-infected men.
J Clin Epidemiol
PUBLISHED: 04-08-2009
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To compare three ad hoc methods to estimate the marginal hazard of incident cancer acquired immune deficiency syndrome (AIDS) in a highly active antiretroviral therapy (1996-2006) relative to a monotherapy/combination therapy (1990-1996) calendar period, accounting for other AIDS events and deaths as competing risks.
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Microbial translocation, the innate cytokine response, and HIV-1 disease progression in Africa.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 04-08-2009
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Reports from the United States have demonstrated that elevated markers of microbial translocation from the gut may be found in chronic and advanced HIV-1 infection and are associated with an increase in immune activation. However, this phenomenons role in HIV-1 disease in Africa is unknown. This study examined the longitudinal relationship between microbial translocation and circulating inflammatory cytokine responses in a cohort of people with varying rates of HIV-1 disease progression in Rakai, Uganda. Multiple markers for microbial translocation (lipopolysaccharide, endotoxin antibody, and sCD14) did not change significantly during HIV-1 disease progression. Moreover, circulating immunoreactive cytokine levels either decreased or remained virtually unchanged throughout disease progression. These data suggest that microbial translocation and its subsequent inflammatory immune response do not have a causal relationship with HIV-1 disease progression in Africa.
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Fidelity of SNP array genotyping using Epstein Barr virus-transformed B-lymphocyte cell lines: implications for genome-wide association studies.
PLoS ONE
PUBLISHED: 04-07-2009
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As availability of primary cells can be limited for genetic studies of human disease, lymphoblastoid cell lines (LCL) are common sources of genomic DNA. LCL are created in a transformation process that entails in vitro infection of human B-lymphocytes with the Epstein-Barr Virus (EBV).
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Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation.
J. Clin. Invest.
PUBLISHED: 03-16-2009
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The development of highly active antiretroviral therapy (HAART) to treat individuals infected with HIV-1 has dramatically improved patient outcomes, but HAART still fails to cure the infection. The latent viral reservoir in resting CD4+ T cells is a major barrier to virus eradication. Elimination of this reservoir requires reactivation of the latent virus. However, strategies for reactivating HIV-1 through nonspecific T cell activation have clinically unacceptable toxicities. We describe here the development of what we believe to be a novel in vitro model of HIV-1 latency that we used to search for compounds that can reverse latency. Human primary CD4+ T cells were transduced with the prosurvival molecule Bcl-2, and the resulting cells were shown to recapitulate the quiescent state of resting CD4+ T cells in vivo. Using this model system, we screened small-molecule libraries and identified a compound that reactivated latent HIV-1 without inducing global T cell activation, 5-hydroxynaphthalene-1,4-dione (5HN). Unlike previously described latency-reversing agents, 5HN activated latent HIV-1 through ROS and NF-kappaB without affecting nuclear factor of activated T cells (NFAT) and PKC, demonstrating that TCR pathways can be dissected and utilized to purge latent virus. Our study expands the number of classes of latency-reversing therapeutics and demonstrates the utility of this in vitro model for finding strategies to eradicate HIV-1 infection.
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Recreational drug use and risk of Kaposis sarcoma in HIV- and HHV-8-coinfected homosexual men.
AIDS Res. Hum. Retroviruses
PUBLISHED: 03-13-2009
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Experimental data suggested that exposure to recreational drugs might adversely affect antitumor immunity, which led us to examine the hypothesis that use of marijuana, cocaine, poppers, and amphetamines might increase the risk of Kaposis sarcoma (KS) in HIV- and HHV-8-coinfected homosexual men. We analyzed data prospectively collected from the Multicenter AIDS Cohort Study (MACS) between 1984 and 2002. Among the 1335 HIV- and HHV-8-coinfected white men, 401 KS cases were identified. Multivariable Cox regression models were used to estimate the effects of time-varying recreational drug use on KS risk adjusting for potential confounders. The effects of both recent use (6 months prior) of recreational drugs and lagged exposure (i.e., use from 3 and 5 years prior) were examined. We did not observe any clear association with KS for recent use of any of the four drugs. In the analyses using lagged exposures, KS risk was associated with use of poppers 3-5 years prior [hazard ratio (HR)(3 years prior) = 1.27, 95% CI (0.97-1.67), HR(5 years prior) = 1.46 (1.01-2.13)]. However, no clear dose-response relationship was observed. These findings do not support a biological association between use of these substances and KS development in HIV- and HHV-8-coinfected homosexual men.
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Tolerability and efficacy of PI versus NNRTI-based regimens in subjects receiving HAART during acute or early HIV infection.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 02-06-2009
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Little is known about modifications to highly active antiretroviral therapy (HAART) initiated during acute or early HIV infection.
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Relationship between a frailty-related phenotype and progressive deterioration of the immune system in HIV-infected men.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 02-06-2009
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Immunological similarities have been noted between HIV-infected individuals and older HIV-negative adults. Immunologic alterations with aging have been noted in frailty in older adults, a clinical syndrome of high risk for mortality and other adverse outcomes. Using a frailty-related phenotype (FRP), we investigated in the Multicenter AIDS Cohort Study whether progressive deterioration of the immune system among HIV-positive individuals independently predicts onset of FRP.
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A prospective randomized trial of povidone-iodine prophylactic cleansing of the rectum before transrectal ultrasound guided prostate biopsy.
J. Urol.
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Transrectal ultrasound guided prostate biopsy can lead to urinary tract infections in 3% to 11% and sepsis in 0.1% to 5% of patients. We investigated the efficacy of rectal cleansing with povidone-iodine before transrectal ultrasound guided prostate biopsy to reduce infectious complications.
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Early HLA-B*57-restricted CD8+ T lymphocyte responses predict HIV-1 disease progression.
J. Virol.
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Although HLA-B*57 (B57) is associated with slow progression to disease following HIV-1 infection, B57 heterozygotes display a wide spectrum of outcomes, including rapid progression, viremic slow progression, and elite control. Efforts to identify differences between B57-positive (B57(+)) slow progressors and B57(+) rapid progressors have largely focused on cytotoxic T lymphocyte (CTL) phenotypes and specificities during chronic stages of infection. Although CTL responses in the early months of infection are likely to be the most important for the long-term rate of HIV-1 disease progression, few data on the early CTL responses of eventual slow progressors have been available. Utilizing the Multicenter AIDS Cohort Study (MACS), we retrospectively examined the early HIV-1-specific CTL responses of 14 B57(+) individuals whose time to development of disease ranged from 3.5 years to longer than 25 years after infection. In general, a greater breadth of targeting of epitopes from structural proteins, especially Gag, as well as of highly conserved epitopes from any HIV-1 protein, correlated with longer times until disease. The single elite controller in the cohort was an outlier on several correlations of CTL targeting and time until disease, consistent with reports that elite control is typically not achieved solely by protective HLA-mediated CTLs. When targeting of individual epitopes was analyzed, we found that early CTL responses to the IW9 (ISPRTLNAW) epitope of Gag, while generally subdominant, correlated with delayed progression to disease. This is the first study to identify early CTL responses to IW9 as a correlate of protection in persons with HLA-B*57.
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A protective role for human IL-10-expressing CD4+ T cells in colitis.
J. Immunol.
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IL-10 is an immunoregulatory cytokine expressed by numerous cell types. Studies in mice confirm that different IL-10-expressing cell subsets contribute differentially to disease phenotypes. However, little is known about the relationship between cell- or tissue-specific IL-10 expression and disease susceptibility in humans. In this study, we used the previously described human (h)IL10BAC transgenic model to examine the role of hIL-10 in maintaining intestinal homeostasis. Genomically controlled hIL-10 expression rescued Il10(-/-) mice from Helicobacter-induced colitis and was associated with control of proinflammatory cytokine expression and Th17 cell accumulation in gut tissues. Resistance to colitis was associated with an accumulation of hIL-10-expressing CD4(+)Foxp3(+) regulatory T cells specifically within the lamina propria but not other secondary lymphoid tissues. Cotransfer of CD4(+)CD45RB(lo) cells from Il10(-/-)/hIL10BAC mice rescued Rag1(-/-) mice from colitis, further suggesting that CD4(+) T cells represent a protective source of hIL-10 in the colon. In concordance with an enhanced capacity to express IL-10, CD4(+)CD44(+) T cells isolated from the lamina propria exhibited lower levels of the repressive histone mark H3K27Me3 and higher levels of the permissive histone mark acetylated histone H3 in both the human and mouse IL10 locus compared with the spleen. These results provide experimental evidence verifying the importance of T cell-derived hIL-10 expression in controlling inflammation within the colonic mucosa. We also provide molecular evidence suggesting the tissue microenvironment influences IL-10 expression patterns and chromatin structure in the human (and mouse) IL10 locus.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.