clinical and population sciences
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Publication
Journal: Science
January/23/2013
Abstract
Concentrations of acetyl-coenzyme A and nicotinamide adenine dinucleotide (NAD(+)) affect histone acetylation and thereby couple cellular metabolic status and transcriptional regulation. We report that the ketone body d-β-hydroxybutyrate (βOHB) is an endogenous and specific inhibitor of class I histone deacetylases (HDACs). Administration of exogenous βOHB, or fasting or calorie restriction, two conditions associated with increased βOHB abundance, all increased global histone acetylation in mouse tissues. Inhibition of HDAC by βOHB was correlated with global changes in transcription, including that of the genes encoding oxidative stress resistance factors FOXO3A and MT2. Treatment of cells with βOHB increased histone acetylation at the Foxo3a and Mt2 promoters, and both genes were activated by selective depletion of HDAC1 and HDAC2. Consistent with increased FOXO3A and MT2 activity, treatment of mice with βOHB conferred substantial protection against oxidative stress.
Publication
Journal: Nature Reviews Immunology
October/8/2012
Abstract
Given the limitations of antiretroviral therapy and recent advances in our understanding of HIV persistence during effective treatment, there is a growing recognition that a cure for HIV infection is both needed and feasible. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. Several priorities for basic, translational and clinical research were identified. This Opinion article summarizes the group's recommended key goals for the international community.
Publication
Journal: Journal of Biological Chemistry
February/13/2013
Abstract
The sirtuins are a family of NAD(+)-dependent protein deacetylases that regulate cell survival, metabolism, and longevity. Three sirtuins, SIRT3-5, localize to mitochondria. Expression of SIRT3 is selectively activated during fasting and calorie restriction. SIRT3 regulates the acetylation level and enzymatic activity of key metabolic enzymes, such as acetyl-CoA synthetase, long-chain acyl-CoA dehydrogenase, and 3-hydroxy-3-methylglutaryl-CoA synthase 2, and enhances fat metabolism during fasting. SIRT5 exhibits demalonylase/desuccinylase activity, and lysine succinylation and malonylation are abundant mitochondrial protein modifications. No convincing enzymatic activity has been reported for SIRT4. Here, we review the emerging role of mitochondrial sirtuins as metabolic sensors that respond to changes in the energy status of the cell and modulate the activities of key metabolic enzymes via protein deacylation.
Publication
Journal: Blood
August/5/2013
Abstract
The CCR5 inhibitor maraviroc has been hypothesized to decrease T-cell activation in HIV-infected individuals, but its independent immunologic effects have not been established in a placebo-controlled trial. We randomized 45 HIV-infected subjects with CD4 counts <350 cells per mm(3) and plasma HIV RNA levels <48 copies per mL on antiretroviral therapy (ART) to add maraviroc vs placebo to their regimen for 24 weeks followed by 12 weeks on ART alone. Compared with placebo-treated subjects, maraviroc-treated subjects unexpectedly experienced a greater median increase in % CD38+HLA-DR+ peripheral blood CD8+ T cells at week 24 (+2.2% vs -0.7%, P = .014), and less of a decline in activated CD4+ T cells (P < .001). The % CD38+HLA-DR+ CD4+ and CD8+ T cells increased nearly twofold in rectal tissue (both P < .001), and plasma CC chemokine receptor type 5 (CCR5) ligand (macrophage-inflammatory protein 1β) levels increased 2.4-fold during maraviroc intensification (P < .001). During maraviroc intensification, plasma lipopolysaccharide declined, whereas sCD14 levels and neutrophils tended to increase in blood and rectal tissue. Although the mechanisms explaining these findings remain unclear, CCR5 ligand-mediated activation of T cells, macrophages, and neutrophils via alternative chemokine receptors should be explored. These results may have relevance for trials of maraviroc for HIV preexposure prophylaxis and graft-versus-host disease. This trial was registered at www.clinicaltrials.gov as #NCT00735072.
Publication
Journal: AIDS
November/29/2011
Abstract
OBJECTIVE
Increasing evidence supports a parallel between HIV-1 infection and immune aging, which is particularly apparent with common changes in naive versus memory T-cell proportions. Here, we aimed at refining the value of common T-cell-associated markers of immunosenescence during HIV disease progression or aging, and at exploring further the impact in this context of old age as well as cytomegalovirus (CMV) co-infection, which is predominant in HIV-1-infected individuals.
METHODS
Frequencies of naive or CD57(+) memory T cells as well as the magnitude of CMV-pp65 T cells were measured in HIV-1-infected patients grouped according to disease progression status, treatment and age.
RESULTS
Our results indicate that the decline in naive T-cell levels rather than the accumulation of CD57(+) senescent T cells identifies best the premature development of an immunosenescence phenotype with HIV disease progression. Moreover, advanced age or mounting of strong CMV-specific responses impact independently on CD4(+) T-cell counts and recovery with antiretroviral therapy.
CONCLUSIONS
The present findings indicate that HIV-1 infection amplifies the effect of age on naive T-cell levels, and highlight the constraint on the capacity of treated patients to reconstitute their CD4(+) T-cell compartment due to age and CMV co-infection.
Publication
Journal: Journal of Acquired Immune Deficiency Syndromes
February/3/2013
Abstract
BACKGROUND
Increases in multimorbidity and obesity have been noted in HIV-infected populations in the current treatment era. Patterns of multimorbid disease clustering and the impact of obesity on multimorbidity are understudied in this population.
METHODS
We examined obesity and multimorbidity patterns among 1844 HIV-infected patients in the UAB 1917 Clinic. Exploratory factor analysis was used to identify the underlying factor structure responsible for clustering. Patterns among the resulting morbidity factors by body mass index (BMI) category were explored. Multivariable logistic regression models were fit to identify predictors of multimorbidity cluster patterns.
RESULTS
The prevalence of multimorbidity was 65% (1205/1844). Prevalence increased with progressive BMI categories from underweight (64%) to obese (79%). Three multimorbidity clusters were identified: "metabolic," including hypertension, gout, diabetes mellitus, and chronic kidney disease (range, 0.41-0.84; P < 0.001); "Behavioral," including mood disorders, dyslipidemia, chronic obstructive pulmonary disease, chronic ulcer disease, osteoarthritis, obstructive sleep apnea, and cardiac disorders (range, 0.32-0.57; P < 0.001); "Substance Use," including alcohol abuse, substance abuse, tobacco abuse, and hepatitis C (range, 0.53-0.89; P < 0.001). Obesity was associated with increased odds of multimorbidity (obese vs. normal BMI category: OR = 1.52, 95% CI: 1.15 to 2.00).
CONCLUSIONS
Three patterns of disease clustering were identified. Obesity was associated with a higher likelihood of multimorbidity. The management of multimorbidity and obesity will need to be addressed in future clinical practice guidelines to enhance long-term outcomes of HIV-infected patients in the current treatment era.
Publication
Journal: Journal of Acquired Immune Deficiency Syndromes
July/7/2013
Abstract
BACKGROUND
Delays and failures in initiation of antiretroviral therapy (ART) among treatment eligible patients may compromise the effectiveness of HIV care in Africa. An accurate understanding, however, of the pace and completeness of ART initiation and mortality during the waiting period is obscured by frequent losses to follow-up.
METHODS
We evaluated newly ART-eligible HIV-infected adults from 2007 to 2011 in a prototypical clinic in Mbarara, Uganda. A random sample of patients lost to follow-up was tracked in the community to determine vital status and ART initiation after leaving the original clinic. Outcomes among the tracked patients were incorporated using probability weights, and a competing risks approach was used in analyses.
RESULTS
Among 2633 ART-eligible patients, 490 were lost to follow-up, of whom a random sample of 132 was tracked and 111 (84.0%) had outcomes ascertained. After incorporating the outcomes among the lost, the cumulative incidence of ART initiation at 30, 90, and 365 days after eligibility was 16.0% [95% confidence interval (CI): 14.2 to 17.7], 64.5% (95% CI: 60.9 to 68.1), and 81.7% (95% CI: 77.7 to 85.6). Death before ART was 7.7% at 1 year. Male sex, higher CD4 count, and no education were associated with delayed ART initiation. Lower CD4 level, malnourishment, and travel time to clinic were associated with mortality.
CONCLUSIONS
Using a sampling-based approach to account for losses to follow-up revealed that both the speed and the completeness of ART initiation were suboptimal in a prototypical large clinic in Uganda. Improving the kinetics of ART initiation in Africa is needed to make ART more in real-world populations.
Publication
Journal: Nature Medicine
September/22/2013
Abstract
The contribution of HLA class II-restricted CD4(+) T cell responses to HIV immune control is poorly defined. Here, we delineated previously uncharacterized peptide-DRB1 restrictions in functional assays and analyzed the host genetic effects of HLA-DRB1 alleles on HIV viremia in a large cohort of HIV controllers and progressors. We found distinct stratifications in the effect of HLA-DRB1 alleles on HIV viremia, with HLA-DRB1*15:02 significantly associated with low viremia and HLA-DRB1*03:01 significantly associated with high viremia. Notably, a subgroup of HLA-DRB1 variants linked with low viremia showed the ability to promiscuously present a larger breadth of peptides with lower functional avidity when compared to HLA-DRB1 variants linked with high viremia. Our data provide systematic evidence that HLA-DRB1 variant expression has a considerable impact on the control of HIV replication, an effect that seems to be mediated primarily by the protein specificity of CD4(+) T cell responses to HIV Gag and Nef.
Publication
Journal: Journal of Infectious Diseases
January/16/2007
Abstract
OBJECTIVE
To characterize the effect of partially suppressive combination antiretroviral therapy on cerebrospinal fluid (CSF) human immunodeficiency virus (HIV)-1 RNA levels and CSF inflammation.
METHODS
The study was a cross-sectional analysis of 139 HIV-1-infected subjects without active neurological disease, categorized as having successful therapy (plasma HIV-1 RNA level < or =500 copies/mL), having failure of therapy (plasma HIV-1 RNA level >500 copies/mL), or not receiving therapy. The control group consisted of 48 HIV-negative subjects. CSF and plasma HIV-1 RNA assays had a lower limit of quantification of 2.5 copies/mL. Genotypic resistance testing was performed on a subset of subjects.
RESULTS
Of the 47 subjects with successful therapy, CSF HIV-1 RNA levels were <2.5 copies/mL in 34 (72%). Only 1 had an HIV-1 RNA level >500 copies/mL. Although plasma HIV-1 RNA levels were similar in 35 subjects with failed therapy and 57 of those not receiving therapy (P=.84), CSF HIV-1 RNA levels were at least 10-fold lower in subjects with failed therapy (P<.0001). This disproportionate effect of treatment on CSF HIV-1 RNA levels was found across the range of plasma HIV-1 RNA levels and was not explained by differences in levels of drug resistance in plasma or CSF. Therapy reduced CSF inflammation in both treated groups.
CONCLUSIONS
In our cohort, antiretroviral therapy had a greater effect on HIV-1 RNA levels in CSF than in plasma and reduced intrathecal inflammation, even in the presence of drug resistance.
Publication
Journal: Journal of Infectious Diseases
September/30/2012
Abstract
BACKGROUND
We address the key emerging question of whether Lin(-)/CD34(+) hematopoietic precursor cells (HPCs) represent an important latent reservoir of human immunodeficiency virus type 1 (HIV-1) during long-term suppressive therapy.
METHODS
To estimate the frequency of HIV-1 infection in bone marrow, we sorted Lin(-)/CD34(+) HPCs and 3 other cell types (Lin(-)/CD34(-), Lin(-)/CD4(+), and Lin(+)/CD4(+)) from 8 patients who had undetectable viral loads for 3-12 years. Using a single-proviral sequencing method, we extracted, amplified, and sequenced multiple single HIV-1 DNA molecules from these cells and memory CD4(+) T cells from contemporaneous peripheral blood samples.
RESULTS
We analyzed 100,000-870,000 bone marrow Lin(-)/CD34(+) HPCs from the 8 patients and found no HIV-1 DNA. We did isolate HIV-1 DNA from their bone marrow Lin(+)/CD4(+) cells that was genetically similar to HIV-1 DNA from lymphoid cells located in the peripheral blood, indicating an exchange of infected cells between these compartments.
CONCLUSIONS
The absence of infected HPCs provides strong evidence that the HIV-1 infection frequency of Lin(-)/CD34(+) HPCs from bone marrow, if it occurred, was <.003% (highest upper 95% confidence interval) in all 8 patients. These results strongly suggest that Lin(-)/CD34(+) HPCs in bone marrow are not a source of persistent HIV-1 in patients on long-term suppressive therapy.
Publication
Journal: American journal of reproductive immunology (New York, N.Y. : 1989)
August/26/2013
Abstract
The developing fetus must actively learn to tolerate benign antigens or suffer the consequences of broken tolerance. Tolerance of self-antigens prevents development of autoimmune diseases and is achieved by both deletion of autoreactive T cell clones in the thymus (central tolerance) and by the suppressive influence of CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) in the periphery. Fetal CD4(+) T cells have a strong predisposition to differentiate into tolerogenic Tregs that actively promote self-tolerance, as well as tolerance to non-inherited antigens on chimeric maternal cells that reside in fetal tissues. As the fetus nears birth, a crucial transition must occur between the tolerogenic fetal immune system and a more defensive adult-type immune system that is able to combat pathogens. This paper will review the unique tolerogenic nature of fetal T cells and will examine evidence for a novel model of fetal immune development: the layered immune system hypothesis.
Publication
Journal: Cell
June/22/2017
Abstract
Cells operate through protein interaction networks organized in space and time. Here, we describe an approach to resolve both dimensions simultaneously by using proximity labeling mediated by engineered ascorbic acid peroxidase (APEX). APEX has been used to capture entire organelle proteomes with high temporal resolution, but its breadth of labeling is generally thought to preclude the higher spatial resolution necessary to interrogate specific protein networks. We provide a solution to this problem by combining quantitative proteomics with a system of spatial references. As proof of principle, we apply this approach to interrogate proteins engaged by G-protein-coupled receptors as they dynamically signal and traffic in response to ligand-induced activation. The method resolves known binding partners, as well as previously unidentified network components. Validating its utility as a discovery pipeline, we establish that two of these proteins promote ubiquitin-linked receptor downregulation after prolonged activation.
Publication
Journal: Cell host & microbe
September/25/2017
Abstract
A population of CD4 T lymphocytes harboring latent HIV genomes can persist in patients on antiretroviral therapy, posing a barrier to HIV eradication. To examine cellular complexes controlling HIV latency, we conducted a genome-wide screen with a pooled ultracomplex shRNA library and in vitro system modeling HIV latency and identified the mTOR complex as a modulator of HIV latency. Knockdown of mTOR complex subunits or pharmacological inhibition of mTOR activity suppresses reversal of latency in various HIV-1 latency models and HIV-infected patient cells. mTOR inhibitors suppress HIV transcription both through the viral transactivator Tat and via Tat-independent mechanisms. This inhibition occurs at least in part via blocking the phosphorylation of CDK9, a p-TEFb complex member that serves as a cofactor for Tat-mediated transcription. The control of HIV latency by mTOR signaling identifies a pathway that may have significant therapeutic opportunities.
Publication
Journal: AIDS Patient Care and STDs
December/15/2013
Abstract
In 2010, the iPrEx study demonstrated efficacy of daily emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) pre-exposure prophylaxis (PrEP) in reducing HIV acquisition among men who have sex with men. Adherence to study product was critical for PrEP efficacy, and varied considerably, with FTC/TDF detection rates highest in the United States. We conducted a qualitative study to gain insights into the experiences of iPrEx participants in San Francisco (SF) where there was high confirmed adherence, to understand individual and contextual factors influencing study product use in this community. In 2009 and 2011, we conducted focus groups and in-depth interviews in 36 and 16 SF iPrEx participants, respectively. Qualitative analyses indicate that participants joined the study out of altruism. They had a clear understanding of study product use, and pill taking was facilitated by establishing or building on an existing routine. Participants valued healthcare provided by the study and relationships with staff, whom they perceived as nonjudgmental, and found client-centered counseling to be an important part of the PrEP package. This facilitated pill taking and accurate reporting of missed doses. Adherence barriers included changes in routine, side effects/intercurrent illnesses, and stress. Future PrEP adherence interventions should leverage existing routines and establish client-centered relationships/ environments to support pill taking and promote accurate reporting.
Publication
Journal: Vox Sanguinis
July/6/2006
Abstract
OBJECTIVE
Previous studies have shown that volunteer, community-recruited donors have a higher prevalence of human immunodeficiency virus (HIV) infection in São Paulo, Brazil, than replacement donors. One hypothesis which may explain this unexpected finding is that some individuals donate blood because they are seeking HIV testing. The objective of this study was to characterize test-seeking blood donors and to determine whether they are at higher risk for HIV infection compared with other donors.
METHODS
Subjects presenting for blood donation were asked to participate in a study assessing their motivations (including test seeking) to donate, as measured by perceiving donation as a means to obtain infectious disease test results. Participants completed the standard blood bank predonation screening questions plus our additional survey, and were tested for HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), human T-cell lymphocytotrophic virus (HTLV) I/II, syphilis and Chagas' disease. As a result of anticipated low statistical power to directly measure the association between test-seeking motivation and HIV infection, we tested for herpes simplex virus type 2 (HSV-2) as a marker of sexual risk for HIV. Our survey includes accepted donors as well as persons whose risk-behaviour histories would result in their exclusion from donation according to routine screening procedures.
RESULTS
Of 1,720 potential blood donors randomly selected and approached, 1,600 (93.0%) participated. Overall, 141 (8.8%) were classified as test seekers; 15.6% of these were HSV-2 positive. The proportion of test seekers was the same among community-recruited and replacement donors. Test seekers had a higher prevalence of HSV-2 [adjusted odds ratio (AOR) 1.66; 95% confidence interval (CI): 1.06-2.59] adjusting for age, gender and prior donation. The association was significant among community-recruited blood donors whose previous donation was more than 1 year ago (i.e. 'lapsed donors') (AOR 2.55; 95% CI: 1.20-5.44). Test seekers were not more likely to be rejected from blood donation as a result of health reasons, self-reported HIV risk-related behaviour, or by their own confidential unit exclusion. We found no difference in HSV-2 prevalence between persons accepted for donation (15.7%) and those rejected because of self-reported sexual risk (16.7%).
CONCLUSIONS
We did not detect a difference in the proportion of test seekers across different types of blood donors; however, we did detect an association between HSV-2 infection and test seeking, especially among community-recruited lapsed blood donors. Of note, questions on test-seeking behaviour detected donors with increased prevalence of HSV-2, but the self-reported sexual risk behaviours currently used for deferral criteria did not. Incentives to get tested at sites other than blood banks may decrease the residual risk of HIV in the blood supply.
Publication
Journal: AIDS
December/21/2004
Publication
Journal: PLoS ONE
August/4/2014
Abstract
Attempts to eradicate HIV have been thwarted by the persistence of a small pool of quiescent memory CD4 T cells that harbor a transcriptionally silent, integrated form of the virus that can produce infectious virions following an anamnestic immune response. Transcription factors downstream of T-cell receptor activation, such as NF-κB/Rel and nuclear factor of activated T cells (NFAT) transcription members, are considered important regulators of HIV transcription during acute HIV infection. We now report studies exploring their precise role as antagonists of HIV latency using cell and primary CD4 T cell models of HIV-1 latency. Surprisingly, RNA interference studies performed in J-Lat CD4 T cells suggested that none of the NFATs, including NFATc1, NFATc2, NFATc3, and NFAT5, played a key role in the reactivation of latent HIV. However, cyclosporin A markedly inhibited the reactivation response. These results were reconciled when calcium signaling through calcineurin was shown to potentiate prostratin induced activation of NF-κB that in turn stimulated the latent HIV long terminal repeat (LTR). Similar effects of calcineurin were confirmed in a primary CD4 T cell model of HIV latency. These findings highlight an important role for calcineurin in NF-κB-dependent induction of latent HIV transcription. Innovative approaches exploiting the synergistic actions of calcineurin and prostratin in the absence of generalized T-cell activation merit exploration as a means to attack the latent viral reservoir.
Publication
Journal: Journal of Virology
August/14/2012
Abstract
Mutations at amino acids 143, 148, and 155 in HIV-1 integrase (IN) define primary resistance pathways in subjects failing raltegravir (RAL)-containing treatments. Although each pathway appears to be genetically distinct, shifts in the predominant resistant virus population have been reported under continued drug pressure. To better understand this dynamic, we characterized the RAL susceptibility of 200 resistant viruses, and we performed sequential clonal analysis for selected cases. Patient viruses containing Y143R, Q148R, or Q148H mutations consistently exhibited larger reductions in RAL susceptibility than patient viruses containing N155H mutations. Sequential analyses of virus populations from three subjects revealed temporal shifts in subpopulations representing N155H, Y143R, or Q148H escape pathways. Evaluation of molecular clones isolated from different time points demonstrated that Y143R and Q148H variants exhibited larger reductions in RAL susceptibility and higher IN-mediated replication capacity (RC) than N155H variants within the same subject. Furthermore, shifts from the N155H pathway to either the Q148R or H pathway or the Y143R pathway were dependent on the amino acid substitution at position 148 and the secondary mutations in Y143R- or Q148R- or H-containing variants and correlated with reductions in RAL susceptibility and restorations in RC. Our observations in patient viruses were confirmed by analyzing site-directed mutations. In summary, viruses that acquire mutations defining the 143 or 148 escape pathways are less susceptible to RAL and exhibit greater RC than viruses containing 155 pathway mutations. These selective pressures result in the displacement of N155H variants by 143 or 148 variants under continued drug exposure.
Publication
Journal: Journal of Acquired Immune Deficiency Syndromes
February/23/2009
Abstract
OBJECTIVE
Compared with other sexually active adults, men who have sex with men (MSM) are more frequently infected with several pathogens including cytomegalovirus, hepatitis B virus, and Kaposi sarcoma-associated herpesvirus. Because one common element between these organisms is their presence in saliva, we evaluated saliva exposure among MSM in a heretofore relatively unrecognized route-via use of saliva as a lubricant in anal sex.
METHODS
MSM in a San Francisco population-based cohort were interviewed regarding use of saliva by the insertive partner as a lubricant in various anal sexual practices.
RESULTS
Among 283 MSM, 87% used saliva as a lubricant in insertive or receptive penile-anal intercourse or fingering/fisting at some point during their lifetime; 31%-47% did so, depending upon the act, in the prior 6 months. Saliva use as a lubricant was more common among younger men and among HIV-infected men when with HIV-infected partners. Even among MSM following safe sex guidelines by avoiding unprotected penile-anal intercourse, 26% had anal exposure to saliva via use as a lubricant.
CONCLUSIONS
Among MSM, use of saliva as a lubricant is a common, but not ubiquitous, practice in anal sex. The findings provide the rationale for formal investigation of whether saliva use in this way contributes to transmission of saliva-borne pathogens in MSM.
Publication
Journal: BMC Bioinformatics
August/17/2017
Abstract
BACKGROUND
RNA-Seq has supplanted microarrays as the preferred method of transcriptome-wide identification of differentially expressed genes. However, RNA-Seq analysis is still rapidly evolving, with a large number of tools available for each of the three major processing steps: read alignment, expression modeling, and identification of differentially expressed genes. Although some studies have benchmarked these tools against gold standard gene expression sets, few have evaluated their performance in concert with one another. Additionally, there is a general lack of testing of such tools on real-world, physiologically relevant datasets, which often possess qualities not reflected in tightly controlled reference RNA samples or synthetic datasets.
RESULTS
Here, we evaluate 219 combinatorial implementations of the most commonly used analysis tools for their impact on differential gene expression analysis by RNA-Seq. A test dataset was generated using highly purified human classical and nonclassical monocyte subsets from a clinical cohort, allowing us to evaluate the performance of 495 unique workflows, when accounting for differences in expression units and gene- versus transcript-level estimation. We find that the choice of methodologies leads to wide variation in the number of genes called significant, as well as in performance as gauged by precision and recall, calculated by comparing our RNA-Seq results to those from four previously published microarray and BeadChip analyses of the same cell populations. The method of differential gene expression identification exhibited the strongest impact on performance, with smaller impacts from the choice of read aligner and expression modeler. Many workflows were found to exhibit similar overall performance, but with differences in their calibration, with some biased toward higher precision and others toward higher recall.
CONCLUSIONS
There is significant heterogeneity in the performance of RNA-Seq workflows to identify differentially expressed genes. Among the higher performing workflows, different workflows exhibit a precision/recall tradeoff, and the ultimate choice of workflow should take into consideration how the results will be used in subsequent applications. Our analyses highlight the performance characteristics of these workflows, and the data generated in this study could also serve as a useful resource for future development of software for RNA-Seq analysis.
Publication
Journal: Molecular Cell
October/11/2017
Abstract
BET proteins commonly activate cellular gene expression, yet inhibiting their recruitment paradoxically reactivates latent HIV-1 transcription. Here we identify the short isoform of BET family member BRD4 (BRD4S) as a corepressor of HIV-1 transcription. We found that BRD4S was enriched in chromatin fractions of latently infected T cells, and it was more rapidly displaced from chromatin upon BET inhibition than the long isoform. BET inhibition induced marked nucleosome remodeling at the latent HIV-1 promoter, which was dependent on the activity of BRG1-associated factors (BAF), an SWI/SNF chromatin-remodeling complex with known repressive functions in HIV-1 transcription. BRD4S directly bound BRG1, a catalytic subunit of BAF, via its bromodomain and extraterminal (ET) domain, and this isoform was necessary for BRG1 recruitment to latent HIV-1 chromatin. Using chromatin immunoprecipitation sequencing (ChIP-seq) combined with assay for transposase-accessible chromatin coupled to high-throughput sequencing (ATAC-seq) data, we found that the latent HIV-1 promoter phenotypically resembles endogenous long terminal repeat (LTR) sequences, pointing to a select role of BRD4S-BRG1 complexes in genomic silencing of invasive retroelements.
Publication
Journal: Journal of Acquired Immune Deficiency Syndromes
March/13/1991
Abstract
The sensitivity and specificity of the polymerase chain reaction (PCR) for the detection of HIV-1 proviral DNA was determined in five laboratories with extensive experience in PCR testing. Five panels consisting of 105 HIV-1-seronegative specimens from regularly repeating blood donors with no risk factors for HIV infection and 99 HIV-1-seropositive and culture-positive specimens from a cohort of homosexual/bisexual men were sent under code to each laboratory. Amplification procedures and testing algorithms by which specimens were judged positive, negative, or indeterminate varied between laboratories. The average sensitivity for the five laboratories was 99.0%, with two laboratories achieving 100%. The average specificity was 94.7%, varying between 90.5 and 100%. The overall false-positive rate was 1.8%, the false-negative rate was 0.8%, and the indeterminate rate was 1.9%. Of 1,005 determinations made by the five laboratories, 32 (3.2%) were misclassifications. Most of the classification errors occurred in specimens from uninfected individuals and were distributed among the laboratories in such a way as to indicate laboratory error rather than the inherent reactivity of some samples. This emphasizes the need for standardization of PCR testing and caution in interpreting positive PCR reactions in HIV-1-seronegative persons.
Publication
Journal: British Journal of Haematology
October/8/2014
Abstract
Until recently, primary central nervous system lymphoma (PCNSL) was associated with a uniformly dismal prognosis. It is now reasonable to anticipate long-term survival and possibly cure for a significant proportion of patients diagnosed with PCNSL. Accumulated data generated over the past 10 years has provided evidence that long-term progression-free survival (PFS) can reproducibly be attained in a significant fraction of PCNSL patients that receive dose-intensive chemotherapy consolidation, without whole brain radiotherapy. One consolidative regimen that has reproducibly demonstrated promise is the combination of infusional etoposide plus high-dose cytarabine (EA), administered in first complete remission after methotrexate, temozolomide and rituximab-based induction. Given evolving principles of management and the mounting evidence for reproducible improvements in survival rates in prospective clinical series, our goal in this review is to highlight and update principles in diagnosis, staging and management as well as to review data regarding the pathogenesis of central nervous system lymphomas, information that is likely to constitute a basis for the implementation of novel therapies that are requisite for further progress in this unique phenotype of non-Hodgkin lymphoma.
Publication
Journal: Archives of Sexual Behavior
June/8/2014
Abstract
Unprotected anal intercourse (UAI) remains a main risk factor for HIV among men who have sex with men (MSM) and this is of particular concern for partners of HIV serodiscordant status. However, HIV transmission risk has been demonstrated to vary by the sexual position adopted among partners. Guided by interdependence theory, this study examined how relational factors were differentially associated with risk taking (HIV-positive/insertive and HIV-negative/receptive) and strategic positioning (HIV-positive/receptive and HIV-negative/insertive) UAI within serodiscordant same-sex male couples. HIV-positive men and their HIV-negative partners (n couples = 91; n individuals = 182) simultaneously but independently completed computerized questionnaires and HIV-positive men had blood drawn for viral load. A minority of couples (30 %) engaged in risk taking and/or strategic positioning unprotected anal sex. Results of multinomial logistic regression indicated that HIV-negative partners' levels of relationship commitment were positively associated with the odds of engaging in strategic positioning sexual behaviors. For HIV-negative partners, reports of relationship intimacy, and sexual satisfaction were negatively associated with odds of reporting risk taking behavior. In contrast, HIV-positive partners' reported sexual satisfaction was positively associated with odds of engaging in risk taking behavior. Findings suggested that aspects of relational quality may be differentially associated with sexual decision making for same-sex male couples in serodiscordant relationships. Study findings lend support for the incorporation of discussions of HIV risk reduction strategies, enhancing communication between partners, and support for general relationship functioning in HIV care.
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