bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potent and Broad Anti-HIV-1 Activity Exhibited by a Glycosyl-Phosphatidylinositol-Anchored Peptide Derived from the CDR H3 of Broadly Neutralizing Antibody PG16
Authors: Liu Lihong , Wen Michael , Wang Weiming , Wang Shumei , Yang Lifei , Liu Yong , Qian Mengran , Zhang Linqi , Shao Yiming , Kimata Jason T. , Zhou Paul 
Published: June 2011

ABSTRACT

PG9 and PG16 are two recently isolated quaternary-specific human monoclonal antibodies that neutralize 70 to 80% of circulating HIV-1 isolates. The crystal structure of PG16 shows that it contains an exceptionally long CDR H3 that forms a unique stable subdomain that towers above the antibody surface to confer fine specificity. To determine whether this unique architecture of CDR H3 itself is sufficient for epitope recognition and neutralization, we cloned CDR H3 subdomains derived from human monoclonal antibodies PG16, PG9, b12, E51, and AVF and genetically linked them to a glycosyl-phosphatidylinositol (GPI) attachment signal. Each fusion gene construct is expressed and targeted to lipid rafts of plasma membranes through a GPI anchor. Moreover, GPI-CDR H3(PG16, PG9, and E51), but not GPI-CDR H3(b12 and AVF), specifically neutralized multiple clades of HIV-1 isolates with a great degree of potency when expressed on the surface of transduced TZM-bl cells. Furthermore, GPI-anchored CDR H3(PG16), but not GPI-anchored CDR H3(AVF), specifically confers resistance to HIV-1 infection when expressed on the surface of transduced human CD4
+
T cells. Finally, the CDR H3 mutations (Y100HF, D100IA, and G7) that were previously shown to compromise the neutralization activity of antibody PG16 also abolished the neutralization activity of GPI-CDR H3(PG16). Thus, we conclude that the CDR H3 subdomain of PG16 neutralizes HIV-1 when targeted to the lipid raft of the plasma membrane of HIV-1-susceptible cells and that GPI-CDR H3 can be an alternative approach for determining whether the CDR H3 of certain antibodies alone can exert epitope recognition and neutralization.
Glyceraldehyde 3-Phosphate Dehydrogenase Negatively Regulates the Replication of Bamboo Mosaic Virus and Its Associated Satellite RNA
Authors: Prasanth K. Reddisiva , Huang Ying-Wen , Liou Ming-Ru , Wang Robert Yung-Liang , Hu Chung-Chi , Tsai Ching-Hsiu , Meng Menghsiao , Lin Na-Sheng , Hsu Yau-Heiu 
Published: June 2011

ABSTRACT

The identification of cellular proteins associated with virus replicase complexes is crucial to our understanding of virus-host interactions, influencing the host range, replication, and virulence of viruses. A previous
in vitro
study has demonstrated that partially purified
Bamboo mosaic virus
(BaMV) replicase complexes can be employed for the replication of both BaMV genomic and satellite BaMV (satBaMV) RNAs. In this study, we investigated the BaMV and satBaMV 3′ untranslated region (UTR) binding proteins associated with these replicase complexes. Two cellular proteins with molecular masses of ∼35 and ∼55 kDa were specifically cross-linked with RNA elements, whereupon the ∼35-kDa protein was identified as the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Gel mobility shift assays confirmed the direct interaction of GAPDH with the 3′ UTR sequences, and competition gel shift analysis revealed that GAPDH binds preferentially to the positive-strand BaMV and satBaMV RNAs over the negative-strand RNAs. It was observed that the GAPDH protein binds to the pseudoknot poly(A) tail of BaMV and stem-loop-C poly(A) tail of satBaMV 3′ UTR RNAs. It is important to note that knockdown of GAPDH in
Nicotiana benthamiana
enhances the accumulation of BaMV and satBaMV RNA; conversely, transient overexpression of GAPDH reduces the accumulation of BaMV and satBaMV RNA. The recombinant GAPDH principally inhibits the synthesis of negative-strand RNA in exogenous RdRp assays. These observations support the contention that cytosolic GAPDH participates in the negative regulation of BaMV and satBaMV RNA replication.
The Herpes Simplex Virus 1 Latency-Associated Transcript Promotes Functional Exhaustion of Virus-Specific CD8
+
T Cells in Latently Infected Trigeminal Ganglia: a Novel Immune Evasion Mechanism
Authors: Chentoufi Aziz A. , Kritzer Elizabeth , Tran Michael V. , Dasgupta Gargi , Lim Chang Hyun , Yu David C. , Afifi Rasha E. , Jiang Xianzhi , Carpenter Dale , Osorio Nelson , Hsiang Chinhui , Nesburn Anthony B. , Wechsler Steven L. , BenMohamed Lbachir 
Published: June 2011

ABSTRACT

Following ocular herpes simplex virus 1 (HSV-1) infection of C57BL/6 mice, HSV-specific (HSV-gB
498–505
tetramer
+
) CD8
+
T cells are induced, selectively retained in latently infected trigeminal ganglia (TG), and appear to decrease HSV-1 reactivation. The HSV-1 latency-associated transcript (LAT) gene, the only viral gene that is abundantly transcribed during latency, increases reactivation. Previously we found that during latency with HSV-1 strain McKrae-derived viruses, more of the total TG resident CD8 T cells expressed markers of exhaustion with LAT
+
virus compared to LAT
−
virus. Here we extend these findings to HSV-1 strain 17syn+-derived LAT
+
and LAT
−
viruses and to a virus expressing just the first 20% of LAT. Thus, the previous findings were not an artifact of HSV-1 strain McKrae, and the LAT function involved mapped to the first 1.5 kb of LAT. Importantly, to our knowledge, we show here for the first time that during LAT
+
virus latency, most of the HSV-1-specific TG resident CD8 T cells were functionally exhausted, as judged by low cytotoxic function and decreased gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) production. This resulted in LAT
−
TG having more functional HSV-gB
498–505
tetramer
+
CD8
+
T cells compared to LAT
+
TG. In addition, LAT expression, in the absence of other HSV-1 gene products, appeared to be able to directly or indirectly upregulate both PD-L1 and major histocompatibility complex class I (MHC-I) on mouse neuroblastoma cells (Neuro2A). These findings may constitute a novel immune evasion mechanism whereby the HSV-1 LAT directly or indirectly promotes functional exhaustion (i.e., dysfunction) of HSV-specific CD8
+
T cells in latently infected TG, resulting in increased virus reactivation.
Phenotypic and Immunologic Comparison of Clade B Transmitted/Founder and Chronic HIV-1 Envelope Glycoproteins
Authors: Wilen Craig B. , Parrish Nicholas F. , Pfaff Jennifer M. , Decker Julie M. , Henning Elizabeth A. , Haim Hillel , Petersen Josiah E. , Wojcechowskyj Jason A. , Sodroski Joseph , Haynes Barton F. , Montefiori David C. , Tilton John C. , Shaw George M. , Hahn Beatrice H. , Doms Robert W. 
Published: June 2011

ABSTRACT

Sexual transmission of human immunodeficiency virus type 1 (HIV-1) across mucosal barriers is responsible for the vast majority of new infections. This relatively inefficient process results in the transmission of a single transmitted/founder (T/F) virus, from a diverse viral swarm in the donor, in approximately 80% of cases. Here we compared the biological activities of 24 clade B T/F envelopes (Envs) with those from 17 chronic controls to determine whether the genetic bottleneck that occurs during transmission is linked to a particular Env phenotype. To maximize the likelihood of an intact mucosal barrier in the recipients and to enhance the sensitivity of detecting phenotypic differences, only T/F Envs from individuals infected with a single T/F variant were selected. Using pseudotyping to assess Env function in single-round infectivity assays, we compared coreceptor tropism, CCR5 utilization efficiencies, primary CD4
+
T cell subset tropism, dendritic cell
trans
-infections, fusion kinetics, and neutralization sensitivities. T/F and chronic Envs were phenotypically equivalent in most assays; however, T/F Envs were modestly more sensitive to CD4 binding site antibodies b12 and VRC01, as well as pooled human HIV Ig. This finding was independently validated with a panel of 14 additional chronic HIV-1 Env controls. Moreover, the enhanced neutralization sensitivity was associated with more efficient binding of b12 and VRC01 to T/F Env trimers. These data suggest that there are subtle but significant structural differences between T/F and chronic clade B Envs that may have implications for HIV-1 transmission and the design of effective vaccines.
Epigenetic Silencing of HIV-1 by the Histone H3 Lysine 27 Methyltransferase Enhancer of Zeste 2
Authors: Friedman Julia , Cho Won-Kyung , Chu Chung K. , Keedy Kara S. , Archin Nancie M. , Margolis David M. , Karn Jonathan 
Published: June 2011

ABSTRACT
Latent HIV proviruses are silenced as the result of deacetylation and methylation of histones located at the viral long terminal repeat (LTR). Inhibition of histone deacetylases (HDACs) leads to the reemergence of HIV-1 from latency, but the contribution of histone lysine methyltransferases (HKMTs) to maintaining HIV latency remains uncertain. Chromatin immunoprecipitation experiments using latently infected Jurkat T-cell lines demonstrated that the HKMT enhancer of Zeste 2 (EZH2) was present at high levels at the LTR of silenced HIV proviruses and was rapidly displaced following proviral reactivation. Knockdown of EZH2, a key component of the Polycomb repressive complex 2 (PRC2) silencing machinery, and the enzyme which is required for trimethyl histone lysine 27 (H3K27me3) synthesis induced up to 40% of the latent HIV proviruses. In contrast, there was less than 5% induction of latent proviruses following knockdown of SUV39H1, which is required for H3K9me3 synthesis. Knockdown of EZH2 also sensitized latent proviruses to external stimuli, such as T-cell receptor stimulation, and slowed the reversion of reactivated proviruses to latency. Similarly, cell populations that responded poorly to external stimuli carried HIV proviruses that were enriched in H3K27me3 and relatively depleted in H3K9me3. Treating latently infected cells with the HKMT inhibitor 3-deazaneplanocin A, which targets EZH2, led to the reactivation of silenced proviruses, whereas chaetocin and BIX01294 showed only minimal reactivation activities. These findings suggest that PRC2-mediated silencing is an important feature of HIV latency and that inhibitors of histone methylation may play a useful role in induction strategies designed to eradicate latent HIV pools.
The Role of Amino-Terminal Sequences in Cellular Localization and Antiviral Activity of APOBEC3B
Authors: Pak Vladimir , Heidecker Gisela , Pathak Vinay K. , Derse David 
Published: June 2011

ABSTRACT

Human APOBEC3B (A3B) has been described as a potent inhibitor of retroviral infection and retrotransposition. However, we found that the predominantly nuclear A3B only weakly restricted infection by HIV-1, HIV-1Δ
vif
, and human T-cell leukemia virus type 1 (HTLV-1), while significantly inhibiting LINE-1 retrotransposition. The chimeric construct A3G/B, in which the first 60 amino acids of A3B were replaced with those of A3G, restricted HIV-1, HIV-1Δ
vif
, and HTLV-1 infection, as well as LINE-1 retrotransposition. In contrast to the exclusively cytoplasmic A3G, which is inactive against LINE-1 retrotransposition, the A3G/B protein, while localized mainly to the cytoplasm, was also present in the nucleus. Further mutational analysis revealed that residues 18, 19, 22, and 24 in A3B were the major determinants for nuclear versus cytoplasmic localization and antiretroviral activity. HIV-1Δ
vif
packages A3G, A3B, and A3G/B into particles with close-to-equal efficiencies. Mutation E68Q or E255Q in the active centers of A3G/B resulted in loss of the inhibitory activity against HIV-1Δ
vif
, while not affecting activity against LINE-1 retrotransposition. The low inhibition of HIV-1Δ
vif
by A3B correlated with a low rate of G-to-A hypermutation. In contrast, viruses that had been exposed to A3G/B showed a high number of G-to-A transitions. The mutation pattern was similar to that previously reported for A3B, with a preference for the GA context. In summary, these observations suggest that changing 4 residues in the amino terminus of A3B not only retargets the protein from the nucleus to the cytoplasm but also enhances its ability to restrict HIV while retaining inhibition of retrotransposition.
Activation of the Retroviral Budding Factor ALIX
Authors: Zhai Qianting , Landesman Michael B. , Chung Hyo-Young , Dierkers Adam , Jeffries Cy M. , Trewhella Jill , Hill Christopher P. , Sundquist Wesley I. 
Published: June 2011

ABSTRACT
The cellular ALIX protein functions within the ESCRT pathway to facilitate intralumenal endosomal vesicle formation, the abscission stage of cytokinesis, and enveloped virus budding. Here, we report that the C-terminal proline-rich region (PRR) of ALIX folds back against the upstream domains and auto-inhibits V domain binding to viral late domains. Mutations designed to destabilize the closed conformation of the V domain opened the V domain, increased ALIX membrane association, and enhanced virus budding. These observations support a model in which ALIX activation requires dissociation of the autoinhibitory PRR and opening of the V domain arms.
The Cytoplasmic Domain of Rhesus Cytomegalovirus Rh178 Interrupts Translation of Major Histocompatibility Class I Leader Peptide-Containing Proteins prior to Translocation
Authors: Richards Rebecca , Scholz Isabel , Powers Colin , Skach William R. , Früh Klaus 
Published: June 2011

ABSTRACT

Cytomegalovirus (CMV) efficiently evades many host immune defenses and encodes a number of proteins that prevent antigen presentation by major histocompatibility complex class I (MHC-I) molecules in order to evade recognition and killing of infected cells by cytotoxic CD8
+
T cells. We recently showed that rhesus CMV-specific Rh178 intercepts MHC-I protein translation before interference of MHC-I maturation by homologues of the human CMV US6 family. Here, we demonstrate that Rh178 localizes to the membrane of the endoplasmic reticulum, displaying a short luminal and large cytosolic domain, and that the membrane-proximal cytosolic portion is essential for inhibition of MHC-I expression. We further observed that Rh178 does not require synthesis of full-length MHC-I heavy chains but is capable of inhibiting the translation of short, unstable amino-terminal fragments of MHC-I. Moreover, the transfer of amino-terminal fragments containing the MHC-I signal peptide renders recipient proteins susceptible to targeting by Rh178. The cytosolic orientation of Rh178 and its ability to target protein fragments carrying the MHC-I signal peptide are consistent with Rh178 intercepting partially translated MHC-I heavy chains after signal recognition particle-dependent transfer to the endoplasmic reticulum membrane. However, interference with MHC-I translation by Rh178 seems to occur prior to SEC61-dependent protein translocation, since inhibition of MHC-I translocation by eeyarestatin 1 resulted in a full-length degradation intermediate that can be stabilized by proteasome inhibitors. These data are consistent with Rh178 blocking protein translation of MHC-I heavy chains at a step prior to the start of translocation, thereby downregulating MHC-I at a very early stage of translation.
Effects of statin medication on mortality risk associated with type 2 diabetes in older persons: the population-based AGES-Reykjavik Study
Authors: Olafsdottir Elin , Aspelund Thor , Sigurdsson Gunnar , Thorsson Bolli , Eiriksdottir Gudny , Harris Tamara B , Launer Lenore J , Benediktsson Rafn , Gudnason Vilmundur 
Published: June 2011

ObjectiveTo examine if the beneficial effect of statin medication on mortality seen in randomised clinical trials of type 2 diabetes applies equally to observational studies in the general population of older people.DesignA prospective, population-based cohort study.SettingReykjavik, Iceland.Participants5152 men and women from the Age, Gene/Environment Susceptibility-Reykjavik Study, mean age 77 years, range of 66–96 years.Main outcome measureCardiovascular and all-cause mortalities and the RR of dying according to statin use and history of coronary heart disease (CHD) in persons with type 2 diabetes and those without diabetes with a median follow-up time of 5.3 years, until end of 2009.ResultsThe prevalence of type 2 diabetes was 12.4% of which 35% used statins. Statin use was associated with a 50% (95% CI 8% to 72%) lower cardiovascular mortality and 53% (29% to 68%) lower all-cause mortalities in persons with diabetes. For those without diabetes, statin use was associated with a 16% (−24% to 43%) lower cardiovascular and 30% (11% to 46%) lower all-cause mortalities. Persons with diabetes using statins had a comparable risk of cardiovascular and all-cause mortality to that of the general population without diabetes. The effect was independent of the level of glycaemic control.ConclusionThis observational study lends important support to existing data from randomised clinical trials. These data suggest that in the general population of older people with diabetes, statin medication markedly reduces the excess cardiovascular and all-cause mortality risk, irrespective of the presence or absence of coronary heart disease or glucose-lowering medication.
Formaldehyde substitute fixatives: effects on nucleic acid preservation
Authors: Moelans Cathy B , Oostenrijk Daphne , Moons Michiel J , van Diest Paul J 
Published: June 2011

AimsIn surgical pathology, formalin-fixed paraffin-embedded tissues are increasingly being used as a source of DNA and RNA for molecular assays in addition to histopathological evaluation. However, the commonly used formalin fixative is carcinogenic, and its crosslinking impairs DNA and RNA quality.MethodsThe suitability of three new presumably less toxic, crosslinking (F-Solv) and non-crosslinking (FineFIX, RCL2) alcohol-based fixatives was tested for routine molecular pathology in comparison with neutral buffered formalin (NBF) as gold standard. Size ladder PCR, epidermal growth factor receptor sequence analysis, microsatellite instability (MSI), chromogenic (CISH), fluorescence in situ hybridisation (FISH) and qPCR were performed.ResultsThe alcohol-based non-crosslinking fixatives (FineFIX and RCL2) resulted in a higher DNA yield and quality compared with crosslinking fixatives (NBF and F-Solv). Size ladder PCR resulted in a shorter amplicon size (300 bp) for both crosslinking fixatives compared with the non-crosslinking fixatives (400 bp). All four fixatives were directly applicable for MSI and epidermal growth factor receptor sequence analysis. All fixatives except F-Solv showed clear signals in CISH and FISH. RNA yield and quality were superior after non-crosslinking fixation. qPCR resulted in lower Ct values for RCL2 and FineFIX.ConclusionThe alcohol-based non-crosslinking fixatives performed better than crosslinking fixatives with regard to DNA and RNA yield, quality and applicability in molecular diagnostics. Given the higher yield, less starting material may be necessary, thereby increasing the applicability of biopsies for molecular studies.
Regression of Glioma in Rat Models by Intranasal Application of Parvovirus H-1
Authors: Kiprianova Irina , Thomas Nadja , Ayache Ali , Fischer Manuel , Leuchs Barbara , Klein Michèle , Rommelaere Jean , Schlehofer Jörg R. 
Published: June 2011

Abstract
Purpose: In previous studies, we have shown that the apathogenic rat parvovirus H-1 (H-1PV) is capable to induce regression of advanced symptomatic rat and human gliomas in a rat model, when the virus was injected in the tumor (intracranially) or intravenously. Infection with H-1PV did not provoke any pathology in nontumor tissue. This study addresses the question whether also intranasal application of this oncolytic virus is suitable and sufficient for treating gliomas in this animal model.
Experimental Design: Rat (RG-2) or human (U87) glioma cells were grafted stereotactically in the brain of rats (Wistar or RNU, respectively), and after development of tumors visible by MRI, H-1PV was instilled intranasally. Tumor regression was monitored by MRI, and survival was analyzed by Kaplan–Meier analysis. Brains from sacrificed animals were analyzed for histologic alterations, presence of viral DNA and proteins and infectious virions. In addition, distribution of virus to other organs was determined.
Results: A single intranasal instillation of H-1PV was sufficient to induce efficient regression of rat glioma, leading to significant prolongation of survival without any toxicity for other tissues. It is shown that the virus reaches brain and other tissues, and that the viral replication-associated (and oncolysis-associated) regulatory proteins are exclusively expressed in the tumor tissue. In rats with xenografts of human glioma, oncolytic activity of H-1PV was less pronounced, however, leading to significant prolongation of survival.
Conclusion: In view of an ongoing clinical trial on the use of H-1PV for oncolytic virotherapy of glioma, the option of applying the virus intranasally may be a valuable alternative to invasive routes of infection. Clin Cancer Res; 17(16); 5333–42. ©2011 AACR.
Prognostic Value of Baseline Plasma Amino-Terminal Pro-Brain Natriuretic Peptide and Its Interactions With Irbesartan Treatment Effects in Patients With Heart Failure and Preserved Ejection Fraction
Authors: Anand Inder S. , Rector Thomas S. , Cleland John G. , Kuskowski Michael , McKelvie Robert S. , Persson Hans , McMurray John J. , Zile Michael R. , Komajda Michel , Massie Barry M. , Carson Peter E. 
Published: June 2011

Background—
Plasma concentrations of natriuretic peptides (NPs) are associated with morbidity and mortality in patients with systolic heart failure (HF). However, the role of NP as a prognostic marker in patients with HF and preserved ejection fraction (HFpEF) has not been studied in a large cohort of well-characterized patients. Moreover, it is unclear whether treatments have a differential effect on morbidity and mortality across the spectrum of NP levels.

Methods and Results—

N-terminal pro-brain natriuretic peptide (NT-proBNP) was measured at baseline in 3480 patients in the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction Trial). In a multivariable Cox regression model, NT-proBNP above the median of 339 pg/mL was independently associated with an increased risk of the primary end point of all-cause mortality and prespecified cardiovascular hospitalizations (adjusted hazard ratio [HR], 1.79; 95% CI, 1.56 to 2.10;
P
<0.001); all-cause mortality (adjusted HR, 2.04; 95% CI, 1.68 to 2.47;
P
<0.001); and a composite of HF events, including death due to worsening HF or sudden death or hospitalization due to worsening HF (adjusted HR, 1.77; 95% CI, 1.43 to 2.20;
P
<0.001). There were significant interactions between the effect of irbesartan and median split of baseline NT-proBNP for the primary outcome (
P
=0.005), all-cause mortality (
P
=0.05), and the HF composite outcome (
P
<0.001). Use of irbesartan was associated with improved outcomes in patients with NT-proBNP below, but not above, the median. After adjusting for 20 baseline covariates, irbesartan still had a beneficial effect on the primary outcome (HR, 0.74; 95% CI, 0.60 to 90;
P
=0.003), all-cause mortality (HR, 0.75; 95% CI, 0.56 to 0.99;
P
=0.046), and HF composite outcome (HR, 0.57; 95% CI, 0.41 to 0.80;
P
=0.001) in patients with NT-proBNP below the median.

Conclusions—
The unexpected benefit of irbesartan in lower-risk patients with HFpEF in this post hoc analysis may indicate effects on early, but not later, high-risk stages of the disease. These findings question the strategy of using elevated plasma concentrations of NP as a patient selection criterion in HFpEF trials. More studies are needed to support or contest this practice.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00095238.