Immunology and Infectious Disease Commons^™

Mutation In The Plasmodium Falciparum Crt Protein Determines The Stereospecific Activity Of Antimalarial Cinchona Alkaloids, Carol E. Griffin, Jonathan M. Hoke, Upeka Samarakoon, Junhui Duan, Jianbing Mu, Michael T. Ferdig, David C. Warhurst, Roland Cooper

Roland A. Cooper

The Cinchona alkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (-)-quinine and (+)-quinidine. The potency of (+)-isomers is greater than the (-)-isomers in vitro and in vivo against Plasmodium falciparum malaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (P. falciparum chloroquine resistance transporter), reversed the normal potency order of quinine and quinidine toward P. falciparum. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured the in vitro susceptibility …

Accumulation Of Artemisinin Trioxane Derivatives Within Neutral Lipids Of Plasmodium Falciparum Malaria Parasites Is Endoperoxide-Dependent, Carmony L. Hartwig, Andrew S. Rosenthal, John D'Angelo, Carol E. Griffin, Gary H. Posner, Roland A. Cooper

Roland A. Cooper

The antimalarial trioxanes, exemplified by the naturally occurring sesquiterpene lactone artemisinin and its semi-synthetic derivatives, contain an endoperoxide pharmacophore that lends tremendous potency against Plasmodium parasites. Despite decades of research, their mechanism of action remains unresolved. A leading model of anti-plasmodial activity hypothesizes that iron-mediated cleavage of the endoperoxide bridge generates cytotoxic drug metabolites capable of damaging cellular macromolecules. To probe the malarial targets of the endoperoxide drugs, we studied the distribution of fluorescent dansyl trioxane derivatives in living, intraerythrocytic-stage Plasmodium falciparum parasites using microscopic imaging. The fluorescent trioxanes rapidly accumulated in parasitized erythrocytes, localizing within digestive vacuole-associated neutral lipid …

Genome-Wide Compensatory Changes Accompany Drugselected Mutations In The Plasmodium Falciparum Crt Gene, Hongying Jiang, Jigar J. Patel, Ming Yi, Jianbing Mu, Jinhui Ding, Robert Stephens, Roland Cooper, Michael T. Ferdig, Xin-Zhuan Su

Roland A. Cooper

Mutations in PfCRT (Plasmodium falciparum chloroquine-resistant transporter), particularly the substitution at amino acid position 76, confer chloroquine (CQ) resistance in P. falciparum. Point mutations in the homolog of the mammalian multidrug resistance gene (pfmdr1) can also modulate the levels of CQ response. Moreover, parasites with the same pfcrt and pfmdr1 alleles exhibit a wide range of drug sensitivity, suggesting that additional genes contribute to levels of CQ resistance (CQR). Reemergence of CQ sensitive parasites after cessation of CQ use indicates that changes in PfCRT are deleterious to the parasite. Some CQR parasites, however, persist in the field and grow well …

Design, Synthesis, And Evaluation Of 10-N-Substituted Acridones As Novel Chemosensitizers In Plasmodium Falciparum, Jane X. Kelly, Martin J. Smilkstein, Roland A. Cooper, Kristin D. Lane, Robert A. Johnson, Aaron Janowsky, Rozalia A. Dodean, Rolf Winter, Michael Riscoe

Roland A. Cooper

A series of novel 10-N-substituted acridones, bearing alkyl side chains with tertiary amine groups at the terminal position, were designed, synthesized, and evaluated for the ability to enhance the potency of quinoline drugs against multidrug-resistant (MDR) Plasmodium falciparum malaria parasites. A number of acridone derivatives, with side chains bridged three or more carbon atoms apart between the ring nitrogen and terminal nitrogen, demonstrated chloroquine (CQ)-chemosensitizing activity against the MDR strain of P. falciparum (Dd2). Isobologram analysis revealed that selected candidates demonstrated significant synergy with CQ in the CQ-resistant (CQR) parasite Dd2 but only additive (or indifferent) interaction in the CQ-sensitive …

Detection Of Panulirus Argus Virus 1 (Pav1) In The Caribbean Spiny Lobster Using Fluorescence In Situ Hybridization (Fish), Caiwen Li, Jeffrey D. Shields, Hamish J. Small, Kimberly S. Reece, Carmony L. Hartwig, Roland A. Cooper, Robert E. Ratzlaff

Roland A. Cooper

Panulirus argus Virus 1 (PaV1) is the first virus known to be pathogenic to a wild lobster. It infects the Caribbean spiny lobster P. argus from the Florida Keys, and has a predilection for juveniles. The monitoring of the virus in wild populations and study of its behavior in the laboratory require the development of reliable diagnostic tools. A sensitive and specific fluorescence in situ hybridization (FISH) assay was developed for detection of PaV1. The lower detection limit using a 110 bp DNA probe in a dot-blot hybridization for PaV1 DNA was 10 pg of cloned template PaV1 DNA and …

Caenorhabditis Elegans Micrornas Of The Let-7 Family Act In Innate Immune Response Circuits And Confer Robust Developmental Timing Against Pathogen Stress, Zhiji Ren, Victor R. Ambros

Victor R. Ambros

Animals maintain their developmental robustness against natural stresses through numerous regulatory mechanisms, including the posttranscriptional regulation of gene expression by microRNAs (miRNAs). Caenorhabditis elegans miRNAs of the let-7 family (let-7-Fam) function semiredundantly to confer robust stage specificity of cell fates in the hypodermal seam cell lineages. Here, we show reciprocal regulatory interactions between let-7-Fam miRNAs and the innate immune response pathway in C. elegans. Upon infection of C. elegans larvae with the opportunistic human pathogen Pseudomonas aeruginosa, the developmental timing defects of certain let-7-Fam miRNA mutants are enhanced. This enhancement is mediated by the p38 MAPK innate immune pathway acting …

Molecular And Morphometric Evidence For Separate Species Of Uncinaria (Nematoda: Ancylostomatidae) In California Sea Lions And Northern Fur Seals: Hypothesis Testing Supplants Verification, Steven A. Nadler, Byron J. Adams, Eugene T. Lyons, Robert L. Delong, Sharon R. Melin

Byron Adams

California sea lions (Zalophus californianus) and northern fur seals (Callorhinus ursinus) are each believed to host distinct hookworm species (Uncinaria spp.). However, a recent morphometric analysis suggested that a single species parasitizes multiple pinniped hosts, and that the observed differences are host-induced. To explore the systematics of these hookworms and test these competing hypotheses, we obtained nucleotide sequences of nuclear ribosomal DNA (D2/D3 28S, D18/D19 28S, and internal transcribed spacer [ITS] regions) from 20 individual hookworms parasitizing California sea lion and northern fur seal pups where their breeding grounds are sympatric. Five individuals from an allopatric population of California sea …

Progression Of Non-Alcoholic Steatosis To Steatohepatitis And Fibrosis Parallels Cumulative Accumulation Of Danger Signals That Promote Inflammation And Liver Tumors In A High Fat-Cholesterol-Sugar Diet Model In Mice, Michal Ganz, Terence N. Bukong, Timea Csak, Banishree Saha, Jin-Kyu Park, Aditya Ambade, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming a pandemic. While multiple 'hits' have been reported to contribute to NAFLD progression to non-alcoholic steatohepatitis (NASH), fibrosis and liver cancer, understanding the natural history of the specific molecular signals leading to hepatocyte damage, inflammation and fibrosis, is hampered by the lack of suitable animal models that reproduce disease progression in humans. The purpose of this study was first, to develop a mouse model that closely mimics progressive NAFLD covering the spectrum of immune, metabolic and histopathologic abnormalities present in human disease; and second, to characterize the temporal relationship between sterile/exogenous danger …

Topical Lipophilic Epigallocatechin-3-Gallate On Herpes Labialis: A Phase Ii Clinical Trial Of Averteax Formula, Man Zhao, Rong Zheng, Jinyan Jiang, Douglas Dickinson, Baiping Fu, Tin-Chun Chu, Lee Lee, Hanna Pearl, Stephen Hsu

Tin-Chun Chu, Ph.D.

Objectives The aim of this study was to clinically evaluate a topical proprietary formulation containing lipophilic catechins (AverTeaX) on recurrent herpes labialis. Methods A double blind, placebo-controlled, randomized trial with 40 participants initially in two groups. Results Compared to the vehicle group, AverTeaX applied topically 6-8 times daily resulted in a significant reduction of clinical episode duration (median 4.5 days, range 1-11 days vs. 9 days, range 2-11 days, p=0.003) and shortened blistering/ulceration stages within an episode from a median of 3 (range 0-6) days to 1 (range 0-3) day (p=0.0003). Median quality of life scores based on a multi-question …

Evaluation Of Cardiac Involvement In Children With Dengue By Serial Echocardiographic Studies, Tawatchai Kirawittaya, In-Kyu Yoon, Sineewanlaya Wichit, Sharone Green, Francis A. Ennis, Robert V. Gibbons, Stephen J. Thomas, Alan L. Rothman, Siripen Kalayanarooj, Anon Srikiatkhachorn

Sharone Green

BACKGROUND: Infection with dengue virus results in a wide range of clinical manifestations from dengue fever (DF), a self-limited febrile illness, to dengue hemorrhagic fever (DHF) which is characterized by plasma leakage and bleeding tendency. Although cardiac involvement has been reported in dengue, the incidence and the extent of cardiac involvement are not well defined. METHODS AND PRINCIPAL FINDINGS: We characterized the incidence and changes in cardiac function in a prospective in-patient cohort of suspected dengue cases by serial echocardiography. Plasma leakage was detected by serial chest and abdominal ultrasonography. Daily cardiac troponin-T levels were measured. One hundred and eighty …

Differential Expression Of Ape1 And Ape2 In Germinal Centers Promotes Error-Prone Repair And A:T Mutations During Somatic Hypermutation, Janet Stavnezer, Erin K. Linehan, Mikayla R. Thompson, Ghaith Habboub, Anna J. Ucher, Tatenda Kadungure, Daisuke Tsuchimoto, Yusaku Nakabeppu, Carol E. Schrader

Janet M. Stavnezer

Somatic hypermutation (SHM) of antibody variable region genes is initiated in germinal center B cells during an immune response by activation-induced cytidine deaminase (AID), which converts cytosines to uracils. During accurate repair in nonmutating cells, uracil is excised by uracil DNA glycosylase (UNG), leaving abasic sites that are incised by AP endonuclease (APE) to create single-strand breaks, and the correct nucleotide is reinserted by DNA polymerase beta. During SHM, for unknown reasons, repair is error prone. There are two APE homologs in mammals and, surprisingly, APE1, in contrast to its high expression in both resting and in vitro-activated splenic B …

Inhibition Of Sterile Danger Signals, Uric Acid And Atp, Prevents Inflammasome Activation And Protects From Alcoholic Steatohepatitis In Mice., Arvin Iracheta-Vellve, Jan Petrasek, Abhishek Satishchandran, Benedek Gyongyosi, Banishree Saha, Karen Kodys, Katherine Fitzgerald, Evelyn Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

Background & Aims: The inflammasome is a well-characterized inducer of inflammation in alcoholic steatohepatitis (ASH). Inflammasome activation requires two signals for mature interleukin (IL)-1β production. Here we asked whether metabolic danger signals trigger inflammasome activation in ASH.

Results:The sterile danger signals, ATP and uric acid, were increased in the serum and liver of alcohol-fed mice. Depletion of uric acid or ATP, or lack of ATP signaling attenuated ASH and prevented inflammasome activation and its major downstream cytokine, IL-1β. Pharmacological depletion of uric acid with allopurinol provided significant protection from alcohol-induced inflammatory response, steatosis and liver damage, and additional protection was …

Metabolic Danger Signals, Uric Acid And Atp, Mediate Inflammatory Cross-Talk Between Hepatocytes And Immune Cells In Alcoholic Liver Disease., Jan Petrasek, Arvin Iracheta-Vellve, Banishree Saha, Abhishek Satishchandran, Karen Kodys, Katherine Fitzgerald, Evelyn Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

Inflammation defines the progression of ALD from reversible to advanced stages. Translocation of bacterial LPS to the liver from the gut is necessary for alcohol-induced liver inflammation. However, it is not known whether endogenous, metabolic danger signals are required for inflammation in ALD. Uric acid and ATP, 2 major proinflammatory danger signals, were evaluated in the serum of human volunteers exposed to a single dose of ethanol or in supernatants of primary human hepatocytes exposed to ethanol. In vitro studies were used to evaluate the role of uric acid and ATP in inflammatory cross-talk between hepatocytes and immune cells. The …

The Spatial Dynamics Of Dengue Virus In Kamphaeng Phet, Thailand, Piraya Bhoomiboonchoo, Robert V. Gibbons, Angkana Huang, In-Kyu Yoon, Darunee Buddhari, Ananda Nisalak, Natkamol Chansatiporn, Mathuros Thipayamongkolgul, Siripen Kalanarooj, Timothy Endy, Alan L. Rothman, Anon Srikiatkhachorn, Sharone Green, Mammen P. Mammen, Derek A. Cummings, Henrik Salje

Sharone Green

BACKGROUND: Dengue is endemic to the rural province of Kamphaeng Phet, Northern Thailand. A decade of prospective cohort studies has provided important insights into the dengue viruses and their generated disease. However, as elsewhere, spatial dynamics of the pathogen remain poorly understood. In particular, the spatial scale of transmission and the scale of clustering are poorly characterized. This information is critical for effective deployment of spatially targeted interventions and for understanding the mechanisms that drive the dispersal of the virus.

METHODOLOGY/PRINCIPAL FINDINGS: We geocoded the home locations of 4,768 confirmed dengue cases admitted to the main hospital in Kamphaeng Phet …

Preliminary Evaluation Of Near Infrared Spectroscopy As A Method To Detect Plasma Leakage In Children With Dengue Hemorrhagic Fever, Babs R. Soller, Anon Srikiatkhachorn, Fengmei Zou, Alan L. Rothman, In-Kyu Yoon, Robert V. Gibbons, Siripen Kalayanarooj, Stephen J. Thomas, Sharone Green

Sharone Green

BACKGROUND: Dengue viral infections are prevalent in the tropical and sub-tropical regions of the world, resulting in substantial morbidity and mortality. Clinical manifestations range from a self-limited fever to a potential life-threatening plasma leakage syndrome (dengue hemorrhagic fever). The objective of this study was to assess the utility of near infrared spectroscopy (NIRS) measurements of muscle oxygen saturation (SmO2) as a possible continuous measure to detect plasma leakage in children with dengue.

METHODS: Children ages 6 months to 15 years of age admitted with suspected dengue were enrolled from the dengue ward at Queen Sirikit National Institute for Child Health. …

Sequential Dengue Virus Infections Detected In Active And Passive Surveillance Programs In Thailand, 1994-2010, Piraya Bhoomiboonchoo, Ananda Nisalak, Natkamol Chansatiporn, In-Kyu Yoon, Siripen Kalayanarooj, Mathuros Thipayamongkolgul, Timothy Endy, Alan L. Rothman, Sharone Green, Anon Srikiatkhachorn, Darunee Buddhari, Mammen P. Mammen, Robert V. Gibbons

Sharone Green

BACKGROUND: The effect of prior dengue virus (DENV) exposure on subsequent heterologous infection can be beneficial or detrimental depending on many factors including timing of infection. We sought to evaluate this effect by examining a large database of DENV infections captured by both active and passive surveillance encompassing a wide clinical spectrum of disease.

METHODS: We evaluated datasets from 17 years of hospital-based passive surveillance and nine years of cohort studies, including clinical and subclinical DENV infections, to assess the outcomes of sequential heterologous infections. Chi square or Fisher's exact test was used to compare proportions of infection outcomes such …

Positive Selection Drives Preferred Segment Combinations During Influenza Virus Reassortment, Konstantin Zeldovich, Ping Liu, Nicholas Renzette, Matthieu Foll, Serena Pham, Sergey Venev, Glen Gallagher, Daniel Bolon, Evelyn Kurt-Jones, Jeffrey Jensen, Daniel Caffrey, Celia Schiffer, Timothy Kowalik, Jennifer Wang, Robert Finberg

Celia A. Schiffer

Influenza A virus (IAV) has a segmented genome that allows for the exchange of genome segments between different strains. This reassortment accelerates evolution by breaking linkage, helping IAV cross species barriers to potentially create highly virulent strains. Challenges associated with monitoring the process of reassortment in molecular detail have limited our understanding of its evolutionary implications. We applied a novel deep sequencing approach with quantitative analysis to assess the in vitro temporal evolution of genomic reassortment in IAV. The combination of H1N1 and H3N2 strains reproducibly generated a new H1N2 strain with the hemagglutinin and nucleoprotein segments originating from H1N1 …

Alcohol And Hcv: Implications For Liver Cancer, Gyongyi Szabo, Banishree Saha, Terence Bukong

Gyongyi Szabo

Liver cancers are one of the deadliest known malignancies which are increasingly becoming a major public health problem in both developed and developing countries. Overwhelming evidence suggests a strong role of infection with hepatitis B and C virus (HBV and HCV), alcohol abuse, as well as metabolic diseases such as obesity and diabetes either individually or synergistically to cause or exacerbate the development of liver cancers. Although numerous etiologic mechanisms for liver cancer development have been advanced and well characterized, the lack of definite curative treatments means that gaps in knowledge still exist in identifying key molecular mechanisms and pathways …

A Novel Human Radixin Peptide Inhibits Hepatitis C Virus Infection At The Level Of Cell Entry, Terence Bukong, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

Hepatitis C virus infection of hepatocytes is a multistep process involving the interaction between viral and host cell molecules. Recently, we identified ezrin-moesin-radixin proteins and spleen tyrosine kinase (SYK) as important host therapeutic targets for HCV treatment development. Previously, an ezrin hinge region peptide (Hep1) has been shown to exert anti-HCV properties in vivo, though its mechanism of action remains limited. In search of potential novel inhibitors of HCV infection and their functional mechanism we analyzed the anti-HCV properties of different human derived radixin peptides. Sixteen different radixin peptides were derived, synthesized and tested. Real-time quantitative PCR, cell toxicity assay, …

The Genetics Of Hepatitis C Virus Underlie Its Ability To Escape Humoral Immunity, Jay Kolls, Gyongyi Szabo

Gyongyi Szabo

Hepatitis C virus (HCV) is a leading cause of chronic liver disease, and efforts to develop therapeutic vaccine strategies have been limited by immune escape due to HCV variants that are resistant to current vaccines or HCV variants that rapidly acquire new resistance-conferring mutations. Recently, the crystal structure of the viral envelope protein E2 region was resolved as well as how E2 docks to the host CD81 protein; therefore, antibodies that block this interaction should prevent viral entry into host cells. In this issue of the JCI, Bailey and colleagues show that immune escape of HCV can occur by naturally …

Expert–Novice Differences In Mental Models Of Viruses, Vaccines, And The Causes Of Infectious Disease, Benjamin D. Jee, David H. Uttal, Amy N. Spiegel, Judy Diamond

Amy N. Spiegel

Humans are exposed to viruses everywhere they live, play, and work. Yet people’s beliefs about viruses may be confused or inaccurate, potentially impairing their understanding of scientific information. This study used semi-structured interviews to examine people’s beliefs about viruses, vaccines, and the causes of infectious disease. We compared people at different levels of science expertise: middle school students, teachers, and professional virologists. The virologists described more entities involved in microbiological processes, how these entities behaved, and why. Quantitative and qualitative analyses revealed distinctions in the cognitive organization of several concepts, including infection and vaccination. For example, some students and teachers …

Human Sewage Identified As Likely Source Of White Pox Disease Of The Threatened Caribbean Elkhorn Coral, Kathryn Sutherland, James Porter, Jeffrey Turner, Brian Thomas, Erin Looney, Trevor Luna, Meredith Meyers, J. Futch, Erin Lipp

Kathryn Patterson Sutherland PhD

Caribbean elkhorn coral, Acropora palmata, has been decimated in recent years, resulting in the listing of this species as threatened under the United States Endangered Species Act. A major contributing factor in the decline of this iconic species is white pox disease. In 2002, we identified the faecal enterobacterium, Serratia marcescens, as an etiological agent for white pox. During outbreaks in 2003 a unique strain of S. marcescens was identified in both human sewage and white pox lesions. This strain (PDR60) was also identified from corallivorious snails (Coralliophila abbreviata), reef water, and two non-acroporid coral species, Siderastrea siderea and Solenastrea …

Antiviral Activity Of Theaflavin Digallate Against Herpes Simplex Virus Type 1, Aline De Oliveira, Derek Prince, Chih-Yu Lo, Lee Lee, Tin-Chun Chu

Tin-Chun Chu, Ph.D.

Tea is the second most consumed drink in the world. The beneficial effects of tea have been mostly attributed to its catechin content. Black tea is derived from the leaves of Camellia sinensis plant, and it is rich in theaflavin polyphenols, in particular theaflavin (TF1), theaflavin-3-monogallate (TF2A), theaflavin-3′-monogallate (TF2B), and theaflavin-3,3′-digallate (TF3). Vero and A549 cells were used to evaluate the effect of purified individual black tea theaflavins as anti-herpes simplex virus 1 agents. With the rise of HSV resistant strains, there is a critical need to develop novel antiherpesviral treatments. Results of the cytotoxicity assay tested by MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium] …

Alcohol-Induced Mir-27a Regulates Differentiation And M2 Macrophage Polarization Of Normal Human Monocytes, Banishree Saha, Johanna Bruneau, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

Alcohol abuse is a leading cause of liver disease characterized by liver inflammation, fatty liver, alcoholic hepatitis, or liver cirrhosis. Immunomodulatory effects of alcohol on monocytes and macrophages contribute to alcoholic liver disease. Alcohol use, an independent risk factor for progression of hepatitis C virus (HCV) infection-mediated liver disease, impairs host defense and alters cytokine production and monocyte/macrophage activation. We hypothesized that alcohol and HCV have synergistic effects on the phenotype and function of monocytes. Our data show that acute alcohol binge drinking in healthy volunteers results in increased frequency of CD16(+) and CD68(+) and M2-type (CD206(+), dendritic cell [DC]-SIGN(+)-expressing …

A Lipopolysaccharide-Induced Dna-Binding Protein For A Class Ii Gene In B Cells Is Distinct From Nf-Kappa B, Ellen M. Gravallese, Mark R. Boothby, Cynthia M. Smas, Laurie H. Glimcher

Ellen M. Gravallese

Class II (Ia) major histocompatibility complex molecules are cell surface proteins normally expressed by a limited subset of cells of the immune system. These molecules regulate the activation of T cells and are required for the presentation of antigens and the initiation of immune responses. The expression of Ia in B cells is determined by both the developmental stage of the B cell and by certain external stimuli. It has been demonstrated previously that treatment of B cells with lipopolysaccharide (LPS) results in increased surface expression of Ia protein. However, we have confirmed that LPS treatment results in a significant …

Critical Roles For Interleukin 1 And Tumor Necrosis Factor Alpha In Antibody-Induced Arthritis, Hong Ji, Allison Pettit, Koichiro Ohmura, Adriana Ortiz-Lopez, Veronique Duchatelle, Claude Degott, Ellen M. Gravallese, Diane Mathis, Christophe Benoist

Ellen M. Gravallese

In spontaneous inflammatory arthritis of K/BxN T cell receptor transgenic mice, the effector phase of the disease is provoked by binding of immunoglobulins (Igs) to joint surfaces. Inflammatory cytokines are known to be involved in human inflammatory arthritis, in particular rheumatoid arthritis, although, overall, the pathogenetic mechanisms of the human affliction remain unclear. To explore the analogy between the K/BxN model and human patients, we assessed the role and relative importance of inflammatory cytokines in K/BxN joint inflammation by transferring arthritogenic serum into a panel of genetically deficient recipients. Interleukin (IL)-1 proved absolutely necessary. Tumor necrosis factor (TNF)-alpha was also …

Exosomes From Hepatitis C Infected Patients Transmit Hcv Infection And Contain Replication Competent Viral Rna In Complex With Ago2-Mir122-Hsp90, Terence N. Bukong, Fatemeh Momen-Heravi, Karen Kodys, Shashi Bala, Gyongyi Szabo

Gyongyi Szabo

Antibodies targeting receptor-mediated entry of HCV into hepatocytes confer limited therapeutic benefits. Evidence suggests that exosomes can transfer genetic materials between cells; however, their role in HCV infection remains obscure. Here, we show that exosomes isolated from sera of chronic HCV infected patients or supernatants of J6/JFH1-HCV-infected Huh7.5 cells contained HCV RNA. These exosomes could mediate viral receptor-independent transmission of HCV to hepatocytes. Negative sense HCV RNA, indicative of replication competent viral RNA, was present in exosomes of all HCV infected treatment non-responders and some treatment-naive individuals. Remarkably, HCV RNA was associated with Ago2, HSP90 and miR-122 in exosomes isolated …

Influenza Virus Drug Resistance: A Time-Sampled Population Genetics Perspective, Matthieu Foll, Yu Poh, Nicholas Renzette, Anna Admetlla, Claudia Bank, Hyunjin Shim, Anna Malaspinas, Gregory Ewing, Ping Liu, Daniel Wegmann, Daniel Caffrey, Konstantin Zeldovich, Daniel Bolon, Jennifer Wang, Timothy Kowalik, Celia Schiffer, Robert Finberg, Jeffrey Jensen

Celia A. Schiffer

The challenge of distinguishing genetic drift from selection remains a central focus of population genetics. Time-sampled data may provide a powerful tool for distinguishing these processes, and we here propose approximate Bayesian, maximum likelihood, and analytical methods for the inference of demography and selection from time course data. Utilizing these novel statistical and computational tools, we evaluate whole-genome datasets of an influenza A H1N1 strain in the presence and absence of oseltamivir (an inhibitor of neuraminidase) collected at thirteen time points. Results reveal a striking consistency amongst the three estimation procedures developed, showing strongly increased selection pressure in the presence …

Hiv-1 Protease-Substrate Coevolution In Nelfinavir Resistance, Madhavi Kolli, Aysegul Ozen, Nese Yilmaz, Celia Schiffer

Celia A. Schiffer

Resistance to various human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) challenges the effectiveness of therapies in treating HIV-1-infected individuals and AIDS patients. The virus accumulates mutations within the protease (PR) that render the PIs less potent. Occasionally, Gag sequences also coevolve with mutations at PR cleavage sites contributing to drug resistance. In this study, we investigated the structural basis of coevolution of the p1-p6 cleavage site with the nelfinavir (NFV) resistance D30N/N88D protease mutations by determining crystal structures of wild-type and NFV-resistant HIV-1 protease in complex with p1-p6 substrate peptide variants with L449F and/or S451N. Alterations of residue …

Assessment And Weeding Of A Clinical Hiv/Aids Collection In An Academic Library: A Case Study, Sharon Leslie, Ida Martinez

Sharon Leslie

Maintaining a clinical HIV/AIDS section in an academic library collection that is both current and historically significant for research is essential. This paper reports on a collection management project that was undertaken to weed HIV/AIDS books in targeted clinical areas of an academic library using a timeline model developed by Ondrusek (2001) as a supplement to traditional weeding methods. The combination proved effective for identifying clinical materials that were outdated and needed to be deaccessioned while maintaining historically-relevant materials in these areas.