Table of Contents

Abstract: The first wave of the 2009 influenza H1N1 pandemic (H1N1pdm) in Milwaukee, WI has been recognized as the largest reported regional outbreak in the United States. The epidemiologic and clinical characteristics of this large first wave outbreak from April 28^th 2009–July 25^th 2009, studied using both passive and targeted surveillance methodologies are presented. A total of 2791 individuals with H1N1pdm infection were identified; 60 % were 5–18 years old. The 5–18 year and 0–4 year age groups had high infection (1131 and 1101 per 100,000) and hospitalization (49 and 12 per 100,000) rates respectively. Non-Hispanic blacks and Hispanics had the highest hospitalization and infection rates. In targeted surveillance, infected patients had fever (78%), cough (80%), sore throat (38%), and vomiting or diarrhea (8%). The “influenza like illness” definition captured only 68 % of infected patients. Modeling estimates that 10.3 % of Milwaukee population was infected in the first wave and 59% were asymptomatic. The distinct epidemiologic profile of H1N1pdm infections observed in the study has direct implications for predicting the burden of infection and hospitalization in the next waves of H1N1pdm. Careful consideration of demographic predictors of infection and hospitalization with H1N1pdm will be important for effective preparedness for subsequent influenza seasons.

Abstract: The study of enveloped animal viruses has greatly advanced our understanding of the general properties of membrane fusion and of the specific pathways that viruses use to infect the host cell. The membrane fusion proteins of the alphaviruses and flaviviruses have many similarities in structure and function. As reviewed here, alphaviruses use receptor-mediated endocytic uptake and low pH-triggered membrane fusion to deliver their RNA genomes into the cytoplasm. Recent advances in understanding the biochemistry and structure of the alphavirus membrane fusion protein provide a clearer picture of this fusion reaction, including the protein’s conformational changes during fusion and the identification of key domains. These insights into the alphavirus fusion mechanism suggest new areas for experimental investigation and potential inhibitor strategies for anti-viral therapy.

Abstract: Hepatitis C virus (HCV) represents a major health burden, with an estimated 180 million chronically infected individuals worldwide. These patients are at increased risk of developing liver cirrhosis and hepatocellular carcinoma. Infection with HCV is the leading cause of liver transplantation in the Western world. Currently, the standard of care (SoC) consists of pegylated interferon alpha (pegIFN-α) and ribavirin (RBV). However this therapy has a limited efficacy and is associated with serious side effects. Therefore more tolerable, highly potent inhibitors of HCV replication are urgently needed. Both Specifically Targeted Antiviral Therapy for HCV (STAT-C) and inhibitors that are believed to interfere with the host-viral interaction are discussed.

Abstract: We evaluated the effect of combination anti-retroviral treatment (cART) on the host control of EBV infection in moderately immunosuppressed HIV-1 patients. Twenty HIV-1 infected individuals were followed for five years with repeated measurements of EBV DNA load in peripheral blood lymphocytes in relation to HIV-RNA titers and CD4+ cell counts. Individuals with optimal response, i.e. durable non-detectable HIV-RNA, showed a decline of EBV load to the level of healthy controls. Individuals with non-optimal HIV-1 control did not restore their EBV control. Long-lasting suppression of HIV-replication after early initiation of cART is a prerequisite for re-establishing the immune control of EBV.

Abstract: HIV-1 reverse transcriptase (RT) inhibitors currently used in antiretroviral therapy can be divided into two classes: (i) nucleoside analog RT inhibitors (NRTIs), which compete with natural nucleoside substrates and act as terminators of proviral DNA synthesis, and (ii) non-nucleoside RT inhibitors (NNRTIs), which bind to a hydrophobic pocket close to the RT active site. In spite of the efficiency of NRTIs and NNRTIs, the rapid emergence of multidrug-resistant mutations requires the development of new RT inhibitors with an alternative mechanism of action. Recently, several studies reported the discovery of novel non-nucleoside inhibitors with a distinct mechanism of action. Unlike classical NNRTIs, they compete with the nucleotide substrate, thus forming a new class of RT inhibitors: nucleotide-competing RT inhibitors (NcRTIs). In this review, we discuss current progress in the understanding of the peculiar behavior of these compounds.

Abstract: Since the human immunodeficiency virus (HIV) was discovered as the etiological agent of acquired immunodeficiency syndrome (AIDS), it has encouraged much research into antiviral compounds. The reverse transcriptase (RT) of HIV has been a main target for antiviral drugs. However, all drugs developed so far inhibit the polymerase function of the enzyme, while none of the approved antiviral agents inhibit specifically the necessary ribonuclease H (RNase H) function of RT. This review provides a background on structure-function relationships of HIV-1 RNase H, as well as an outline of current attempts to develop novel, potent chemotherapeutics against a difficult drug target.

Abstract: Like other pathogens that readily persist in animal hosts, members of the Bornaviridae family have evolved effective mechanisms to evade the innate immune response. The prototype of this virus family, Borna disease virus employs an unusual replication strategy that removes the triphosphates from the 5’ termini of the viral RNA genome. This strategy allows the virus to avoid activation of RIG-I and other innate immune response receptors in infected cells. Here we determined whether the newly discovered avian bornaviruses (ABV) might use a similar strategy to evade the interferon response. We found that de novo infection of QM7 and CEC32 quail cells with two different ABV strains was efficiently inhibited by exogenous chicken IFN-α. IFN-α also reduced the viral load in QM7 and CEC32 cells persistently infected with both ABV strains, suggesting that ABV is highly sensitive to type I IFN. Although quail cells persistently infected with ABV contained high levels of viral RNA, the supernatants of infected cultures did not contain detectable levels of biologically active type I IFN. RNA from cells infected with ABV failed to induce IFN-β synthesis if transfected into human cells. Furthermore, genomic RNA of ABV was susceptible to 5’-monophosphate-specific RNase, suggesting that it lacks 5’-triphospates like BDV. These results indicate that bornaviruses of mammals and birds use similar strategies to evade the host immune response.

Abstract: This mini-review summarizes the process of reverse-transcription, an obligatory step in retrovirus replication during which the retroviral RNA/DNA-dependent DNA polymerase (RT) copies the single-stranded genomic RNA to generate the double-stranded viral DNA while degrading the genomic RNA via its associated RNase H activity. The hybridization of complementary viral sequences by the nucleocapsid protein (NC) receives a special focus, since it acts to chaperone the strand transfers obligatory for synthesis of the complete viral DNA and flanking long terminal repeats (LTR). Since the physiological microenvironment can impact on reverse-transcription, this mini-review also focuses on factors present in the intra-cellular or extra-cellular milieu that can drastically influence both the timing and the activity of reverse-transcription and hence virus infectivity.

Abstract: Three different Bacillus bacteriophages designated TP21 are known from the literature. We have determined the sequence and structure of the TP21-L genome, and compared it to the other phages. The genome is 37.5 kb in size, possesses fixed invariable genome ends and features the typical modular organization of a temperate siphovirus. TP21-L is neither identical to TP21 isolated by Thorne (TP21-T), as shown by a PCR-based approach nor to TP21 isolated by He et al. (TP21-H), as estimated from phage dimensions. For reasons of clarity, we suggest renaming the different TP21 isolates.

Abstract: Poxviruses replicate in the cytoplasm, where they acquire multiple lipoprotein membranes. Although a proposal that the initial membrane arises de novo has not been substantiated, there is no accepted explanation for its formation from cellular membranes. A subsequent membrane-wrapping step involving modified trans-Golgi or endosomal cisternae results in a particle with three membranes. These wrapped virions traverse the cytoplasm on microtubules; the outermost membrane is lost during exocytosis, the middle one is lost just prior to cell entry, and the remaining membrane fuses with the cell to allow the virus core to enter the cytoplasm and initiate a new infection.

Abstract: Tetherin is an antiviral restriction factor made by mammalian cells to protect them from viral infection. It prevents newly formed virus particles from leaving infected cells. Its antiviral mechanism appears to be remarkably uncomplicated. In 2 studies published in PLoS Pathogens electron microscopy is used to support the hypothesis that the tethers that link HIV-1 virions to tetherin expressing cells contain tetherin and are likely to contain tetherin alone. They also show that the HIV-1 encoded tetherin antagonist that is known to cause tetherin degradation, Vpu, serves to reduce the amount of tetherin in the particles thereby allowing their release.

Abstract: Commentary on Ge, P.; Tsao, J.; Schein, S.; Green, T.J.; Luo, M.; Zhou, Z.H. Cryo-EM model of the bullet-shaped vesicular stomatitis virus. Science 2010, 327, 689-693.

Abstract: Over the last three decades, interest in the field of gene therapy seems to have fluctuated between hot and cold. Encouraging pre-clinical and clinical data has demonstrated the potential of genetic therapies and yet setbacks in clinical trials have cast doubts in some minds over the clinical future of gene therapy [1-3]. In the last two years, a number of studies have demonstrated therapeutic benefits in clinical trials aimed towards specific monogenetic disorders [4-6], and this has brought renewed optimism to the field. [...]

Abstract: The direct movement of viruses between contacting cells as a mode of dissemination distinct from the release of cell-free virions was hinted at in pioneering experiments first reported almost eighty years ago [1], and confirmed and extended 30 years later [2,3]. This early work was carried out using the tools of the time in the absence of the modern cell biological, immunological and virological techniques available today. As such, although many of the basic concepts were established for cell-to-cell spread prior to the discovery of retroviruses, descriptions of the molecular and cellular mechanisms underlying this phenomenon were lacking. Papers from two decades ago revealed that HIV-1 could spread between cultured lymphocytes by cell-to-cell spread [4], proposed that this mechanism of dissemination was substantially more efficient than diffusion-limited spread of cell-free virions [5,6], and suggested that this might be a mechanism of evasion from antibody neutralization [4]. [...]

Abstract: Glycosphingolipids are ubiquitous molecules composed of a lipid and a carbohydrate moiety. Their main functions are as antigen/toxin receptors, in cell adhesion/recognition processes, or initiation/modulation of signal transduction pathways. Microbes take advantage of the different carbohydrate structures displayed on a specific cell surface for attachment during infection. For some viruses, such as the polyomaviruses, binding to gangliosides determines the internalization pathway into cells. For others, the interaction between microbe and carbohydrate can be a critical determinant for host susceptibility. In this review, we summarize the role of glycosphingolipids as receptors for members of the non-enveloped calici-, rota-, polyoma- and parvovirus families.