Worm.com

Rapid Increase in Use of E-Mail with Disguised Web Links to Infect Users

LINDON, Utah — Avinti, a developer of proactive e-mail security solutions, has issued a security alert about a new e-mail attack that disguises malicious code behind a seemingly harmless e-greeting. This latest e-mail attack is part of a recent increase in spam-like greetings that encourage users to click on a link in the body of the e-mail to view an apparently legitimate site, but instead links to malicious code or malware. The latest version of this type of blended threat includes the subject line "Movie-quality ecard" and provides an e-mail address of the sender to trick the recipient into clicking on the harmful link.

"Clicking on the Web site address link in the e-mail triggers an installation of one or two files on the user’s machine, designed to capture user data. There is no user intervention required; the download is automatic," said Dave Green, Avinti’s CTO. "The e-mail appears as plain text but most e-mail clients pick up the plain-text URL and highlight it for the user to click on," he added. "So the e-mail, as plain text, will pass through other antivirus (AV) gateways completely undetected. In case the Web address doesn’t get highlighted, the e-mail also encourages users to copy and paste the URL into their browser."

The links lead to IP addresses in various locations, including the U.S. and Eastern Europe, and many that are registered to U.S. Internet Service Providers (ISPs). Some addresses have been associated with previous exploits, and others from ISPs are actually personal computers that have been infected with the malicious code to execute this exploit. The downloaded files are new variants of the Storm Worm that was first detected in January 2007. "Online scanner Virustotal.com shows about one-third of AV vendors tested do not detect the malware," said Green. "However, because this comes through as a blended threat e-mail, it will completely bypass AV products because there is no attached file to scan."

Blended threat attacks have risen, as hackers have increasingly used the tactic to circumvent detection by traditional signature-based AV products. Several versions of e-mails have been used in the last few weeks, all carrying URL-based blended threats, under subject lines such as Animated Postcard, Greeting eCard, and Neighbor Sent You a Greeting. The e-mails often include highlighted domains of reputable Web sites, including postcards.com, egreetings.com, netfuncards.com, hallmark.com, and 2000greetings.com. Other versions will certainly appear as hackers are quickly changing e-mail names, domain names, URLs, and IP addresses to avoid detection.

"This shouldn’t be classified as spam," said Green. "There is no motivation to get the user to buy anything or pump up stock prices. These e-mails should be considered malware attacks as they are attempts by hackers to infect machines with malware to steal data and propagate their network of bots. Users should take caution with any variations of these e-mails and should never click on the URLs or IP addresses highlighted in the e-mail."

Avinti’s iSolation Server, a proactive e-mail security solution, stops stealthy, complicated threats such as this attack and other zero-day malware attacks, targeted threats, blended threats, and mass variants. Its patent-pending technology complements existing security solutions by detecting threats without having to rely on signatures. Avinti’s approach is unique because it safely observes actual behavior of potentially threatening messages, rather than relying on reactive signature-based approaches.

About Avinti

Avinti is a proactive e-mail security solutions company that has taken a different approach to protecting enterprises from security threats. Avinti’s iSolation Server proactively and safely blocks threats not detected by traditional security solutions. The company’s investors include Sequel Venture Partners, Symantec, and vSpring Capital. More information is available at www.Avinti.com.

COPYRIGHT 2007 Business Wire
COPYRIGHT 2008 Gale, Cengage Learning

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ABSTRACT

Viruses are compact biological nanoparticles whose elastic and dynamical properties are hardly known. Inelastic (Brillouin) light scattering was used to characterize these properties, from microcrystals of the Satellite Tobacco Mosaic Virus, a nearly spherical plant virus of 17-nm diameter. Longitudinal sound velocities in wet and dry Satellite Tobacco Mosaic Virus crystals were determined and compared to that of the well-known protein crystal, lysozyme. Localized vibrational modes of the viral particles (i.e., particle modes) were sought in the relevant frequency ranges, as derived assuming the viruses as full free nanospheres. Despite very favorable conditions, regarding virus concentration and expected low damping in dry microcrystals, no firm evidence of virus particle modes could be detected.

INTRODUCTION

Viruses are biological objects with nanometric dimensions (typically from 10 nm to 100 nm) whose dynamical properties are poorly documented in contrast to their structural characterization allowed by x-ray crystallography and cryoelectron microscopy. As pointed out by Witz and Brown (1), the sole knowledge of virus structures may not be sufficient to account for alterations that occur upon interaction of the virus with its environment. For instance, it is well known that under specific conditions viruses undergo significant morphology changes (like swelling (1,2)) associated with transient local modifications of the virus structure; these changes inherently depend on the elastic properties of the virions that only very few experimental studies have reported on so far.

One important challenge in characterizing the dynamical properties of viruses is to assess the existence of collective vibrational modes that induce large-scale periodic deformations of the particle overall shapes. These types of modes (also referred to as particle modes) have long been studied for solid nanoparticles like metallic clusters or carbon nanotubes, allowing a unique characterization of the global elastic properties of the nano-objeets. As mechanically tough, compact, and highly symmetrical particles, viruses have been predicted to possess similar modes of vibration, involving the coherent motions of their main constituents (3-8). Although not yet experimentally identified, recent normal mode analyses (NMA) performed on several viral capsids (9,10) suggested that such types of modes may be involved in some large scale structural rearrangements of viruses, thereby calling for further identifications of viruses’ vibrational properties. Such modes were also evidenced through molecular dynamics simulations of a rhinovirus capsid (11).

In this article, we report an investigation on the dynamical properties of viruses through inelastic Brillouin light-scattering, providing a first determination of viruses’ elastic parameters. These data are key information for the computation of vibrational mode frequencies (like NMA); they may also be useful in predicting the mechanical stability of viral structures (12,13). The sound velocity deduced from these measurements turns out to significantly differ from that of the archetype protein crystal, i.e., lysozyme, often used as reference data for normal mode calculations of viruses. During this study, we show that particle modes of viruses are not observed through inelastic light scattering, from either concentrated aqueous solutions or crystalline assemblies.

The virus under study is the Satellite Tobacco Mosaic Virus (STMV), for which extensive structural data exist (14,15). In addition, a very recent all-atom molecular dynamics simulation of the STMV gave unprecedented insights into the dynamical behavior of the complete virion ( 16). In the frame of our research, the choice for this virus is manifold. Firstly, as described further, the small size of this virus (~17 nm diameter) is associated with vibration mode frequencies ν that are sufficiently large (ν ≥ ~5 GHz) to be experimentally reached unambiguously. Secondly, the nearly spherical shape of the STMV (of actual icosahedral structure) makes it an ideal reference case for calculations based on the assumption of spherical particles (4,5.8). Another important aspect of STMV is that it is by far the easiest virus to produce in the form of microcrystallites that, in one respect, one can consider as the most concentrated virus samples.

SAMPLES AND EXPERIMENTAL METHODS

STMV samples

Different STMV samples associated with different condilionings were investigated: solutions, fully hydrated crystals (wet crystals) and severely dehydrated crystals (dry crystals).

The solution is a puritied preparation of STMV that was twice recrystallized from NaCl, with a tina) concentration of 8.5 mg/ml (optical density of 1.8). The buffer solution is 0.025 M sodium sulfate at pH 6.8.

STMV crystals were grown using the hanging-drop method at room temperature. Crystals with sizes as large as 200 µm were obtained and transferred into sealed glass capillaries for x-ray diffraction (XRD) and for selected light-scattering experiments. Upon transfer, a minimum amount of surrounding mother liquor was kept to ensure full hydration and stability of the microcrystals. XRD patterns with 2 [Angstrom] resolution assessed the good quality of the microcrystals, before and after the light-scattering experiments. All crystals investigated had orthorhombic unit cells.

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ABSTRACT

Infection by membrane-enveloped viruses requires the binding of receptors on the target cell membrane to glycoproteins, or “spikes,” on the viral membrane. The initial entry mechanism is usually classified as fusogenic or endocytotic. However, binding of viral spikes to cell surface receptors not only initiates the viral adhesion and the wrapping process necessary for internalization, but can simultaneously initiate direct fusion with the cell membrane. Both fusion and internalization have been observed to be viable pathways for many viruses. We develop a stochastic model for viral entry that incorporates a competition between receptor-mediated fusion and endocytosis. The relative probabilities of fusion and endocytosis of a virus particle initially nonspecifically adsorbed on the host cell membrane are computed as functions of receptor concentration, binding strength, and number of spikes. We find different parameter regimes where the entry pathway probabilities can be analytically expressed. Experimental tests of our mechanistic hypotheses are proposed and discussed.

INTRODUCTION

Viral entry mechanisms are typically classified as either endocytotic, or as fusogenic (1). In the latter, the virus membrane, after association with the surface of the host cell, fuses and becomes contiguous with the cell membrane. This process is mediated by the binding of cell surface receptors to glycoprotein spikes on the viral membrane surface, forming fusion competent complexes spanning the viral and cell membranes. In endocytosis, the host cell first internalizes the virus particle, wrapping it in a vesicle before acidificationinduced fusion with the endosomal membrane can occur. Wrapping can occur only after cell surface receptors, which also act as attachment factors, bind to the viral spikes. Experimentally, both fusion with the cell membrane and internalization can be observed and distinguished using microscopy (2,3).

Many viruses, such as influenza and hepatitis B, use endocytosis as their primary mode of entry (4,5). The surface of an influenza virus is coated with ~400 hemagglutinin (HA) protein spikes (6). The HA adheres to sialic acid-containing glycoproteins and lipids on the cell surface leading to wrapping of the virus particle. Particle wrapping may also be mediated by the recruitment of pit-forming clathrin/caveolin compounds (7). Cell membrane pinch-off. leading to internalization of the virus, usually requires additional enzymes such as dynamin and endophilin (8). Endosomal acidification oligomerizes the HA. priming them to fuse with the endosomal membrane. Direct fusion of the influenza virus with the host cell membrane is precluded since HA is activated only in the acidic endosomal environment. However, low pH conditions have also been shown to induce the direct fusion of influenza virus with certain cells (9).

Recent experiments on the avian leukosis retrovirus have provided evidence both for a pH-dependent direct fusion mechanism (10.11), and an endocytotic pathway (12). Moreover, the entry pathway of some viruses such as Semliki Forest Virus can be shifted from endocytosis to fusion by acid treatment, but only in certain host cell types (13). In this case, low pH triggering of receptor-primed envelope glycoproteins can initiate fusion before the virus can be wrapped and endocytosed. Vaccinia and HIV (typically infecting cells via fusion after association with the cell surface receptor CD4) have also been shown to exploit both entry mechanisms (7,14-16). For example, fusion-independent mechanisms of HIV-I capture and internalization in mature dendritic cells, mediated by DC-SIGN (17). can be a significant mode of HIV transmission through dendritic cells and lymphatic tissue (18). Capture by DC-SIGN and CLEC-2 adhesion molecules also internalizes HIV in platelets (19). Thus, depending upon physical conditions and cell type, both entry pathways are potentially accessible to certain viruses. The choice seems to depend on the type of receptors the viruses engages, whether they are receptors/coreceptors that induce fusion (perhaps triggered by low pH), or simply attachment factors such as sialic acid-rich glycoproteins that do not induce fusion. In this latter ease, complete wrapping before an irreversible fusion event is more likely to occur, and internalization is favored.

It is not surprising that subtle changes in the interactions between viral membrane proteins and cell receptors dramatically affect the infectivity of a virus, as recently demonstrated for the 1918 influenza virus (20). In this article, we model virus-receptor kinetics and propose a mechanism consistent with experimental observations, which describes viral entry by incorporating both fusion and endocytosis entry pathways in a probabilistic manner. In the next section, we develop a stochastic one-species receptor model for the binding of receptors necessary to start the virus wrapping process. These receptors, upon binding, can induce membrane fusion at each receptor-spike complex. In the Results, we find parameter regimes in which each of the entry mechanisms dominate. Explicit expressions for the entry pathway probabilities, as functions of the relevant kinetic rates, are given in the Appendix. In the Discussion and Summary, we explore the connection between our parameters and experimentally controllable physical conditions such as receptor/ coreceptor density, spike density, and cell membrane rigidity. Experimental tests are proposed and extensions of our analysis to more realistically incorporate biological features are discussed.

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ABSTRACT

We present a single virion method to determine absolute distributions of copy number in the protein composition of viruses and apply it to herpes simplex virus type 1. Using two-color coincidence fluorescence spectroscopy, we determine the virion-to-virion variability in copy numbers of fluorescently labeled tegument and envelope proteins relative to a capsid protein by analyzing fluorescence intensity ratios for ensembles of individual dual-labeled virions and fitting the resulting histogram of ratios. Using EYFP-tagged capsid protein VP26 as a reference for fluorescence intensity, we are able to calculate the mean and also for the first time to our knowledge, the variation in numbers of gD, VP16, and VP22 tegument. The measurement of the number of glycoprotein D molecules was in good agreement with independent measurements of average numbers of these glycoproteins in bulk virus preparations, validating the method. The accuracy, straightforward data processing, and high throughput of this technique make it widely applicable to the analysis of the molecular composition of large complexes in general, and it is particularly suited to providing insights into virus structure, assembly, and infectivity.

INTRODUCTION

Viruses are large and sophisticated macromolecular complexes, whose assembly is still poorly understood and whose composition may vary from one particle to another. The variation in the protein composition of virions may affect the biological characteristics of different populations and may determine important properties such as infectivity and the ability to neutralize the virus with antibodies. Furthermore, characterizing variability in the protein composition of populations of virions produced during virus replication is fundamental to understanding mechanisms of virus assembly and packaging. To date, it has not been possible to explore these relationships due to the lack of suitable methods for assessing compositional heterogeneity at the single-particle level. However, recently developed single-molecule fluorescence methods ( 1 ) have offered the opportunity to study such variation for large numbers of individual molecules or assemblies of molecules. Applying these techniques to virions enables us to measure the extent to which individual virus particles vary in terms of their compositional makeup. Such information is not available from ensemble methods and extends the application of single-molecule methods to the virion-by-virion measurement of the variation in protein distribution. We demonstrate here a single-virion fluorescence spectroscopy method that facilitates the analysis of tens of thousands of individual virus particles to accurately examine both the mean number of proteins present per virion and the variation of this protein composition in the population. This method is applied to herpes simplex virus type 1 (HSVl ), one of the largest and most complex virus structures known.

Herpesviruses are enveloped viruses containing asymmetric structural features including an outer membrane and an amorphous protein layer (tegument) inside the envelope that makes analysis by x-ray crystallography or cryoelectron microscopy difficult. The human herpesv iruses are associated with a wide range of diseases, including cold sores, genital lesions, chicken pox, and glandular fever. All herpesviruses share a common virion morphology: a double-stranded DNA genome is contained within an icosahcdral protein shell (capsid), and this is surrounded by a layer of ~20 types of tegument proteins and a lipid bilayer envelope containing 1 1 types of embedded viral glycoproteins (2,3). The 125-nmdiameter capsid of HSVl has been studied in detail by cryoelectron microscopy, and its structure is known to 8.5-[Angstrom] resolution (4). The tegument and envelope layers of HSVl virions, 225 nm in diameter, have been observed to ~70-[Angstrom] resolution by cryoelectron tomography (2). At this resolution, 600-750 spikes could be observed on the virion surface but could not be identified as specific glycoproteins. Proteins within the irregular tegument layer could not be resolved (2). At present it is unclear how the assembly process of HSV is regulated and how the virus ensures that all the virion components are incorporated at the correct stoichiometrics into the mature virus particle. Due to the lack of detailed structural information available for the irregular tegument and envelope layers of the virus, there are currently no data available on whether the protein composition of these layers can vary considerably between virus particles or whether tight regulation of copy number is important for virus infectivity.

The fluorescently tagged capsid protein VP26 has previously been shown by confocal microscopy to be present at homogenous levels within herpes virions (5,6). Homogeneous expression of capsid proteins is expected because of the regular geometry of the capsid, which can incorporate only a fixed number of its component proteins. Only one previous study, however, has directly examined virion-to-virion variability in levels of a noncapsid protein, del Rio et al. (5) measured the total fluorescence from 200 individual purified virions expressing green fluorescent protein (GFP)-VP22 (a tegument protein of the α-herpesvirus. Pseudorabies virus) by confocal microscopy. The authors make some incisive conclusions about the distributions of tegument proteins, which are supported by our measurements and which we discuss later in more detail. However, they do not attempt to deline these distributions in terms of absolute copy numbers, and their sample sizes are quite limited by the labor-intensive method used to collect data (in contrast to our method, which can easily sample 10,000 virions, as detailed below).

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