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Viruses, Volume 2, Issue 12 (December 2010), Pages 2559-2830

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Editorial

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Open AccessEditorial Viral Genomics and Bioinformatics
Viruses 2010, 2(12), 2587-2593; doi:10.3390/v2122587
Received: 29 November 2010 / Accepted: 29 November 2010 / Published: 30 November 2010
Cited by 3 | PDF Full-text (41 KB)
Abstract
From the recognition by Ivanovski in 1892 that tobacco mosaic disease is caused and transmitted by fine pore filtrates [1], viruses have been isolated, characterized, identified and studied from animals, plants, protists, bacteria and even other viruses [2,3]. As human and global [...] Read more.
From the recognition by Ivanovski in 1892 that tobacco mosaic disease is caused and transmitted by fine pore filtrates [1], viruses have been isolated, characterized, identified and studied from animals, plants, protists, bacteria and even other viruses [2,3]. As human and global public health pathogens that can be highly contagious and have devastating morbidity and mortality consequences, viruses are the focus of much research. The difficult challenge has been to define and study a miniscule “being” with the appropriate tools. In the past, these tools often provided only low-resolution views. A first approach to studying an unknown virus is to know exactly its identity, and to place it into context of other related and non-related viruses. For human and public health, this is important as the identity may provide a course of action to limit the effects of the pathogen. [...] Full article
(This article belongs to the Special Issue Viral Genomics and Bioinformatics)

Research

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Open AccessArticle Profound Differences in Virus Population Genetics Correspond to Protection from CD4 Decline Resulting from Feline Lentivirus Coinfection
Viruses 2010, 2(12), 2663-2680; doi:10.3390/v2122663
Received: 9 November 2010 / Revised: 25 November 2010 / Accepted: 29 November 2010 / Published: 10 December 2010
Cited by 3 | PDF Full-text (625 KB)
Abstract
CD4 decline is a hallmark of disease onset in individuals infected with Feline Immunodeficiency Virus (FIV) or Human Immunodeficiency Virus type 1 (HIV-1). Cats that are infected with a poorly replicating, apathogenic FIV (PLV) prior to exposure to a virulent FIV strain [...] Read more.
CD4 decline is a hallmark of disease onset in individuals infected with Feline Immunodeficiency Virus (FIV) or Human Immunodeficiency Virus type 1 (HIV-1). Cats that are infected with a poorly replicating, apathogenic FIV (PLV) prior to exposure to a virulent FIV strain (FIVC) maintain CD4 numbers by mechanisms that are not correlated with a measurable adaptive immune response or reduction in circulating viral load. We employed population genetic approaches based on the 3' portion of the viral genome to estimate the population structure of FIVC from single and dual infected cats. In dual infected cats, FIVC effective population size was decreased during the initial viral expansion phase, and after three weeks of infection, the population declined sharply. The FIVC population recovered to pre-bottleneck levels approximately seven weeks post-FIVC infection. However, the population emerging from the bottleneck in dual infected cats was distinct based on estimates of temporal population structure and substitution profiles. The transition to transversion rate ratio (k) increased from early to late phases in dual infected cats due primarily to a decrease in transversions whereas in single infected cats, k declined over time. Although one clone with extensive G to A substitutions, indicative of host cytidine deaminase editing, was recovered from a dual infected cat during the bottleneck, the post bottleneck population had an overall reduction in G to A substitutions. These data are consistent with a model of PLV-induced host restriction, putatively involving host DNA editing, that alters the dynamics of FIVC throughout the course of infection leading to disease attenuation. Full article
(This article belongs to the Special Issue Virus Dynamics and Evolution)
Open AccessArticle Development of CMX001 for the Treatment of Poxvirus Infections
Viruses 2010, 2(12), 2740-2762; doi:10.3390/v2122740
Received: 28 October 2010 / Revised: 17 November 2010 / Accepted: 22 November 2010 / Published: 17 December 2010
Cited by 33 | PDF Full-text (439 KB)
Abstract
CMX001 (phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl] ester) is a lipid conjugate of the acyclic nucleotide phosphonate, cidofovir (CDV). CMX001 is currently in Phase II clinical trials for the prophylaxis of human cytomegalovirus infection and under development using the Animal Rule for smallpox infection. It [...] Read more.
CMX001 (phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl] ester) is a lipid conjugate of the acyclic nucleotide phosphonate, cidofovir (CDV). CMX001 is currently in Phase II clinical trials for the prophylaxis of human cytomegalovirus infection and under development using the Animal Rule for smallpox infection. It has proven effective in reduction of morbidity and mortality in animal models of human smallpox, even after the onset of lesions and other clinical signs of disease. CMX001 and CDV are active against all five families of double-stranded DNA (dsDNA) viruses that cause human morbidity and mortality, including orthopoxviruses such as variola virus, the cause of human smallpox. However, the clinical utility of CDV is limited by the requirement for intravenous dosing and a high incidence of acute kidney toxicity. The risk of nephrotoxicity necessitates pre-hydration and probenecid administration in a health care facility, further complicating high volume CDV use in an emergency situation. Compared with CDV, CMX001 has a number of advantages for treatment of smallpox in an emergency including greater potency in vitro against all dsDNA viruses that cause human disease, a high genetic barrier to resistance, convenient oral administration as a tablet or liquid, and no evidence to date of nephrotoxicity in either animals or humans. The apparent lack of nephrotoxicity observed with CMX001 in vivo is because it is not a substrate for the human organic anion transporters that actively secrete CDV into kidney cells. The ability to test the safety and efficacy of CMX001 in patients with life-threatening dsDNA virus infections which share many basic traits with variola is a major advantage in the development of this antiviral for a smallpox indication. Full article
(This article belongs to the Special Issue Antivirals Against Poxviruses)
Open AccessArticle Exploratory Spatial Analysis of in vitro Respiratory Syncytial Virus Co-infections
Viruses 2010, 2(12), 2782-2802; doi:10.3390/v2122782
Received: 15 November 2010 / Revised: 12 December 2010 / Accepted: 13 December 2010 / Published: 22 December 2010
Cited by 2 | PDF Full-text (644 KB)
Abstract
The cell response to virus infection and virus perturbation of that response is dynamic and is reflected by changes in cell susceptibility to infection. In this study, we evaluated the response of human epithelial cells to sequential infections with human respiratory syncytial [...] Read more.
The cell response to virus infection and virus perturbation of that response is dynamic and is reflected by changes in cell susceptibility to infection. In this study, we evaluated the response of human epithelial cells to sequential infections with human respiratory syncytial virus strains A2 and B to determine if a primary infection with one strain will impact the ability of cells to be infected with the second as a function of virus strain and time elapsed between the two exposures. Infected cells were visualized with fluorescent markers, and location of all cells in the tissue culture well were identified using imaging software. We employed tools from spatial statistics to investigate the likelihood of a cell being infected given its proximity to a cell infected with either the homologous or heterologous virus. We used point processes, K-functions, and simulation procedures designed to account for specific features of our data when assessing spatial associations. Our results suggest that intrinsic cell properties increase susceptibility of cells to infection, more so for RSV-B than for RSV-A. Further, we provide evidence that the primary infection can decrease susceptibility of cells to the heterologous challenge virus but only at the 16 h time point evaluated in this study. Our research effort highlights the merits of integrating empirical and statistical approaches to gain greater insight on in vitro dynamics of virus-host interactions. Full article
(This article belongs to the Special Issue Virus Dynamics and Evolution)

Review

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Open AccessReview Hantaviruses in the Americas and Their Role as Emerging Pathogens
Viruses 2010, 2(12), 2559-2586; doi:10.3390/v2122559
Received: 25 October 2010 / Revised: 15 November 2010 / Accepted: 24 November 2010 / Published: 25 November 2010
Cited by 37 | PDF Full-text (598 KB)
Abstract
The continued emergence and re-emergence of pathogens represent an ongoing, sometimes major, threat to populations. Hantaviruses (family Bunyaviridae) and their associated human diseases were considered to be confined to Eurasia, but the occurrence of an outbreak in 1993–94 in the southwestern United [...] Read more.
The continued emergence and re-emergence of pathogens represent an ongoing, sometimes major, threat to populations. Hantaviruses (family Bunyaviridae) and their associated human diseases were considered to be confined to Eurasia, but the occurrence of an outbreak in 1993–94 in the southwestern United States led to a great increase in their study among virologists worldwide. Well over 40 hantaviral genotypes have been described, the large majority since 1993, and nearly half of them pathogenic for humans. Hantaviruses cause persistent infections in their reservoir hosts, and in the Americas, human disease is manifest as a cardiopulmonary compromise, hantavirus cardiopulmonary syndrome (HCPS), with case-fatality ratios, for the most common viral serotypes, between 30% and 40%. Habitat disturbance and larger-scale ecological disturbances, perhaps including climate change, are among the factors that may have increased the human caseload of HCPS between 1993 and the present. We consider here the features that influence the structure of host population dynamics that may lead to viral outbreaks, as well as the macromolecular determinants of hantaviruses that have been regarded as having potential contribution to pathogenicity. Full article
(This article belongs to the Special Issue Pathogenesis of Emerging and Re-Emerging RNA Viruses)
Open AccessReview Insights into Arbovirus Evolution and Adaptation from Experimental Studies
Viruses 2010, 2(12), 2594-2617; doi:10.3390/v2122594
Received: 22 October 2010 / Revised: 18 November 2010 / Accepted: 22 November 2010 / Published: 2 December 2010
Cited by 26 | PDF Full-text (160 KB)
Abstract
Arthropod-borne viruses (arboviruses) are maintained in nature by cycling between vertebrate hosts and haematophagous invertebrate vectors. These viruses are responsible for causing a significant public health burden throughout the world, with over 100 species having the capacity to cause human disease. Arbovirus [...] Read more.
Arthropod-borne viruses (arboviruses) are maintained in nature by cycling between vertebrate hosts and haematophagous invertebrate vectors. These viruses are responsible for causing a significant public health burden throughout the world, with over 100 species having the capacity to cause human disease. Arbovirus outbreaks in previously naïve environments demonstrate the potential of these pathogens for expansion and emergence, possibly exacerbated more recently by changing climates. These recent outbreaks, together with the continued devastation caused by endemic viruses, such as Dengue virus which persists in many areas, demonstrate the need to better understand the selective pressures that shape arbovirus evolution. Specifically, a comprehensive understanding of host-virus interactions and how they shape both host-specific and virus‑specific evolutionary pressures is needed to fully evaluate the factors that govern the potential for host shifts and geographic expansions. One approach to advance our understanding of the factors influencing arbovirus evolution in nature is the use of experimental studies in the laboratory. Here, we review the contributions that laboratory passage and experimental infection studies have made to the field of arbovirus adaptation and evolution, and how these studies contribute to the overall field of arbovirus evolution. In particular, this review focuses on the areas of evolutionary constraints and mutant swarm dynamics; how experimental results compare to theoretical predictions; the importance of arbovirus ecology in shaping viral swarms; and how current knowledge should guide future questions relevant to understanding arbovirus evolution. Full article
(This article belongs to the Special Issue Virus Dynamics and Evolution)
Open AccessReview Jaagsiekte Sheep Retrovirus Biology and Oncogenesis
Viruses 2010, 2(12), 2618-2648; doi:10.3390/v2122618
Received: 25 October 2010 / Revised: 22 November 2010 / Accepted: 23 November 2010 / Published: 3 December 2010
Cited by 14 | PDF Full-text (301 KB)
Abstract
Jaagsiekte sheep retrovirus (JSRV) is the causative agent of a lung cancer in sheep known as ovine pulmonary adenocarcinoma (OPA). The disease has been identified around the world in several breeds of sheep and goats, and JSRV infection typically has a serious [...] Read more.
Jaagsiekte sheep retrovirus (JSRV) is the causative agent of a lung cancer in sheep known as ovine pulmonary adenocarcinoma (OPA). The disease has been identified around the world in several breeds of sheep and goats, and JSRV infection typically has a serious impact on affected flocks. In addition, studies on OPA are an excellent model for human lung carcinogenesis. A unique feature of JSRV is that its envelope (Env) protein functions as an oncogene. The JSRV Env-induced transformation or oncogenesis has been studied in a variety of cell systems and in animal models. Moreover, JSRV studies have provided insights into retroviral genomic RNA export/expression mechanisms. JSRV encodes a trans-acting factor (Rej) within the env gene necessary for the synthesis of Gag protein from unspliced viral RNA. This review summarizes research pertaining to JSRV‑induced pathogenesis, Env transformation, and other aspects of JSRV biology. Full article
(This article belongs to the Special Issue Cell Transformation by RNA Viruses)
Open AccessReview Treatment of Vaccinia and Cowpox Virus Infections in Mice with CMX001 and ST-246
Viruses 2010, 2(12), 2681-2695; doi:10.3390/v2122681
Received: 8 November 2010 / Revised: 6 December 2010 / Accepted: 6 December 2010 / Published: 13 December 2010
Cited by 9 | PDF Full-text (245 KB)
Abstract
Although a large number of compounds have been identified with antiviral activity against orthopoxviruses in tissue culture systems, it is highly preferred that these compounds have activity in vivo before they can be seriously considered for further development. One of the most [...] Read more.
Although a large number of compounds have been identified with antiviral activity against orthopoxviruses in tissue culture systems, it is highly preferred that these compounds have activity in vivo before they can be seriously considered for further development. One of the most commonly used animal models for the confirmation of this activity has been the use of mice infected with either vaccinia or cowpox viruses. These model systems have the advantage that they are relatively inexpensive, readily available and do not require any special containment facilities; therefore, relatively large numbers of compounds can be evaluated in vivo for their activity. The two antiviral agents that have progressed from preclinical studies to human safety trials for the treatment of orthopoxvirus infections are the cidofovir analog, CMX001, and an inhibitor of extracellular virus formation, ST-246. These compounds are the ones most likely to be used in the event of a bioterror attack. The purpose of this communication is to review the advantages and disadvantages of using mice infected with vaccinia and cowpox virus as surrogate models for human orthopoxvirus infections and to summarize the activity of CMX001 and ST-246 in these model infections. Full article
(This article belongs to the Special Issue Antivirals Against Poxviruses)
Open AccessReview Comparison of the Mechanisms of Drug Resistance among HIV, Hepatitis B, and Hepatitis C
Viruses 2010, 2(12), 2696-2739; doi:10.3390/v2122696
Received: 24 October 2010 / Revised: 15 November 2010 / Accepted: 7 December 2010 / Published: 14 December 2010
Cited by 19 | PDF Full-text (586 KB)
Abstract
Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) are the most prevalent deadly chronic viral diseases. HIV is treated by small molecule inhibitors. HBV is treated by immunomodulation and small molecule inhibitors. HCV is currently treated primarily [...] Read more.
Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) are the most prevalent deadly chronic viral diseases. HIV is treated by small molecule inhibitors. HBV is treated by immunomodulation and small molecule inhibitors. HCV is currently treated primarily by immunomodulation but many small molecules are in clinical development. Although HIV is a retrovirus, HBV is a double-stranded DNA virus, and HCV is a single-stranded RNA virus, antiviral drug resistance complicates the development of drugs and the successful treatment of each of these viruses. Although their replication cycles, therapeutic targets, and evolutionary mechanisms are different, the fundamental approaches to identifying and characterizing HIV, HBV, and HCV drug resistance are similar. This review describes the evolution of HIV, HBV, and HCV within individuals and populations and the genetic mechanisms associated with drug resistance to each of the antiviral drug classes used for their treatment. Full article
(This article belongs to the Special Issue HIV Drug Resistance 2010)
Open AccessReview Monkeypox Virus Infections in Small Animal Models for Evaluation of Anti-Poxvirus Agents
Viruses 2010, 2(12), 2763-2776; doi:10.3390/v2122763
Received: 10 November 2010 / Revised: 8 December 2010 / Accepted: 10 December 2010 / Published: 20 December 2010
Cited by 7 | PDF Full-text (219 KB)
Abstract
An ideal animal model for the study of a human disease is one which utilizes a route of infection that mimics the natural transmission of the pathogen; the ability to obtain disease with an infectious dose equivalent to that causing disease in [...] Read more.
An ideal animal model for the study of a human disease is one which utilizes a route of infection that mimics the natural transmission of the pathogen; the ability to obtain disease with an infectious dose equivalent to that causing disease in humans; as well having a disease course, morbidity and mortality similar to that seen with human disease. Additionally, the animal model should have a mode(s) of transmission that mimics human cases. The development of small animal models for the study of monkeypox virus (MPXV) has been quite extensive for the relatively short period of time this pathogen has been known, although only a few of these models have been used to study anti-poxvirus agents. We will review those MPXV small animal models that have been developed thus far for the study of therapeutic agents. Full article
(This article belongs to the Special Issue Antivirals Against Poxviruses)
Open AccessReview Cidofovir Activity against Poxvirus Infections
Viruses 2010, 2(12), 2803-2830; doi:10.3390/v2122803
Received: 10 November 2010 / Revised: 9 December 2010 / Accepted: 10 December 2010 / Published: 22 December 2010
Cited by 18 | PDF Full-text (315 KB)
Abstract
Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, HPMPC] is an acyclic nucleoside analog approved since 1996 for clinical use in the treatment of cytomegalovirus (CMV) retinitis in AIDS patients. Cidofovir (CDV) has broad-spectrum activity against DNA viruses, including herpes-, adeno-, polyoma-, papilloma- and poxviruses. Among poxviruses, cidofovir [...] Read more.
Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, HPMPC] is an acyclic nucleoside analog approved since 1996 for clinical use in the treatment of cytomegalovirus (CMV) retinitis in AIDS patients. Cidofovir (CDV) has broad-spectrum activity against DNA viruses, including herpes-, adeno-, polyoma-, papilloma- and poxviruses. Among poxviruses, cidofovir has shown in vitro activity against orthopox [vaccinia, variola (smallpox), cowpox, monkeypox, camelpox, ectromelia], molluscipox [molluscum contagiosum] and parapox [orf] viruses. The anti-poxvirus activity of cidofovir in vivo has been shown in different models of infection when the compound was administered either intraperitoneal, intranasal (aerosolized) or topically. In humans, cidofovir has been successfully used for the treatment of recalcitrant molluscum contagiosum virus and orf virus in immunocompromised patients. CDV remains a reference compound against poxviruses and holds potential for the therapy and short-term prophylaxis of not only orthopox- but also parapox- and molluscipoxvirus infections. Full article
(This article belongs to the Special Issue Antivirals Against Poxviruses)
Figures

Other

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Open AccessCommentary The Complexity of Antibody-Dependent Enhancement of Dengue Virus Infection
Viruses 2010, 2(12), 2649-2662; doi:10.3390/v2122649
Received: 25 October 2010 / Revised: 22 November 2010 / Accepted: 22 November 2010 / Published: 8 December 2010
Cited by 23 | PDF Full-text (275 KB)
Abstract
Antibody-dependent enhancement (ADE) has been proposed as a mechanism to explain dengue hemorrhagic fever (DHF) in the course of a secondary dengue infection. Very recently, Dejnirattisai et al., 2010 [1], published an important article supporting the involvement of anti-prM antibodies in [...] Read more.
Antibody-dependent enhancement (ADE) has been proposed as a mechanism to explain dengue hemorrhagic fever (DHF) in the course of a secondary dengue infection. Very recently, Dejnirattisai et al., 2010 [1], published an important article supporting the involvement of anti-prM antibodies in the ADE phenomenon. The complexity of ADE in the context of a secondary dengue infection is discussed here. Full article
(This article belongs to the Section Editorial)
Open AccessCommentary Modeling the HIV-1 Intasome: A Prototype View of the Target of Integrase Inhibitors
Viruses 2010, 2(12), 2777-2781; doi:10.3390/v2122777
Received: 18 November 2010 / Revised: 4 December 2010 / Accepted: 6 December 2010 / Published: 21 December 2010
Cited by 8 | PDF Full-text (84 KB)
Abstract
The HIV-1 integrase enzyme is essential for integrating the viral DNA into the host chromosome. Infection is aborted in the absence of integration, making integrase an attractive antiviral target. Recently approved inhibitors of integrase bind tightly to integrase assembled in a nucleoprotein [...] Read more.
The HIV-1 integrase enzyme is essential for integrating the viral DNA into the host chromosome. Infection is aborted in the absence of integration, making integrase an attractive antiviral target. Recently approved inhibitors of integrase bind tightly to integrase assembled in a nucleoprotein complex with the viral DNA ends (intasome), but have only low affinity for free integrase. High-resolution structures of HIV-1 intasomes are therefore required to understand the detailed mechanisms of inhibition and resistance. Although the structure of the HIV-1 intasome has not yet been determined, the structure of the related prototype foamy virus (PFV) intasome was recently solved. A new study [1] exploits the PFV structure to model the HIV-1 intasome. The model provides the most reliable picture to date of the active site region of the HIV-1 intasome and is an important advance in studies of inhibition of this essential HIV-1 enzyme. Full article
(This article belongs to the Section Editorial)

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