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Special Issue "Recent Progress in Foamy Virus (FV) Research"

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (31 October 2013)

Special Issue Editors

Lead Guest Editor
Dr. Arifa S. Khan (Website)

Senior Investigator, Laboratory of Retroviruses, Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, 8800 Rockville Pike, HFM-454, Bldg 29B, Room 4NN10, Bethesda, MD 20892 USA
Fax: +301 496 1810
Co-Guest Editor
Prof. Dr. Martin Löchelt (Website)

Group Leader, German Cancer Research Center (DKFZ), Research Program Infection Center, Department Genome Modifications and Carcinogenesis (F020), Im Neuenheimer Feld 242, D-69120 Heidelberg, Germany
Fax: +49 6221 42 4932
Co-Guest Editor
Prof. Dr. Axel Rethwilm (Website)

Professor and Chair, Universität Würzburg, Institut für Virologie und Immunbiologie, Versbacher Str. 7, 97078 Wurzburg, Germany
Fax: +49 931 201 49553

Special Issue Information

Dear Colleagues,

Foamy viruses are ancient retroviruses that naturally occur in non-human primate species and in a variety of other animal species including bovine, equine, and feline. However, human foamy virus infections have been shown to be due to cross-species transmission from infected non-human primates. Although there is no evidence thus far of FV pathogenesis in any species, human exposure should be minimized since infectious foamy virus can stably persist life-long. Studies of virus replication and latency, virus prevalence in the natural host, and human infections can contribute to evaluating  the potential risks of FV infection in humans. Based upon several unique properties of these ancient retroviruses and the lack of known pathogenicity, foamy viruses are being developed as novel vectors for targeted gene delivery and vaccination, with recent improvements for new applications in experimental systems and medicine.

The main focus of this special issue is to review the current knowledge of FVs and present an update of FV research. The topics will include, but not limited to:

  • Simian and non-simian FVs: Overview
  • Natural infections
  • Zoonoses
  • Evolution
  • Molecular Biology and Replication
  • Viral proteins
  • FV vectors
  • Restriction factors
  • Antivirals
  • Virus detection assays
  • Management of potential sources of exposure and infection

Dr. Arifa S. Khan
Prof. Dr. Martin Löchelt
Prof. Dr. Axel Rethwilm
Guest Editors

Published Papers (11 papers)

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Research

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Open AccessArticle Influence of Naturally Occurring Simian Foamy Viruses (SFVs) on SIV Disease Progression in the Rhesus Macaque (Macaca mulatta) Model
Viruses 2013, 5(6), 1414-1430; doi:10.3390/v5061414
Received: 25 April 2013 / Revised: 22 May 2013 / Accepted: 30 May 2013 / Published: 6 June 2013
Cited by 10 | PDF Full-text (477 KB) | HTML Full-text | XML Full-text
Abstract
We have investigated the influence of naturally occurring simian foamy viruses (SFVs) on simian immunodeficiency virus (SIV) infection and disease in Indian rhesus macaques. Animals were divided into two groups based upon presence or absence of SFV; in each group, eight monkeys [...] Read more.
We have investigated the influence of naturally occurring simian foamy viruses (SFVs) on simian immunodeficiency virus (SIV) infection and disease in Indian rhesus macaques. Animals were divided into two groups based upon presence or absence of SFV; in each group, eight monkeys were injected with SIVmac239 virus obtained from a molecular clone and four were injected with medium. Blood was collected every two weeks for evaluation of SIV infection based upon T cell-subsets, plasma viral load, development and persistence of virus-specific antibodies, and clinical changes by physical examination and hematology. Comparative analysis of SFV+/SIV+ and SFV−/SIV+ monkey groups indicated statistically significant differences in the plasma viral load between 6–28 weeks, particularly after reaching plateau at 20–28 weeks, in the CD4+ and CD8+ T-cell numbers over the entire study period (2–43 weeks), and in the survival rates evaluated at 49 weeks. There was an increase in the plasma viral load, a decreasing trend in the CD4+ T cells, and a greater number of animal deaths in the SFV+/SIV+ group. The results, although based upon a small number of animals, indicated that pre-existing SFV infection can influence SIV infection and disease outcome in the rhesus macaque model. The study highlights consideration of the SFV status in evaluating results from SIV pathogenesis and vaccine challenge studies in monkeys and indicates the potential use of the SFV/SIV monkey model to study the dynamics of SFV and HIV-1 dual infections, recently reported in humans. Full article
(This article belongs to the Special Issue Recent Progress in Foamy Virus (FV) Research)
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Review

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Open AccessReview Evolution of Foamy Viruses: The Most Ancient of All Retroviruses
Viruses 2013, 5(10), 2349-2374; doi:10.3390/v5102349
Received: 5 August 2013 / Revised: 27 August 2013 / Accepted: 18 September 2013 / Published: 25 September 2013
Cited by 9 | PDF Full-text (380 KB) | HTML Full-text | XML Full-text
Abstract
Recent evidence indicates that foamy viruses (FVs) are the oldest retroviruses (RVs) that we know and coevolved with their hosts for several hundred million years. This coevolution may have contributed to the non-pathogenicity of FVs, an important factor in development of foamy [...] Read more.
Recent evidence indicates that foamy viruses (FVs) are the oldest retroviruses (RVs) that we know and coevolved with their hosts for several hundred million years. This coevolution may have contributed to the non-pathogenicity of FVs, an important factor in development of foamy viral vectors in gene therapy. However, various questions on the molecular evolution of FVs remain still unanswered. The analysis of the spectrum of animal species infected by exogenous FVs or harboring endogenous FV elements in their genome is pivotal. Furthermore, animal studies might reveal important issues, such as the identification of the FV in vivo target cells, which than require a detailed characterization, to resolve the molecular basis of the accuracy with which FVs copy their genome. The issues of the extent of FV viremia and of the nature of the virion genome (RNA vs. DNA) also need to be experimentally addressed. Full article
(This article belongs to the Special Issue Recent Progress in Foamy Virus (FV) Research)
Open AccessReview Non-Simian Foamy Viruses: Molecular Virology, Tropism and Prevalence and Zoonotic/Interspecies Transmission
Viruses 2013, 5(9), 2169-2209; doi:10.3390/v5092169
Received: 8 August 2013 / Revised: 4 September 2013 / Accepted: 5 September 2013 / Published: 13 September 2013
Cited by 11 | PDF Full-text (38407 KB) | HTML Full-text | XML Full-text
Abstract
Within the field of retrovirus, our knowledge of foamy viruses (FV) is still limited. Their unique replication strategy and mechanism of viral persistency needs further research to gain understanding of the virus-host interactions, especially in the light of the recent findings suggesting [...] Read more.
Within the field of retrovirus, our knowledge of foamy viruses (FV) is still limited. Their unique replication strategy and mechanism of viral persistency needs further research to gain understanding of the virus-host interactions, especially in the light of the recent findings suggesting their ancient origin and long co-evolution with their nonhuman hosts. Unquestionably, the most studied member is the primate/prototype foamy virus (PFV) which was originally isolated from a human (designated as human foamy virus, HFV), but later identified as chimpanzee origin; phylogenetic analysis clearly places it among other Old World primates. Additionally, the study of non-simian animal FVs can contribute to a deeper understanding of FV-host interactions and development of other animal models. The review aims at highlighting areas of special interest regarding the structure, biology, virus-host interactions and interspecies transmission potential of primate as well as non-primate foamy viruses for gaining new insights into FV biology. Full article
(This article belongs to the Special Issue Recent Progress in Foamy Virus (FV) Research)
Open AccessReview Structural and Functional Insights into Foamy Viral Integrase
Viruses 2013, 5(7), 1850-1866; doi:10.3390/v5071850
Received: 24 June 2013 / Revised: 12 July 2013 / Accepted: 12 July 2013 / Published: 18 July 2013
Cited by 1 | PDF Full-text (236 KB) | HTML Full-text | XML Full-text
Abstract
Successful integration of retroviral DNA into the host chromosome is an essential step for viral replication. The process is mediated by virally encoded integrase (IN) and orchestrated by 3'-end processing and the strand transfer reaction. In vitro reaction conditions, such as substrate [...] Read more.
Successful integration of retroviral DNA into the host chromosome is an essential step for viral replication. The process is mediated by virally encoded integrase (IN) and orchestrated by 3'-end processing and the strand transfer reaction. In vitro reaction conditions, such as substrate specificity, cofactor usage, and cellular binding partners for such reactions by the three distinct domains of prototype foamy viral integrase (PFV-IN) have been described well in several reports. Recent studies on the three‑dimensional structure of the interacting complexes between PFV-IN and DNA, cofactors, binding partners, or inhibitors have explored the mechanistic details of such interactions and shown its utilization as an important target to develop anti-retroviral drugs. The presence of a potent, non-transferable nuclear localization signal in the PFV C-terminal domain extends its use as a model for investigating cellular trafficking of large molecular complexes through the nuclear pore complex and also to identify novel cellular targets for such trafficking. This review focuses on recent advancements in the structural analysis and in vitro functional aspects of PFV-IN. Full article
(This article belongs to the Special Issue Recent Progress in Foamy Virus (FV) Research)
Open AccessReview Feline Foamy Virus-Based Vectors: Advantages of an Authentic Animal Model
Viruses 2013, 5(7), 1702-1718; doi:10.3390/v5071702
Received: 1 March 2013 / Revised: 13 June 2013 / Accepted: 25 June 2013 / Published: 12 July 2013
Cited by 4 | PDF Full-text (355 KB) | HTML Full-text | XML Full-text
Abstract
New-generation retroviral vectors have potential applications in vaccination and gene therapy. Foamy viruses are particularly interesting as vectors, because they are not associated to any disease. Vector research is mainly based on primate foamy viruses (PFV), but cats are an alternative animal [...] Read more.
New-generation retroviral vectors have potential applications in vaccination and gene therapy. Foamy viruses are particularly interesting as vectors, because they are not associated to any disease. Vector research is mainly based on primate foamy viruses (PFV), but cats are an alternative animal model, due to their smaller size and the existence of a cognate feline foamy virus (FFV). The potential of replication-competent (RC) FFV vectors for vaccination and replication-deficient (RD) FFV-based vectors for gene delivery purposes has been studied over the past years. In this review, the key achievements and functional evaluation of the existing vectors from in vitro cell culture systems to out-bred cats will be described. The data presented here demonstrate the broad application spectrum of FFV-based vectors, especially in pathogen-specific prophylactic and therapeutic vaccination using RD vectors in cats and in classical gene delivery. In the cat-based system, FFV-based vectors provide an advantageous platform to evaluate and optimize the applicability, efficacy and safety of foamy virus (FV) vectors, especially the understudied aspect of FV cell and organ tropism. Full article
(This article belongs to the Special Issue Recent Progress in Foamy Virus (FV) Research)
Open AccessReview Simian Foamy Virus in Non-Human Primates and Cross-Species Transmission to Humans in Gabon: An Emerging Zoonotic Disease in Central Africa?
Viruses 2013, 5(6), 1536-1552; doi:10.3390/v5061536
Received: 15 May 2013 / Revised: 9 June 2013 / Accepted: 10 June 2013 / Published: 19 June 2013
Cited by 5 | PDF Full-text (19770 KB) | HTML Full-text | XML Full-text
Abstract
It is now known that all human retroviruses have a non-human primate counterpart. It has been reported that the presence of these retroviruses in humans is the result of interspecies transmission. Several authors have described the passage of a simian retrovirus, simian [...] Read more.
It is now known that all human retroviruses have a non-human primate counterpart. It has been reported that the presence of these retroviruses in humans is the result of interspecies transmission. Several authors have described the passage of a simian retrovirus, simian foamy virus (SFV), from primates to humans. To better understand this retroviral “zoonosis” in natural settings, we evaluated the presence of SFV in both captive and wild non-human primates and in humans at high risk, such as hunters and people bitten by a non-human primate, in Gabon, central Africa. A high prevalence of SFV was found in blood samples from non-human primates and in bush meat collected across the country. Mandrills were found to be highly infected with two distinct strains of SFV, depending on their geographical location. Furthermore, samples collected from hunters and non-human primate laboratory workers showed clear, extensive cross-species transmission of SFV. People who had been bitten by mandrills, gorillas and chimpanzees had persistent SFV infection with low genetic drift. Thus, SFV is presumed to be transmitted from non-human primates mainly through severe bites, involving contact between infected saliva and blood. In this review, we summarize and discuss our five-year observations on the prevalence and dissemination of SFV in humans and non-human primates in Gabon. Full article
(This article belongs to the Special Issue Recent Progress in Foamy Virus (FV) Research)
Open AccessReview Foamy Virus Budding and Release
Viruses 2013, 5(4), 1075-1098; doi:10.3390/v5041075
Received: 4 February 2013 / Revised: 25 March 2013 / Accepted: 29 March 2013 / Published: 10 April 2013
Cited by 5 | PDF Full-text (815 KB) | HTML Full-text | XML Full-text
Abstract
Like all other viruses, a successful egress of functional particles from infected cells is a prerequisite for foamy virus (FV) spread within the host. The budding process of FVs involves steps, which are shared by other retroviruses, such as interaction of the [...] Read more.
Like all other viruses, a successful egress of functional particles from infected cells is a prerequisite for foamy virus (FV) spread within the host. The budding process of FVs involves steps, which are shared by other retroviruses, such as interaction of the capsid protein with components of cellular vacuolar protein sorting (Vps) machinery via late domains identified in some FV capsid proteins. Additionally, there are features of the FV budding strategy quite unique to the spumaretroviruses. This includes secretion of non-infectious subviral particles and a strict dependence on capsid-glycoprotein interaction for release of infectious virions from the cells. Virus-like particle release is not possible since FV capsid proteins lack a membrane-targeting signal. It is noteworthy that in experimental systems, the important capsid-glycoprotein interaction could be bypassed by fusing heterologous membrane-targeting signals to the capsid protein, thus enabling glycoprotein-independent egress. Aside from that, other systems have been developed to enable envelopment of FV capsids by heterologous Env proteins. In this review article, we will summarize the current knowledge on FV budding, the viral components and their domains involved as well as alternative and artificial ways to promote budding of FV particle structures, a feature important for alteration of target tissue tropism of FV-based gene transfer systems. Full article
(This article belongs to the Special Issue Recent Progress in Foamy Virus (FV) Research)
Open AccessReview Early Events in Foamy Virus—Host Interaction and Intracellular Trafficking
Viruses 2013, 5(4), 1055-1074; doi:10.3390/v5041055
Received: 27 February 2013 / Revised: 28 March 2013 / Accepted: 29 March 2013 / Published: 8 April 2013
Cited by 4 | PDF Full-text (1445 KB) | HTML Full-text | XML Full-text
Abstract
Here we review viral and cellular requirements for entry and intracellular trafficking of foamy viruses (FVs) resulting in integration of viral sequences into the host cell genome. The virus encoded glycoprotein harbors all essential viral determinants, which are involved in absorption to [...] Read more.
Here we review viral and cellular requirements for entry and intracellular trafficking of foamy viruses (FVs) resulting in integration of viral sequences into the host cell genome. The virus encoded glycoprotein harbors all essential viral determinants, which are involved in absorption to the host membrane and triggering the uptake of virus particles. However, only recently light was shed on some details of FV’s interaction with its host cell receptor(s). Latest studies indicate glycosaminoglycans of cellular proteoglycans, particularly heparan sulfate, to be of utmost importance. In a species-specific manner FVs encounter endogenous machineries of the target cell, which are in some cases exploited for fusion and further egress into the cytosol. Mostly triggered by pH-dependent endocytosis, viral and cellular membranes fuse and release naked FV capsids into the cytoplasm. Intact FV capsids are then shuttled along microtubules and are found to accumulate nearby the centrosome where they can remain in a latent state for extended time periods. Depending on the host cell cycle status, FV capsids finally disassemble and, by still poorly characterized mechanisms, the preintegration complex gets access to the host cell chromatin. Host cell mitosis finally allows for viral genome integration, ultimately starting a new round of viral replication. Full article
(This article belongs to the Special Issue Recent Progress in Foamy Virus (FV) Research)
Open AccessReview The Foamy Virus Gag Proteins: What Makes Them Different?
Viruses 2013, 5(4), 1023-1041; doi:10.3390/v5041023
Received: 25 January 2013 / Revised: 15 March 2013 / Accepted: 20 March 2013 / Published: 26 March 2013
Cited by 7 | PDF Full-text (846 KB) | HTML Full-text | XML Full-text
Abstract
Gag proteins play an important role in many stages of the retroviral replication cycle. They orchestrate viral assembly, interact with numerous host cell proteins, engage in regulation of viral gene expression, and provide the main driving force for virus intracellular trafficking and [...] Read more.
Gag proteins play an important role in many stages of the retroviral replication cycle. They orchestrate viral assembly, interact with numerous host cell proteins, engage in regulation of viral gene expression, and provide the main driving force for virus intracellular trafficking and budding. Foamy Viruses (FV), also known as spumaviruses, display a number of unique features among retroviruses. Many of these features can be attributed to their Gag proteins. FV Gag proteins lack characteristic orthoretroviral domains like membrane-binding domains (M domains), the major homology region (MHR), and the hallmark Cys-His motifs. In contrast, they contain several distinct domains such as the essential Gag-Env interaction domain and the glycine and arginine rich boxes (GR boxes). Furthermore, FV Gag only undergoes limited maturation and follows an unusual pathway for nuclear translocation. This review summarizes the known FV Gag domains and motifs and their functions. In particular, it provides an overview of the unique structural and functional properties that distinguish FV Gag proteins from orthoretroviral Gag proteins. Full article
(This article belongs to the Special Issue Recent Progress in Foamy Virus (FV) Research)
Open AccessReview Foamy Virus Assembly with Emphasis on Pol Encapsidation
Viruses 2013, 5(3), 886-900; doi:10.3390/v5030886
Received: 31 January 2013 / Revised: 11 March 2013 / Accepted: 14 March 2013 / Published: 20 March 2013
Cited by 4 | PDF Full-text (306 KB) | HTML Full-text | XML Full-text
Abstract
Foamy viruses (FVs) differ from all other genera of retroviruses (orthoretroviruses) in many aspects of viral replication. In this review, we discuss FV assembly, with special emphasis on Pol incorporation. FV assembly takes place intracellularly, near the pericentriolar region, at a site [...] Read more.
Foamy viruses (FVs) differ from all other genera of retroviruses (orthoretroviruses) in many aspects of viral replication. In this review, we discuss FV assembly, with special emphasis on Pol incorporation. FV assembly takes place intracellularly, near the pericentriolar region, at a site similar to that used by betaretroviruses. The regions of Gag, Pol and genomic RNA required for viral assembly are described. In contrast to orthoretroviral Pol, which is synthesized as a Gag-Pol fusion protein and packaged through Gag-Gag interactions, FV Pol is synthesized from a spliced mRNA lacking all Gag sequences. Thus, encapsidation of FV Pol requires a different mechanism. We detail how WT Pol lacking Gag sequences is incorporated into virus particles. In addition, a mutant in which Pol is expressed as an orthoretroviral-like Gag-Pol fusion protein is discussed. We also discuss temporal regulation of the protease, reverse transcriptase and integrase activities of WT FV Pol. Full article
(This article belongs to the Special Issue Recent Progress in Foamy Virus (FV) Research)
Open AccessReview Large Animal Models for Foamy Virus Vector Gene Therapy
Viruses 2012, 4(12), 3572-3588; doi:10.3390/v4123572
Received: 15 October 2012 / Revised: 19 November 2012 / Accepted: 28 November 2012 / Published: 7 December 2012
Cited by 7 | PDF Full-text (229 KB) | HTML Full-text | XML Full-text
Abstract
Foamy virus (FV) vectors have shown great promise for hematopoietic stem cell (HSC) gene therapy. Their ability to efficiently deliver transgenes to multi-lineage long-term repopulating cells in large animal models suggests they will be effective for several human hematopoietic diseases. Here, we [...] Read more.
Foamy virus (FV) vectors have shown great promise for hematopoietic stem cell (HSC) gene therapy. Their ability to efficiently deliver transgenes to multi-lineage long-term repopulating cells in large animal models suggests they will be effective for several human hematopoietic diseases. Here, we review FV vector studies in large animal models, including the use of FV vectors with the mutant O6-methylguanine-DNA methyltransferase, MGMTP140K to increase the number of genetically modified cells after transplantation. In these studies, FV vectors have mediated efficient gene transfer to polyclonal repopulating cells using short ex vivo transduction protocols designed to minimize the negative effects of ex vivo culture on stem cell engraftment. In this regard, FV vectors appear superior to gammaretroviral vectors, which require longer ex vivo culture to effect efficient transduction. FV vectors have also compared favorably with lentiviral vectors when directly compared in the dog model. FV vectors have corrected leukocyte adhesion deficiency and pyruvate kinase deficiency in the dog large animal model. FV vectors also appear safer than gammaretroviral vectors based on a reduced frequency of integrants near promoters and also near proto-oncogenes in canine repopulating cells. Together, these studies suggest that FV vectors should be highly effective for several human hematopoietic diseases, including those that will require relatively high percentages of gene-modified cells to achieve clinical benefit. Full article
(This article belongs to the Special Issue Recent Progress in Foamy Virus (FV) Research)

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