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Viruses, Volume 2, Issue 9 (September 2010), Pages 1821-2153

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Research

Jump to: Review

Open AccessArticle A Hypothesis for Bacteriophage DNA Packaging Motors
Viruses 2010, 2(9), 1821-1843; doi:10.3390/v2091821
Received: 4 June 2010 / Revised: 12 August 2010 / Accepted: 18 August 2010 / Published: 26 August 2010
Cited by 15 | PDF Full-text (378 KB)
Abstract
The hypothesis is presented that bacteriophage DNA packaging motors have a cycle comprised of bind/release thermal ratcheting with release-associated DNA pushing via ATP-dependent protein folding. The proposed protein folding occurs in crystallographically observed peptide segments that project into an axial channel of a
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The hypothesis is presented that bacteriophage DNA packaging motors have a cycle comprised of bind/release thermal ratcheting with release-associated DNA pushing via ATP-dependent protein folding. The proposed protein folding occurs in crystallographically observed peptide segments that project into an axial channel of a protein 12-mer (connector) that serves, together with a coaxial ATPase multimer, as the entry portal. The proposed cycle begins when reverse thermal motion causes the connector’s peptide segments to signal the ATPase multimer to bind both ATP and the DNA molecule, thereby producing a dwell phase recently demonstrated by single-molecule procedures. The connector-associated peptide segments activate by transfer of energy from ATP during the dwell. The proposed function of connector/ATPase symmetry mismatches is to reduce thermal noise-induced signaling errors. After a dwell, ATP is cleaved and the DNA molecule released. The activated peptide segments push the released DNA molecule, thereby producing a burst phase recently shown to consist of four mini-bursts. The constraint of four mini-bursts is met by proposing that each mini-burst occurs via pushing by three of the 12 subunits of the connector. If all four mini-bursts occur, the cycle repeats. If the mini-bursts are not completed, a second cycle is superimposed on the first cycle. The existence of the second cycle is based on data recently obtained with bacteriophage T3. When both cycles stall, energy is diverted to expose the DNA molecule to maturation cleavage. Full article
(This article belongs to the Special Issue Bacteriophage Assembly)
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Open AccessArticle JaPaFi: A Novel Program for the Identification of Highly Conserved DNA Sequences
Viruses 2010, 2(9), 1867-1885; doi:10.3390/v2091867
Received: 16 June 2010 / Revised: 5 August 2010 / Accepted: 18 August 2010 / Published: 31 August 2010
Cited by 1 | PDF Full-text (1064 KB)
Abstract We describe the use of Java Pattern Finder (JaPaFi) to identify short ( Full article
(This article belongs to the Special Issue Viral Genomics and Bioinformatics)
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Open AccessArticle Orthopoxvirus Genome Evolution: The Role of Gene Loss
Viruses 2010, 2(9), 1933-1967; doi:10.3390/v2091933
Received: 14 July 2010 / Revised: 25 August 2010 / Accepted: 1 September 2010 / Published: 15 September 2010
Cited by 22 | PDF Full-text (1902 KB) | Supplementary Files
Abstract
Poxviruses are highly successful pathogens, known to infect a variety of hosts. The family Poxviridae includes Variola virus, the causative agent of smallpox, which has been eradicated as a public health threat but could potentially reemerge as a bioterrorist threat. The risk scenario
[...] Read more.
Poxviruses are highly successful pathogens, known to infect a variety of hosts. The family Poxviridae includes Variola virus, the causative agent of smallpox, which has been eradicated as a public health threat but could potentially reemerge as a bioterrorist threat. The risk scenario includes other animal poxviruses and genetically engineered manipulations of poxviruses. Studies of orthologous gene sets have established the evolutionary relationships of members within the Poxviridae family. It is not clear, however, how variations between family members arose in the past, an important issue in understanding how these viruses may vary and possibly produce future threats. Using a newly developed poxvirus-specific tool, we predicted accurate gene sets for viruses with completely sequenced genomes in the genus Orthopoxvirus. Employing sensitive sequence comparison techniques together with comparison of syntenic gene maps, we established the relationships between all viral gene sets. These techniques allowed us to unambiguously identify the gene loss/gain events that have occurred over the course of orthopoxvirus evolution. It is clear that for all existing Orthopoxvirus species, no individual species has acquired protein-coding genes unique to that species. All existing species contain genes that are all present in members of the species Cowpox virus and that cowpox virus strains contain every gene present in any other orthopoxvirus strain. These results support a theory of reductive evolution in which the reduction in size of the core gene set of a putative ancestral virus played a critical role in speciation and confining any newly emerging virus species to a particular environmental (host or tissue) niche. Full article
(This article belongs to the Special Issue Viral Genomics and Bioinformatics)
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Review

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Open AccessReview Increasing the Efficacy of Oncolytic Adenovirus Vectors
Viruses 2010, 2(9), 1844-1866; doi:10.3390/v2091844
Received: 23 July 2010 / Revised: 17 August 2010 / Accepted: 25 August 2010 / Published: 27 August 2010
Cited by 20 | PDF Full-text (318 KB)
Abstract
Oncolytic adenovirus (Ad) vectors present a new modality to treat cancer. These vectors attack tumors via replicating in and killing cancer cells. Upon completion of the vector replication cycle, the infected tumor cell lyses and releases progeny virions that are capable of infecting
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Oncolytic adenovirus (Ad) vectors present a new modality to treat cancer. These vectors attack tumors via replicating in and killing cancer cells. Upon completion of the vector replication cycle, the infected tumor cell lyses and releases progeny virions that are capable of infecting neighboring tumor cells. Repeated cycles of vector replication and cell lysis can destroy the tumor. Numerous Ad vectors have been generated and tested, some of them reaching human clinical trials. In 2005, the first oncolytic Ad was approved for the treatment of head-and-neck cancer by the Chinese FDA. Oncolytic Ads have been proven to be safe, with no serious adverse effects reported even when high doses of the vector were injected intravenously. The vectors demonstrated modest anti-tumor effect when applied as a single agent; their efficacy improved when they were combined with another modality. The efficacy of oncolytic Ads can be improved using various approaches, including vector design, delivery techniques, and ancillary treatment, which will be discussed in this review. Full article
(This article belongs to the Special Issue Adenoviral Vectors)
Open AccessReview Gene Therapy with Helper-Dependent Adenoviral Vectors: Current Advances and Future Perspectives
Viruses 2010, 2(9), 1886-1917; doi:10.3390/v2091886
Received: 21 June 2010 / Revised: 26 August 2010 / Accepted: 30 August 2010 / Published: 3 September 2010
Cited by 22 | PDF Full-text (1586 KB)
Abstract
Recombinant Adenoviral vectors represent one of the best gene transfer platforms due to their ability to efficiently transduce a wide range of quiescent and proliferating cell types from various tissues and species. The activation of an adaptive immune response against the transduced cells
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Recombinant Adenoviral vectors represent one of the best gene transfer platforms due to their ability to efficiently transduce a wide range of quiescent and proliferating cell types from various tissues and species. The activation of an adaptive immune response against the transduced cells is one of the major drawbacks of first generation Adenovirus vectors and has been overcome by the latest generation of recombinant Adenovirus, the Helper-Dependent Adenoviral (HDAd) vectors. HDAds have innovative features including the complete absence of viral coding sequences and the ability to mediate high level transgene expression with negligible chronic toxicity. This review summarizes the many aspects of HDAd biology and structure with a major focus on in vivo gene therapy application and with an emphasis on the unsolved issues that these vectors still presents toward clinical application. Full article
(This article belongs to the Special Issue Adenoviral Vectors)
Open AccessReview Ectromelia Virus Infections of Mice as a Model to Support the Licensure of Anti-Orthopoxvirus Therapeutics
Viruses 2010, 2(9), 1918-1932; doi:10.3390/v2091918
Received: 2 July 2010 / Revised: 30 August 2010 / Accepted: 31 August 2010 / Published: 3 September 2010
Cited by 14 | PDF Full-text (759 KB)
Abstract
The absence of herd immunity to orthopoxviruses and the concern that variola or monkeypox viruses could be used for bioterroristic activities has stimulated the development of therapeutics and safer prophylactics. One major limitation in this process is the lack of accessible human orthopoxvirus
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The absence of herd immunity to orthopoxviruses and the concern that variola or monkeypox viruses could be used for bioterroristic activities has stimulated the development of therapeutics and safer prophylactics. One major limitation in this process is the lack of accessible human orthopoxvirus infections for clinical efficacy trials; however, drug licensure can be based on orthopoxvirus animal challenge models as described in the “Animal Efficacy Rule”. One such challenge model uses ectromelia virus, an orthopoxvirus, whose natural host is the mouse and is the etiological agent of mousepox. The genetic similarity of ectromelia virus to variola and monkeypox viruses, the common features of the resulting disease, and the convenience of the mouse as a laboratory animal underscores its utility in the study of orthopoxvirus pathogenesis and in the development of therapeutics and prophylactics. In this review we outline how mousepox has been used as a model for smallpox. We also discuss mousepox in the context of mouse strain, route of infection, infectious dose, disease progression, and recovery from infection. Full article
(This article belongs to the Special Issue Antivirals Against Poxviruses)
Open AccessReview Antiviral Activity of 4'-thioIDU and Thymidine Analogs against Orthopoxviruses
Viruses 2010, 2(9), 1968-1983; doi:10.3390/v2091968
Received: 5 August 2010 / Revised: 20 August 2010 / Accepted: 7 September 2010 / Published: 16 September 2010
Cited by 4 | PDF Full-text (306 KB)
Abstract
The search for effective therapies for orthopoxvirus infections has identified diverse classes of molecules with antiviral activity. Pyrimidine analogs, such as 5-iodo-2'-deoxyuridine (idoxuridine, IDU) were among the first compounds identified with antiviral activity against a number of orthopoxviruses and have been reported to
[...] Read more.
The search for effective therapies for orthopoxvirus infections has identified diverse classes of molecules with antiviral activity. Pyrimidine analogs, such as 5-iodo-2'-deoxyuridine (idoxuridine, IDU) were among the first compounds identified with antiviral activity against a number of orthopoxviruses and have been reported to be active both in vitro and in animal models of infection. More recently, additional analogs have been reported to have improved antiviral activity against orthopoxviruses including several derivatives of deoxyuridine with large substituents in the 5 position, as well as analogs with modifications in the deoxyribose moiety including (north)-methanocarbathymidine, and 5-iodo-4'-thio-2'-deoxyuridine (4'-thioIDU). The latter molecule has proven to have good antiviral activity against the orthopoxviruses both in vitro and in vivo and has the potential to be an effective therapy in humans. Full article
(This article belongs to the Special Issue Antivirals Against Poxviruses)
Open AccessReview Walleye Dermal Sarcoma Virus: Molecular Biology and Oncogenesis
Viruses 2010, 2(9), 1984-1999; doi:10.3390/v2091984
Received: 6 July 2010 / Revised: 5 August 2010 / Accepted: 2 September 2010 / Published: 22 September 2010
Cited by 11 | PDF Full-text (985 KB)
Abstract
Retroviruses have been detected in most vertebrate species and are etiologic agents of a variety of neoplastic diseases. The study of retroviruses has been instrumental in uncovering the molecular mechanisms responsible for oncogenesis. Retroviruses have been isolated from three neoplastic diseases in fish,
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Retroviruses have been detected in most vertebrate species and are etiologic agents of a variety of neoplastic diseases. The study of retroviruses has been instrumental in uncovering the molecular mechanisms responsible for oncogenesis. Retroviruses have been isolated from three neoplastic diseases in fish, two of which affect the dermis and regress naturally coincident with spawning. This feature provides a unique model to study mechanisms of tumor development and regression. Three complex retroviruses, isolated from walleye (Sander vitreus) with dermal sarcoma and epidermal hyperplasia, are the members of the newest retroviral genus, Epsilonretrovirus. Three accessory proteins, encoded by walleye dermal sarcoma virus (WDSV), function in the regulation of host and viral gene expression and cell cycle, alter cell-signaling pathways to promote cell proliferation and block apoptosis, and, finally, induce apoptosis through dissipation of the mitochondrial membrane potential. Full article
(This article belongs to the Special Issue Cell Transformation by RNA Viruses)
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Open AccessReview Mouse Mammary Tumor Virus Molecular Biology and Oncogenesis
Viruses 2010, 2(9), 2000-2012; doi:10.3390/v2092000
Received: 2 July 2010 / Revised: 25 August 2010 / Accepted: 15 September 2010 / Published: 23 September 2010
Cited by 38 | PDF Full-text (200 KB)
Abstract
Mouse mammary tumor virus (MMTV), which was discovered as a milk‑transmitted, infectious cancer-inducing agent in the 1930s, has been used since that time as an animal model for the study of human breast cancer. Like other complex retroviruses, MMTV encodes a number of
[...] Read more.
Mouse mammary tumor virus (MMTV), which was discovered as a milk‑transmitted, infectious cancer-inducing agent in the 1930s, has been used since that time as an animal model for the study of human breast cancer. Like other complex retroviruses, MMTV encodes a number of accessory proteins that both facilitate infection and affect host immune response. In vivo, the virus predominantly infects lymphocytes and mammary epithelial cells. High level infection of mammary epithelial cells ensures efficient passage of virus to the next generation. It also results in mammary tumor induction, since the MMTV provirus integrates into the mammary epithelial cell genome during viral replication and activates cellular oncogene expression. Thus, mammary tumor induction is a by-product of the infection cycle. A number of important oncogenes have been discovered by carrying out MMTV integration site analysis, some of which may play a role in human breast cancer. Full article
(This article belongs to the Special Issue Cell Transformation by RNA Viruses)
Open AccessReview Improving Adenovirus Based Gene Transfer: Strategies to Accomplish Immune Evasion
Viruses 2010, 2(9), 2013-2036; doi:10.3390/v2092013
Received: 9 July 2010 / Revised: 3 September 2010 / Accepted: 15 September 2010 / Published: 24 September 2010
Cited by 9 | PDF Full-text (301 KB)
Abstract
Adenovirus (Ad) based gene transfer vectors continue to be the platform of choice for an increasing number of clinical trials worldwide. In fact, within the last five years, the number of clinical trials that utilize Ad based vectors has doubled, indicating growing enthusiasm
[...] Read more.
Adenovirus (Ad) based gene transfer vectors continue to be the platform of choice for an increasing number of clinical trials worldwide. In fact, within the last five years, the number of clinical trials that utilize Ad based vectors has doubled, indicating growing enthusiasm for the numerous positive characteristics of this gene transfer platform. For example, Ad vectors can be easily and relatively inexpensively produced to high titers in a cGMP compliant manner, can be stably stored and transported, and have a broad applicability for a wide range of clinical conditions, including both gene therapy and vaccine applications. Ad vector based gene transfer will become more useful as strategies to counteract innate and/or pre-existing adaptive immune responses to Ads are developed and confirmed to be efficacious. The approaches attempting to overcome these limitations can be divided into two broad categories: pre-emptive immune modulation of the host, and selective modification of the Ad vector itself. The first category of methods includes the use of immunosuppressive drugs or specific compounds to block important immune pathways, which are known to be induced by Ads. The second category comprises several innovative strategies inclusive of: (1) Ad-capsid-display of specific inhibitors or ligands; (2) covalent modifications of the entire Ad vector capsid moiety; (3) the use of tissue specific promoters and local administration routes; (4) the use of genome modified Ads; and (5) the development of chimeric or alternative serotype Ads. This review article will focus on both the promise and the limitations of each of these immune evasion strategies, and in the process delineate future directions in developing safer and more efficacious Ad-based gene transfer strategies. Full article
(This article belongs to the Special Issue Adenoviral Vectors)
Open AccessReview Human T Lymphotropic Virus Type 1 (HTLV-1): Molecular Biology and Oncogenesis
Viruses 2010, 2(9), 2037-2077; doi:10.3390/v2092037
Received: 7 July 2010 / Revised: 25 August 2010 / Accepted: 15 September 2010 / Published: 24 September 2010
Cited by 50 | PDF Full-text (438 KB)
Abstract
Human T lymphotropic viruses (HTLVs) are complex deltaretroviruses that do not contain a proto-oncogene in their genome, yet are capable of transforming primary T lymphocytes both in vitro and in vivo. There are four known strains of HTLV including HTLV type 1
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Human T lymphotropic viruses (HTLVs) are complex deltaretroviruses that do not contain a proto-oncogene in their genome, yet are capable of transforming primary T lymphocytes both in vitro and in vivo. There are four known strains of HTLV including HTLV type 1 (HTLV-1), HTLV-2, HTLV-3 and HTLV-4. HTLV-1 is primarily associated with adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-2 is rarely pathogenic and is sporadically associated with neurological disorders. There have been no diseases associated with HTLV-3 or HTLV-4 to date. Due to the difference in the disease manifestation between HTLV-1 and HTLV-2, a clear understanding of their individual pathobiologies and the role of various viral proteins in transformation should provide insights into better prognosis and prevention strategies. In this review, we aim to summarize the data accumulated so far in the transformation and pathogenesis of HTLV-1, focusing on the viral Tax and HBZ and citing appropriate comparisons to HTLV-2. Full article
(This article belongs to the Special Issue Cell Transformation by RNA Viruses)
Open AccessReview Hepatitis C Virus P7—A Viroporin Crucial for Virus Assembly and an Emerging Target for Antiviral Therapy
Viruses 2010, 2(9), 2078-2095; doi:10.3390/v2092078
Received: 22 July 2010 / Revised: 2 September 2010 / Accepted: 6 September 2010 / Published: 27 September 2010
Cited by 29 | PDF Full-text (384 KB)
Abstract
The hepatitis C virus (HCV), a hepatotropic plus-strand RNA virus of the family Flaviviridae, encodes a set of 10 viral proteins. These viral factors act in concert with host proteins to mediate virus entry, and to coordinate RNA replication and virus production.
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The hepatitis C virus (HCV), a hepatotropic plus-strand RNA virus of the family Flaviviridae, encodes a set of 10 viral proteins. These viral factors act in concert with host proteins to mediate virus entry, and to coordinate RNA replication and virus production. Recent evidence has highlighted the complexity of HCV assembly, which not only involves viral structural proteins but also relies on host factors important for lipoprotein synthesis, and a number of viral assembly co-factors. The latter include the integral membrane protein p7, which oligomerizes and forms cation-selective pores. Based on these properties, p7 was included into the family of viroporins comprising viral proteins from multiple virus families which share the ability to manipulate membrane permeability for ions and to facilitate virus production. Although the precise mechanism as to how p7 and its ion channel function contributes to virus production is still elusive, recent structural and functional studies have revealed a number of intriguing new facets that should guide future efforts to dissect the role and function of p7 in the viral replication cycle. Moreover, a number of small molecules that inhibit production of HCV particles, presumably via interference with p7 function, have been reported. These compounds should not only be instrumental in increasing our understanding of p7 function, but may, in the future, merit further clinical development to ultimately optimize HCV-specific antiviral treatments. Full article
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Open AccessReview Use of the Aerosol Rabbitpox Virus Model for Evaluation of Anti-Poxvirus Agents
Viruses 2010, 2(9), 2096-2107; doi:10.3390/v2092096
Received: 26 August 2010 / Revised: 2 September 2010 / Accepted: 8 September 2010 / Published: 27 September 2010
Cited by 7 | PDF Full-text (855 KB)
Abstract
Smallpox is an acute disease caused by infection with variola virus that has had historic effects on the human population due to its virulence and infectivity. Because variola remains a threat to humans, the discovery and development of novel pox therapeutics and vaccines
[...] Read more.
Smallpox is an acute disease caused by infection with variola virus that has had historic effects on the human population due to its virulence and infectivity. Because variola remains a threat to humans, the discovery and development of novel pox therapeutics and vaccines has been an area of intense focus. As variola is a uniquely human virus lacking a robust animal model, the development of rational therapeutic or vaccine approaches for variola requires the use of model systems that reflect the clinical aspects of human infection. Many laboratory animal models of poxviral disease have been developed over the years to study host response and to evaluate new therapeutics and vaccines for the treatment or prevention of human smallpox. Rabbitpox (rabbitpox virus infection in rabbits) is a severe and often lethal infection that has been identified as an ideal disease model for the study of poxviruses in a non-rodent species. The aerosol infection model (aerosolized rabbitpox infection) embodies many of the desired aspects of the disease syndrome that involves the respiratory system and thus may serve as an appropriate model for evaluation of antivirals under development for the therapeutic treatment of human smallpox. In this review we summarize the aerosol model of rabbitpox, discuss the development efforts that have thus far used this model for antiviral testing, and comment on the prospects for its use in future evaluations requiring a poxviral model with a focus on respiratory infection. Full article
(This article belongs to the Special Issue Antivirals Against Poxviruses)
Open AccessReview Oncogenic Potential of Hepatitis C Virus Proteins
Viruses 2010, 2(9), 2108-2133; doi:10.3390/v2092108
Received: 15 July 2010 / Revised: 23 September 2010 / Accepted: 24 September 2010 / Published: 27 September 2010
Cited by 43 | PDF Full-text (453 KB)
Abstract
Chronic hepatitis C virus (HCV) infection is a major risk factor for liver disease progression, and may lead to cirrhosis and hepatocellular carcinoma (HCC). The HCV genome contains a single-stranded positive sense RNA with a cytoplasmic lifecycle. HCV proteins interact with many host-cell
[...] Read more.
Chronic hepatitis C virus (HCV) infection is a major risk factor for liver disease progression, and may lead to cirrhosis and hepatocellular carcinoma (HCC). The HCV genome contains a single-stranded positive sense RNA with a cytoplasmic lifecycle. HCV proteins interact with many host-cell factors and are involved in a wide range of activities, including cell cycle regulation, transcriptional regulation, cell proliferation, apoptosis, lipid metabolism, and cell growth promotion. Increasing experimental evidences suggest that HCV contributes to HCC by modulating pathways that may promote malignant transformation of hepatocytes. At least four of the 10 HCV gene products, namely core, NS3, NS5A and NS5B play roles in several potentially oncogenic pathways. Induction of both endoplasmic reticulum (ER) stress and oxidative stress by HCV proteins may also contribute to hepatocyte growth promotion. The current review identifies important functions of the viral proteins connecting HCV infections and potential for development of HCC. However, most of the putative transforming potentials of the HCV proteins have been defined in artificial cellular systems, and need to be established relevant to infection and disease models. The new insight into the mechanisms for HCV mediated disease progression may offer novel therapeutic targets for one of the most devastating human malignancies in the world today. Full article
(This article belongs to the Special Issue Cell Transformation by RNA Viruses)
Open AccessReview An Update on Canine Adenovirus Type 2 and Its Vectors
Viruses 2010, 2(9), 2134-2153; doi:10.3390/v2092134
Received: 25 June 2010 / Revised: 23 September 2010 / Accepted: 24 September 2010 / Published: 27 September 2010
Cited by 39 | PDF Full-text (536 KB)
Abstract
Adenovirus vectors have significant potential for long- or short-term gene transfer. Preclinical and clinical studies using human derived adenoviruses (HAd) have demonstrated the feasibility of flexible hybrid vector designs, robust expression and induction of protective immunity. However, clinical use of HAd vectors can,
[...] Read more.
Adenovirus vectors have significant potential for long- or short-term gene transfer. Preclinical and clinical studies using human derived adenoviruses (HAd) have demonstrated the feasibility of flexible hybrid vector designs, robust expression and induction of protective immunity. However, clinical use of HAd vectors can, under some conditions, be limited by pre-existing vector immunity. Pre-existing humoral and cellular anti-capsid immunity limits the efficacy and duration of transgene expression and is poorly circumvented by injections of larger doses and immuno-suppressing drugs. This review updates canine adenovirus serotype 2 (CAV-2, also known as CAdV-2) biology and gives an overview of the generation of early region 1 (E1)-deleted to helper-dependent (HD) CAV-2 vectors. We also summarize the essential characteristics concerning their interaction with the anti-HAd memory immune responses in humans, the preferential transduction of neurons, and its high level of retrograde axonal transport in the central and peripheral nervous system. CAV-2 vectors are particularly interesting tools to study the pathophysiology and potential treatment of neurodegenerative diseases, as anti-tumoral and anti-viral vaccines, tracer of synaptic junctions, oncolytic virus and as a platform to generate chimeric vectors. Full article
(This article belongs to the Special Issue Adenoviral Vectors)

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