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Viruses, Volume 2, Issue 2 (February 2010), Pages 334-691

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Research

Jump to: Review, Other

Open AccessArticle Cross-Reactive Human IgM-Derived Monoclonal Antibodies that Bind to HIV-1 Envelope Glycoproteins
Viruses 2010, 2(2), 547-565; doi:10.3390/v2020547
Received: 23 September 2009 / Revised: 21 January 2010 / Accepted: 1 February 2010 / Published: 4 February 2010
Cited by 12 | PDF Full-text (180 KB) | XML Full-text
Abstract
Elicitation of antibodies with potent and broad neutralizing activity against HIV by immunization remains a challenge. Several monoclonal antibodies (mAbs) isolated from humans with HIV-1 infection exhibit such activity but vaccine immunogens based on structures containing their epitopes have not been successful for
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Elicitation of antibodies with potent and broad neutralizing activity against HIV by immunization remains a challenge. Several monoclonal antibodies (mAbs) isolated from humans with HIV-1 infection exhibit such activity but vaccine immunogens based on structures containing their epitopes have not been successful for their elicitation. All known broadly neutralizing mAbs (bnmAbs) are immunoglobulin (Ig) Gs (IgGs) and highly somatically hypermutated which could impede their elicitation. Ig Ms (IgMs) are on average significantly less divergent from germline antibodies and are relevant for the development of vaccine immunogens but are underexplored compared to IgGs. Here we describe the identification and characterization of several human IgM-derived mAbs against HIV-1 which were selected from a large phage-displayed naive human antibody library constructed from blood, lymph nodes and spleens of 59 healthy donors. These antibodies bound with high affinity to recombinant envelope glycoproteins (gp140s, Envs) of HIV-1 isolates from different clades. They enhanced or did not neutralize infection by some of the HIV-1 primary isolates using CCR5 as a coreceptor but neutralized all CXCR4 isolates tested although weakly. One of these antibodies with relatively low degree of somatic hypermutation was more extensively characterized. It bound to a highly conserved region partially overlapping with the coreceptor binding site and close to but not overlapping with the CD4 binding site. These results suggest the existence of conserved structures that could direct the immune response to non-neutralizing or even enhancing antibodies which may represent a strategy used by the virus to escape neutralizing immune responses. Further studies will show whether such a strategy plays a role in HIV infection of humans, how important that role could be, and what the mechanisms of infection enhancement are. The newly identified mAbs could be used as reagents to further characterize conserved non-neutralizing, weakly neutralizing or enhancing epitopes and modify or remove them from candidate vaccine immunogens. Full article
(This article belongs to the Special Issue AIDS Vaccine)
Open AccessArticle The Evolution of HIV-1 Diversity in Rural Cameroon and its Implications in Vaccine Design and Trials
Viruses 2010, 2(2), 639-654; doi:10.3390/v2020639
Received: 30 September 2009 / Revised: 13 January 2010 / Accepted: 9 February 2010 / Published: 12 February 2010
Cited by 6 | PDF Full-text (579 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
West-Central Africa is an epicenter of the HIV pandemic; endemic to Cameroon are HIV-1 viruses belonging to all (sub)subtypes and numerous Circulating Recombinant Forms (CRFs). The rural villages of Cameroon harbor many strains of HIV-1, though these areas are not as well monitored
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West-Central Africa is an epicenter of the HIV pandemic; endemic to Cameroon are HIV-1 viruses belonging to all (sub)subtypes and numerous Circulating Recombinant Forms (CRFs). The rural villages of Cameroon harbor many strains of HIV-1, though these areas are not as well monitored as the urban centers. In the present study, 82 specimens obtained in 2000 and 2001 from subjects living in the rural villages of the South and West Regions of Cameroon were subtyped in gag, pol, and env and compared to 90 specimens obtained in 2006–2008 in the same regions, in order to analyze HIV-1 evolution in these rural areas. It was found that in the South Region, the proportion of unique recombinant forms (URFs) remained constant (~40%), while the amount of URFs containing fragments of a CRF increased by 25%. (Sub)subtypes A1, F2, H, and K, and CRF09_cpx, identified in 2000 and 2001, were replaced by CRFs 01_AE, 13_cpx, 14_BG, and 18_cpx in 2006–2008. In the West Region, (sub)subtypes A2, C, G, and H, and CRFs 01_AE and 09_cpx, identified in 2000–2001, were replaced by sub-subtype A1 and CRFs 25_cpx and 37_cpx in 2006–2008. The proportion of URFs in the West Region dropped significantly over the time period by 43%. In both Regions, the proportion of CRF02_AG increased at all loci. These findings demonstrate that the evolution of HIV-1 is distinct for each endemic region, and suggests that the proportion of URFs containing CRF fragments is increasing as the genetic identity of the virus continues to shift dramatically. This highlights the concern that subtype-specific vaccines may not be relevant in Cameroon, and that the distribution of viral diversity in these regions of Cameroon must be carefully monitored. Full article
(This article belongs to the Special Issue AIDS Vaccine)
Open AccessArticle Restriction of Rift Valley Fever Virus Virulence in Mosquito Cells
Viruses 2010, 2(2), 655-675; doi:10.3390/v2020655
Received: 15 December 2009 / Revised: 7 February 2010 / Accepted: 10 February 2010 / Published: 17 February 2010
Cited by 4 | PDF Full-text (1981 KB) | HTML Full-text | XML Full-text
Abstract
Arboviruses are maintained in a natural cycle that requires blood-sucking arthropod and vertebrate hosts. Arboviruses are believed to persistently infect their arthropod host without overt pathology and cause acute infection with viremia in their vertebrate host. We have focused on elucidating how a
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Arboviruses are maintained in a natural cycle that requires blood-sucking arthropod and vertebrate hosts. Arboviruses are believed to persistently infect their arthropod host without overt pathology and cause acute infection with viremia in their vertebrate host. We have focused on elucidating how a specific arbovirus, Rift Valley fever (RVF) virus, causes cytopathic effect in cells derived from vertebrates and non-cytopathic infection in cells derived from arthropods. We demonstrate that the vertebrate virulence factor, NSs, is functional in arthropod cells but is expressed at significantly lower levels in infected arthropod versus infected vertebrate cells. Full article

Review

Jump to: Research, Other

Open AccessReview Development of Viral Vectors for Use in Cardiovascular Gene Therapy
Viruses 2010, 2(2), 334-371; doi:10.3390/v2020334
Received: 14 December 2009 / Revised: 15 January 2010 / Accepted: 26 January 2010 / Published: 27 January 2010
Cited by 16 | PDF Full-text (348 KB) | HTML Full-text | XML Full-text
Abstract
Cardiovascular disease represents the most common cause of mortality in the developed world but, despite two decades of promising pre-clinical research and numerous clinical trials, cardiovascular gene transfer has so far failed to demonstrate convincing benefits in the clinical setting. In this review
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Cardiovascular disease represents the most common cause of mortality in the developed world but, despite two decades of promising pre-clinical research and numerous clinical trials, cardiovascular gene transfer has so far failed to demonstrate convincing benefits in the clinical setting. In this review we discuss the various targets which may be suitable for cardiovascular gene therapy and the viral vectors which have to date shown the most potential for clinical use. We conclude with a summary of the current state of clinical cardiovascular gene therapy and the key trials which are ongoing. Full article
(This article belongs to the Special Issue Novel Viral Vector Systems for Gene Therapy)
Open AccessReview The Role of Nucleotide Excision by Reverse Transcriptase in HIV Drug Resistance
Viruses 2010, 2(2), 372-394; doi:10.3390/v2020372
Received: 10 December 2009 / Revised: 15 January 2010 / Accepted: 25 January 2010 / Published: 28 January 2010
Cited by 13 | PDF Full-text (416 KB) | HTML Full-text | XML Full-text
Abstract
Nucleoside reverse transcriptase (RT) inhibitors of HIV block viral replication through the ability of HIV RT to incorporate chain-terminating nucleotide analogs during viral DNA synthesis. Once incorporated, the chain-terminating residue must be removed before DNA synthesis can continue. Removal can be accomplished by
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Nucleoside reverse transcriptase (RT) inhibitors of HIV block viral replication through the ability of HIV RT to incorporate chain-terminating nucleotide analogs during viral DNA synthesis. Once incorporated, the chain-terminating residue must be removed before DNA synthesis can continue. Removal can be accomplished by the excision activity of HIV RT, which catalyzes the transfer of the 3'-terminal residue on the blocked DNA chain to an acceptor substrate, probably ATP in most infected cells. Mutations of RT that enhance excision activity are the most common cause of resistance to 3'-azido-3'-deoxythymidine (AZT) and exhibit low-level cross-resistance to most other nucleoside RT inhibitors. The resistance to AZT is suppressed by a number of additional mutations in RT, most of which were identified because they conferred resistance to other RT inhibitors. Here we review current understanding of the biochemical mechanisms responsible for increased or decreased excision activity due to these mutations. Full article
(This article belongs to the Special Issue HIV Drug Resistance 2010)
Figures

Open AccessReview Lentiviral Vectors and Cystic Fibrosis Gene Therapy
Viruses 2010, 2(2), 395-412; doi:10.3390/v2020395
Received: 7 October 2009 / Revised: 26 January 2010 / Accepted: 27 January 2010 / Published: 29 January 2010
Cited by 6 | PDF Full-text (234 KB) | HTML Full-text | XML Full-text
Abstract
Cystic fibrosis (CF) is a chronic autosomic recessive syndrome, caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, a chloride channel expressed on the apical side of the airway epithelial cells. The lack of CFTR activity brings a dysregulated exchange of
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Cystic fibrosis (CF) is a chronic autosomic recessive syndrome, caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, a chloride channel expressed on the apical side of the airway epithelial cells. The lack of CFTR activity brings a dysregulated exchange of ions and water through the airway epithelium, one of the main aspects of CF lung disease pathophysiology. Lentiviral (LV) vectors, of the Retroviridae family, show interesting properties for CF gene therapy, since they integrate into the host genome and allow long-lasting gene expression. Proof-of-principle that LV vectors can transduce the airway epithelium and correct the basic electrophysiological defect in CF mice has been given. Initial data also demonstrate that LV vectors can be repeatedly administered to the lung and do not give rise to a gross inflammatory process, although they can elicit a T cell-mediated response to the transgene. Future studies will clarify the efficacy and safety profile of LV vectors in new complex animal models with CF, such as ferrets and pigs. Full article
(This article belongs to the Special Issue Novel Viral Vector Systems for Gene Therapy)
Open AccessReview RNA Replicons - A New Approach for Influenza Virus Immunoprophylaxis
Viruses 2010, 2(2), 413-434; doi:10.3390/v2020413
Received: 31 August 2009 / Revised: 25 January 2010 / Accepted: 27 January 2010 / Published: 29 January 2010
Cited by 17 | PDF Full-text (452 KB) | HTML Full-text | XML Full-text
Abstract
RNA replicons are derived from either positive- or negative-strand RNA viruses. They represent disabled virus vectors that are not only avirulent, but also unable to revert to virulence. Due to autonomous RNA replication, RNA replicons are able to drive high level, cytosolic expression
[...] Read more.
RNA replicons are derived from either positive- or negative-strand RNA viruses. They represent disabled virus vectors that are not only avirulent, but also unable to revert to virulence. Due to autonomous RNA replication, RNA replicons are able to drive high level, cytosolic expression of recombinant antigens stimulating both the humoral and the cellular branch of the immune system. This review provides an update on the available literature covering influenza virus vaccines based on RNA replicons. The pros and cons of these vaccine strategies will be discussed and future perspectives disclosed. Full article
(This article belongs to the Special Issue Influenza: Pandemics and Vaccinations)
Open AccessReview Heterologous Prime-Boost HIV-1 Vaccination Regimens in Pre-Clinical and Clinical Trials
Viruses 2010, 2(2), 435-467; doi:10.3390/v2020435
Received: 30 September 2009 / Revised: 12 January 2010 / Accepted: 22 January 2010 / Published: 1 February 2010
Cited by 16 | PDF Full-text (216 KB) | HTML Full-text | XML Full-text
Abstract
Currently, there are more than 30 million people infected with HIV-1 and thousands more are infected each day. Vaccination is the single most effective mechanism for prevention of viral disease, and after more than 25 years of research, one vaccine has shown somewhat
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Currently, there are more than 30 million people infected with HIV-1 and thousands more are infected each day. Vaccination is the single most effective mechanism for prevention of viral disease, and after more than 25 years of research, one vaccine has shown somewhat encouraging results in an advanced clinical efficacy trial. A modified intent-to-treat analysis of trial results showed that infection was approximately 30% lower in the vaccine group compared to the placebo group. The vaccine was administered using a heterologous prime-boost regimen in which both target antigens and delivery vehicles were changed during the course of inoculations. Here we examine the complexity of heterologous prime-boost immunizations. We show that the use of different delivery vehicles in prime and boost inoculations can help to avert the inhibitory effects caused by vector-specific immune responses. We also show that the introduction of new antigens into boost inoculations can be advantageous, demonstrating that the effect of ‘original antigenic sin’ is not absolute. Pre-clinical and clinical studies are reviewed, including our own work with a three-vector vaccination regimen using recombinant DNA, virus (Sendai virus or vaccinia virus) and protein. Promising preliminary results suggest that the heterologous prime-boost strategy may possibly provide a foundation for the future prevention of HIV-1 infections in humans. Full article
(This article belongs to the Special Issue AIDS Vaccine)
Open AccessReview PEGylated Adenoviruses: From Mice to Monkeys
Viruses 2010, 2(2), 468-502; doi:10.3390/v2020468
Received: 20 November 2009 / Revised: 20 January 2010 / Accepted: 25 January 2010 / Published: 1 February 2010
Cited by 23 | PDF Full-text (658 KB) | HTML Full-text | XML Full-text
Abstract
Covalent modification with polyethylene glycol (PEG), a non-toxic polymer used in food, cosmetic and pharmaceutical preparations for over 60 years, can profoundly influence the pharmacokinetic, pharmacologic and toxciologic profile of protein and peptide-based therapeutics. This review summarizes the history of PEGylation and PEG
[...] Read more.
Covalent modification with polyethylene glycol (PEG), a non-toxic polymer used in food, cosmetic and pharmaceutical preparations for over 60 years, can profoundly influence the pharmacokinetic, pharmacologic and toxciologic profile of protein and peptide-based therapeutics. This review summarizes the history of PEGylation and PEG chemistry and highlights the value of this technology in the context of the design and development of recombinant viruses for gene transfer, vaccination and diagnostic purposes. Specific emphasis is placed on the application of this technology to the adenovirus, the most potent viral vector with the most highly characterized toxicity profile to date, in several animal models. Full article
(This article belongs to the Special Issue Novel Viral Vector Systems for Gene Therapy)
Open AccessReview HIV Genetic Diversity and Drug Resistance
Viruses 2010, 2(2), 503-531; doi:10.3390/v2020503
Received: 18 November 2009 / Revised: 11 December 2009 / Accepted: 1 February 2010 / Published: 2 February 2010
Cited by 23 | PDF Full-text (244 KB) | HTML Full-text | XML Full-text
Abstract
Most of the current knowledge on antiretroviral (ARV) drug development and resistance is based on the study of subtype B of HIV-1, which only accounts for 10% of the worldwide HIV infections. Cumulative evidence has emerged that different HIV types, groups and subtypes
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Most of the current knowledge on antiretroviral (ARV) drug development and resistance is based on the study of subtype B of HIV-1, which only accounts for 10% of the worldwide HIV infections. Cumulative evidence has emerged that different HIV types, groups and subtypes harbor distinct biological properties, including the response and susceptibility to ARV. Recent laboratory and clinical data highlighting such disparities are summarized in this review. Variations in drug susceptibility, in the emergence and selection of specific drug resistance mutations, in viral replicative capacity and in the dynamics of resistance acquisition under ARV selective pressure are discussed. Clinical responses to ARV therapy and associated confounding factors are also analyzed in the context of infections by distinct HIV genetic variants. Full article
(This article belongs to the Special Issue HIV Drug Resistance 2010)
Open AccessReview Developing Vaccines to Combat Pandemic Influenza
Viruses 2010, 2(2), 532-546; doi:10.3390/v2020532
Received: 25 November 2009 / Revised: 28 January 2010 / Accepted: 29 January 2010 / Published: 2 February 2010
Cited by 11 | PDF Full-text (202 KB) | HTML Full-text | XML Full-text
Abstract
Influenza vaccine manufacturers require antigenically relevant vaccine viruses that have good manufacturing properties and are safe to use. In developing pandemic vaccine viruses, reverse genetics has been employed as a rational approach that can also be used effectively to attenuate the highly virulent
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Influenza vaccine manufacturers require antigenically relevant vaccine viruses that have good manufacturing properties and are safe to use. In developing pandemic vaccine viruses, reverse genetics has been employed as a rational approach that can also be used effectively to attenuate the highly virulent H5N1 virus and at the same time place the H5 HA and N1 NA on a background of PR8, a virus that has been used over many decades to provide high yielding vaccine viruses. Reverse genetics has also been used successfully alongside classical reassorting techniques in the development of (swine flu) pandemic A(H1N1)v vaccine viruses. Full article
(This article belongs to the Special Issue Influenza: Pandemics and Vaccinations)
Open AccessReview CCR5: From Natural Resistance to a New Anti-HIV Strategy
Viruses 2010, 2(2), 574-600; doi:10.3390/v2020574
Received: 23 October 2009 / Revised: 22 December 2009 / Accepted: 4 February 2010 / Published: 5 February 2010
Cited by 7 | PDF Full-text (834 KB) | HTML Full-text | XML Full-text
Abstract
The C-C chemokine receptor type 5 (CCR5) is a key player in HIV infection due to its major involvement in the infection process. Investigations into the role of the CCR5 coreceptor first focused on its binding to the virus and the molecular mechanisms
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The C-C chemokine receptor type 5 (CCR5) is a key player in HIV infection due to its major involvement in the infection process. Investigations into the role of the CCR5 coreceptor first focused on its binding to the virus and the molecular mechanisms leading to the entry and spread of HIV. The identification of naturally occurring CCR5 mutations has allowed scientists to address the CCR5 molecule as a promising target to prevent or limit HIV infection in vivo. Naturally occurring CCR5-specific antibodies have been found in exposed but uninfected people, and in a subset of HIV seropositive people who show long-term control of the infection. This suggests that natural autoimmunity to the CCR5 coreceptor exists and may play a role in HIV control. Such natural immunity has prompted strategies aimed at achieving anti-HIV humoral responses through CCR5 targeting, which will be described here. Full article
(This article belongs to the Special Issue AIDS Vaccine)
Open AccessReview Structural Aspects of Drug Resistance and Inhibition of HIV-1 Reverse Transcriptase
Viruses 2010, 2(2), 606-638; doi:10.3390/v2020606
Received: 2 December 2009 / Revised: 22 January 2010 / Accepted: 3 February 2010 / Published: 11 February 2010
Cited by 41 | PDF Full-text (2554 KB) | HTML Full-text | XML Full-text
Abstract
HIV-1 Reverse Transcriptase (HIV-1 RT) has been the target of numerous approved anti-AIDS drugs that are key components of Highly Active Anti-Retroviral Therapies (HAART). It remains the target of extensive structural studies that continue unabated for almost twenty years. The crystal structures of
[...] Read more.
HIV-1 Reverse Transcriptase (HIV-1 RT) has been the target of numerous approved anti-AIDS drugs that are key components of Highly Active Anti-Retroviral Therapies (HAART). It remains the target of extensive structural studies that continue unabated for almost twenty years. The crystal structures of wild-type or drug-resistant mutant HIV RTs in the unliganded form or in complex with substrates and/or drugs have offered valuable glimpses into the enzyme’s folding and its interactions with DNA and dNTP substrates, as well as with nucleos(t)ide reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTIs) drugs. These studies have been used to interpret a large body of biochemical results and have paved the way for innovative biochemical experiments designed to elucidate the mechanisms of catalysis and drug inhibition of polymerase and RNase H functions of RT. In turn, the combined use of structural biology and biochemical approaches has led to the discovery of novel mechanisms of drug resistance and has contributed to the design of new drugs with improved potency and ability to suppress multi-drug resistant strains. Full article
(This article belongs to the Special Issue Retroviral Enzymes)
Open AccessReview How Flaviviruses Activate and Suppress the Interferon Response
Viruses 2010, 2(2), 676-691; doi:10.3390/v2020676
Received: 24 November 2009 / Revised: 4 February 2010 / Accepted: 4 February 2010 / Published: 23 February 2010
Cited by 17 | PDF Full-text (566 KB) | HTML Full-text | XML Full-text
Abstract
The flavivirus genus includes viruses with a remarkable ability to produce disease on a large scale. The expansion and increased endemicity of dengue and West Nile viruses in the Americas exemplifies their medical and epidemiological importance. The rapid detection of viral infection and
[...] Read more.
The flavivirus genus includes viruses with a remarkable ability to produce disease on a large scale. The expansion and increased endemicity of dengue and West Nile viruses in the Americas exemplifies their medical and epidemiological importance. The rapid detection of viral infection and induction of the innate antiviral response are crucial to determining the outcome of infection. The intracellular pathogen receptors RIG-I and MDA5 play a central role in detecting flavivirus infections and initiating a robust antiviral response. Yet, these viruses are still capable of producing acute illness in humans. It is now clear that flaviviruses utilize a variety of mechanisms to modulate the interferon response. The non-structural proteins of the various flaviviruses reduce expression of interferon dependent genes by blocking phosphorylation, enhancing degradation or down-regulating expression of major components of the JAK/STAT pathway. Recent studies indicate that interferon modulation is an important factor in the development of severe flaviviral illness. This suggests that an increased understanding of viral-host interactions will facilitate the development of novel therapeutics to treat these viral infections and improved biological models to study flavivirus pathogenesis. Full article
(This article belongs to the Special Issue Interferon Antiviral Response and Viral Evasion)
Figures

Other

Jump to: Research, Review

Open AccessCommentary A Host of Factors Regulating Influenza Virus Replication
Viruses 2010, 2(2), 566-573; doi:10.3390/v2020566
Received: 25 January 2010 / Revised: 2 February 2010 / Accepted: 3 February 2010 / Published: 5 February 2010
Cited by 12 | PDF Full-text (230 KB) | HTML Full-text | XML Full-text
Abstract A new series of genetic screens begins to illuminate the interaction between influenza virus and the infected cell. Full article
(This article belongs to the Section Editorial)
Open AccessCommentary Surface Transmission or Polarized Egress? Lessons Learned from HTLV Cell-to-Cell Transmission
Viruses 2010, 2(2), 601-605; doi:10.3390/v2020601
Received: 8 February 2010 / Accepted: 8 February 2010 / Published: 10 February 2010
Cited by 7 | PDF Full-text (115 KB) | HTML Full-text | XML Full-text
Abstract Commentary on Pais-Correia, A.M.; Sachse, M.; Guadagnini, S.; Robbiati, V.; Lasserre, R.; Gessain, A.; Gout, O.; Alcover, A.; Thoulouze, M.I. Biofilm-like extracellular viral assemblies mediate HTLV-1 cell-to-cell transmission at virological synapses. Nat. Med. 2010, 16, 83-89. Full article
(This article belongs to the Section Editorial)

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