Future Virol
· 2015 Jun · PMID 26213563
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Vaccination represents the best option to protect humans against influenza virus. However, improving the effectiveness of current vaccines could better stifle the health burden caused by viral infection. Protein synthesi...Vaccination represents the best option to protect humans against influenza virus. However, improving the effectiveness of current vaccines could better stifle the health burden caused by viral infection. Protein synthesis from individual genes can be downregulated by synthetically deoptimizing a gene's codon usage. With more rapid and affordable nucleotide synthesis, generating viruses that contain genes with deoptimized codons is now feasible. Attenuated, vaccine-candidate viruses can thus be engineered with hitherto uncharacterized properties. With eight gene segments, influenza A viruses with variably recoded genomes can produce a spectrum of attenuation that is contingent on the gene segment targeted and the number of codon changes. This review summarizes different targets and approaches to deoptimize influenza A virus codons for novel vaccine generation.
Future Virol
· 2015 Jun · PMID 26213562
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Herpes simplex virus (HSV) is a prevalent neurotropic virus, which establishes lifelong latent infections in the neurons of sensory ganglia. Despite our long-standing knowledge that HSV predominately infects sensory neur...Herpes simplex virus (HSV) is a prevalent neurotropic virus, which establishes lifelong latent infections in the neurons of sensory ganglia. Despite our long-standing knowledge that HSV predominately infects sensory neurons during its life cycle, little is known about the neuronal antiviral response to HSV infection. Recent studies show that while sensory neurons have impaired intrinsic immunity to HSV infection, paracrine IFN signaling can potentiate a potent antiviral response. Additionally, antiviral autophagy plays an important role in neuronal control of HSV infection. Here we review the literature of antiviral signaling and autophagy in neurons, the mechanisms by which HSV can counteract these responses, and postulate how these two pathways may synergize to mediate neuronal control of HSV infection and yet result in lifelong persistence of the virus.
Future Virol
· 2015 Apr · PMID 26213561
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Peter Wildy first observed genetic recombination between strains of HSV in 1955. At the time, knowledge of DNA repair mechanisms was limited, and it has only been in the last decade that particular DNA damage response (D...Peter Wildy first observed genetic recombination between strains of HSV in 1955. At the time, knowledge of DNA repair mechanisms was limited, and it has only been in the last decade that particular DNA damage response (DDR) pathways have been examined in the context of viral infections. One of the first reports addressing the interaction between a cellular DDR protein and HSV-1 was the observation by Lees-Miller . that DNA-dependent protein kinase catalytic subunit levels were depleted in an ICP0-dependent manner during Herpes simplex virus 1 infection. Since then, there have been numerous reports describing the interactions between HSV infection and cellular DDR pathways. Due to space limitations, this review will focus predominantly on the most recent observations regarding how HSV navigates a potentially hostile environment to replicate its genome.
Future Virol
· 2015 Mar · PMID 26213560
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Despite progress in antiretroviral therapy, HIV-1 rebound after cessation of antiretroviral therapy suggests that establishment of long-term cellular reservoirs of virus is a significant barrier to functional cure. There...Despite progress in antiretroviral therapy, HIV-1 rebound after cessation of antiretroviral therapy suggests that establishment of long-term cellular reservoirs of virus is a significant barrier to functional cure. There is considerable evidence that dendritic cells (DCs) play an important role in systemic virus dissemination. Although productive infection of DCs is inefficient, DCs capture HIV-1 and transfer-captured particles to CD4 T cells, a mechanism of DC-mediated HIV-1 trans infection. Recent findings suggest that DC-mediated trans infection of HIV-1 is dependent on recognition of GM3, a virus-particle-associated host-derived ligand, by CD169 expressed on DCs. In this review, we describe mechanisms of DC-mediated HIV-1 trans infection and discuss specifically the role of CD169 in establishing infection in CD4 T cells.
Future Virol
· 2015 Mar · PMID 26213559
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The current Ebola virus disease (EVD) outbreak in West Africa is the largest with over 5100 deaths in four West African countries as of 14 November 2014. EVD has high case-fatality rates but no licensed treatment or vacc...The current Ebola virus disease (EVD) outbreak in West Africa is the largest with over 5100 deaths in four West African countries as of 14 November 2014. EVD has high case-fatality rates but no licensed treatment or vaccine is yet available. Several vaccine candidates that protected nonhuman primates are not yet available for clinical use. Slow development of vaccine-stimulated immunity, sporadic nature and fast progression of EVD underlines the need for the development of effective postexposure therapeutic drugs. WHO encouraged the use of untested drugs for EVD to curb the fast-spreading outbreak. Here, we summarize therapeutics for EVD including monoclonal antibody-based therapy and inhibitors of viral replication including our recently developed small-molecule inhibitors of VP30 dephosphorylation.
Madara JJ, Han Z, Ruthel G
… +2 more, Freedman BD, Harty RN
Future Virol
· 2015 May · PMID 26120351
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The highly virulent nature of Ebola virus, evident from the 2014 West African pandemic, highlights the need to develop vaccines or therapeutic agents that limit the pathogenesis and spread of this virus. While vaccines r...The highly virulent nature of Ebola virus, evident from the 2014 West African pandemic, highlights the need to develop vaccines or therapeutic agents that limit the pathogenesis and spread of this virus. While vaccines represent an obvious approach, targeting virus interactions with host proteins that critically regulate the virus lifecycle also represent important therapeutic strategies. Among Ebola virus proteins at this critical interface is its matrix protein, VP40, which is abundantly expressed during infection and plays a number of critical roles in the viral lifecycle. In addition to regulating viral transcription, VP40 coordinates virion assembly and budding from infected cells. Details of the molecular mechanisms underpinning these essential functions are currently being elucidated, with a particular emphasis on its interactions with host proteins that control virion assembly and egress. This review focuses on the strategies geared toward developing novel therapeutic agents that target VP40-specific control of host functions critical to virion transcription, assembly and egress.
Human parvovirus B19 (B19V) is a human pathogen that belongs to genus of the family, which is composed of a group of small DNA viruses with a linear single-stranded DNA genome. B19V mainly infects human erythroid proge...Human parvovirus B19 (B19V) is a human pathogen that belongs to genus of the family, which is composed of a group of small DNA viruses with a linear single-stranded DNA genome. B19V mainly infects human erythroid progenitor cells and causes mild to severe hematological disorders in patients. However, recent clinical studies indicate that B19V also infects nonerythroid lineage cells, such as myocardial endothelial cells, and may be associated with other disease outcomes. Several cell culture systems, including permissive and semipermissive erythroid lineage cells, nonpermissive human embryonic kidney 293 cells and recently reported myocardial endothelial cells, have been used to study the mechanisms underlying B19V infection and B19V DNA replication. This review aims to summarize recent advances in B19V studies with a focus on the mechanisms of B19V tropism specific to different cell types and the cellular pathways involved in B19V DNA replication including cellular signaling transduction and cell cycle arrest.
Due to advances in antiretroviral therapy, most HIV-infected children and youth now survive into adulthood. Many experts and professional societies have expressed concern about potential disruptions to care when youth li...Due to advances in antiretroviral therapy, most HIV-infected children and youth now survive into adulthood. Many experts and professional societies have expressed concern about potential disruptions to care when youth living with HIV transition from pediatric to adult-oriented medical care. However, original research focused on this transition process is rare. The existing literature can be organized into the following categories: pre-transition assessments of anticipated barriers and concerns; studies describing provider practices during the transition period; and post-transition retrospective analyses after transition to adult care. Most studies had small sample sizes and focused on vertically infected youth. Further work is needed to document clinical outcomes after transition and to evaluate transition protocols that are in place at some institutions.
The past decade has witnessed steady and rapid progress in HCV research, which has led to the recent breakthrough in therapies against this significant human pathogen. Yet a deeper understanding of the life cycle of the...The past decade has witnessed steady and rapid progress in HCV research, which has led to the recent breakthrough in therapies against this significant human pathogen. Yet a deeper understanding of the life cycle of the virus is required to develop more affordable treatments and to advance vaccine design. HCV entry presents both a challenge for scientific research and an opportunity for alternative intervention approaches, owning to its highly complex nature and the myriad of players involved. More than half a dozen cellular proteins are implicated in HCV entry; and a more definitive picture regarding the structures of the glycoproteins is emerging. A role of apolipoproteins in HCV entry has also been established. Still, major questions remain, and the answers to these, which we summarize in this review, will hopefully close the gaps in our understanding and complete the puzzle that is HCV entry.
Future Virol
· 2015 May · PMID 32201495
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Up to November 2014, Middle East respiratory syndrome coronavirus (MERS-CoV) has infected 935 individuals and killed 371, all originating in or with links to the Middle East. The mechanisms of transmission of the disease...Up to November 2014, Middle East respiratory syndrome coronavirus (MERS-CoV) has infected 935 individuals and killed 371, all originating in or with links to the Middle East. The mechanisms of transmission of the disease are not fully understood, but MERS-CoV seems to sustain itself in the human population through repeated re-introduction from a camel reservoir and is able to cause nosocomial outbreaks. The risk of a global spread of MERS-CoV is low. Epidemiological, serological and phylogenetic research, combined with one health surveillance, dynamic case definitions, active case finding, rigorous infection control, culturally sensitive risk communication and a continuous re-evaluation of new evidence will enable to better understand the disease, limit its spread and quantify its risk in order to better prepare for a hypothetical spread.
Infection with HBV is common worldwide, with over 350 million chronic carriers. Chronic HBV infection is associated with cirrhosis and hepatocellular carcinoma. All currently available oral antivirals are directed agains...Infection with HBV is common worldwide, with over 350 million chronic carriers. Chronic HBV infection is associated with cirrhosis and hepatocellular carcinoma. All currently available oral antivirals are directed against the HBV polymerase enzyme, a reverse transcriptase. HBV polymerase contains several important domains and motifs which define its functions and reveal ways to further target it. This enzyme executes many functions required for the HBV replication cycle, including viral RNA binding, RNA packaging, protein priming, template switching, DNA synthesis and RNA degradation. In addition, HBV polymerase must interact with host proteins for its functions. Future therapeutics may inhibit not only the DNA synthesis steps which are carried out by the reverse transcriptase domain (as all current antivirals do) but other domains, functions and interactions which are essential to the HBV replication cycle.
Future Virol
· 2015 Mar · PMID 25844088
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Lassa virus infection elicits distinctive changes in host gene expression and metabolism. We focus on changes in host gene expression that may be biomarkers that discriminate individual pathogens or may help to provide a...Lassa virus infection elicits distinctive changes in host gene expression and metabolism. We focus on changes in host gene expression that may be biomarkers that discriminate individual pathogens or may help to provide a prognosis for disease. In addition to assessing mRNA changes, functional studies are also needed to discriminate causes of disease from mechanisms of host resistance. Host responses that drive pathogenesis are likely to be targets for prevention or therapy. Host responses to Lassa or its related arenaviruses have been monitored in cell culture, in animal models of hemorrhagic fever, in Lassa-infected nonhuman primates and, to a limited extent, in infected human beings. Here, we describe results from those studies and discuss potential targets for reducing virus replication and mitigating disease.
Patel MC, Shirey KA, Pletneva LM
… +4 more, Boukhvalova MS, Garzino-Demo A, Vogel SN, Blanco JC
Future Virol
· 2014 Sep · PMID 25620999
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Toll-like receptors (TLRs) are sentinel receptors of the host innate immune system that recognize conserved 'pathogen-associated molecular patterns' of invading microbes, including viruses. The activation of TLRs establi...Toll-like receptors (TLRs) are sentinel receptors of the host innate immune system that recognize conserved 'pathogen-associated molecular patterns' of invading microbes, including viruses. The activation of TLRs establishes antiviral innate immune responses and coordinates the development of long-lasting adaptive immunity in order to control viral pathogenesis. However, microbe-induced damage to host tissues may release 'danger-associated molecular patterns' that also activate TLRs, leading to an overexuberant inflammatory response and, ultimately, to tissue damage. Thus, TLRs have proven to be promising targets as therapeutics for the treatment of viral infections that result in inflammatory damage or as adjuvants in order to enhance the efficacy of vaccines. Here, we explore recent advances in TLR biology with a focus on novel drugs that target TLRs (agonists and antagonists) for antiviral therapy.
A molecular understanding of viral infection requires a multi-disciplinary approach. Mass spectrometry has emerged as an indispensable tool to investigate the complex and dynamic interactions between HIV-1 and its host....A molecular understanding of viral infection requires a multi-disciplinary approach. Mass spectrometry has emerged as an indispensable tool to investigate the complex and dynamic interactions between HIV-1 and its host. It has been employed to study protein associations, changes in protein abundance and post-translational modifications occurring after viral infection. Here, we review and provide examples of mass spectrometry-based proteomic approaches currently used to explore virus-host interaction. Efforts in this area are certain to accelerate the discovery of the unique molecular strategies utilized by the virus to commandeer the cell as well as mechanisms of host defense.
Future Virol
· 2014 Sep · PMID 25431616
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The influenza A virus causes a highly contagious respiratory disease that significantly impacts our economy and health. Its replication and transcription is catalyzed by the viral RNA polymerase. This enzyme is also cruc...The influenza A virus causes a highly contagious respiratory disease that significantly impacts our economy and health. Its replication and transcription is catalyzed by the viral RNA polymerase. This enzyme is also crucial for the virus, because it is involved in the adaptation of zoonotic strains. It is thus of major interest for the development of antiviral therapies and is being intensively studied. In this article, we will discuss recent advances that have improved our knowledge of the structure of the RNA polymerase and how mutations in the polymerase help the virus to spread effectively among new hosts.
Future Virol
· 2014 Oct · PMID 25431615
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AIDS has been transformed from a death sentence to a manageable disease for many patients with access to combination antiviral therapy. It is informative to look back on some of the key advances that have led to this tra...AIDS has been transformed from a death sentence to a manageable disease for many patients with access to combination antiviral therapy. It is informative to look back on some of the key advances that have led to this transformation. The arsenal of tools currently available to clinicians now includes inhibitors of the viral reverse transcriptase, protease and integrase enzymes. The author discusses some of the key advances that have led to this transformation with an emphasis on the role of basic science in developing integrase inhibitors. Many of the stepping-stones could not easily have been foreseen to lead to medical advances. Treatments for diseases that are yet to emerge will likely depend on the progress made in basic science today.
Chronic HBV infection is a major public health concern affecting over 240 million people worldwide. Although suppression of HBV replication is achieved in the majority of patients with currently available newer antiviral...Chronic HBV infection is a major public health concern affecting over 240 million people worldwide. Although suppression of HBV replication is achieved in the majority of patients with currently available newer antivirals, discontinuation of therapy prior to hepatitis B surface antigen loss or seroconversion is associated with relapse of HBV in the majority of cases. Thus, new therapeutic modalities are needed to achieve eradication of the virus from chronically infected patients in the absence of therapy. The basis of HBV persistence includes viral and host factors. Here, we review novel strategies to achieve sustained cure or elimination of HBV. The novel approaches include targeting the viral and or host factors required for viral persistence, and novel immune-based therapies, including therapeutic vaccines.
Future Virol
· 2014 May · PMID 25214882
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Zoonotic influenza A viruses originating from the animal reservoir pose a threat for humans, as they have the ability to trigger pandemics upon adaptation to and invasion of an immunologically naive population. Of partic...Zoonotic influenza A viruses originating from the animal reservoir pose a threat for humans, as they have the ability to trigger pandemics upon adaptation to and invasion of an immunologically naive population. Of particular concern are the H5N1 viruses that continue to circulate in poultry in numerous countries in Europe, Asia and Africa, and the recently emerged H7N9 viruses in China, due to their relatively high number of human fatalities and pandemic potential. To start a pandemic, zoonotic influenza A viruses should not only acquire the ability to attach to, enter and replicate in the critical target cells in the respiratory tract of the new host, but also efficiently spread between humans by aerosol or respiratory droplet transmission. Here, we discuss the latest advances on the genetic and phenotypic determinants required for avian influenza A viruses to adapt to and transmit between mammals.