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  • Reprogramming of cellular metabolic pathways by human oncogenic viruses
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2019-11-22
    John G Purdy, Micah A Luftig

    Oncogenic viruses, like all viruses, relies on host metabolism to provide the metabolites and energy needed for virus replication. Many DNA tumor viruses and retroviruses will reprogram metabolism during infection. Additionally, some viral oncogenes may alter metabolism independent of virus replication. Virus infection and cancer development share many similarities regarding metabolic reprogramming as both processes demand increased metabolic activity to produce biomass: cell proliferation in the case of cancer and virion production in the case of infection. This review discusses the parallels in metabolic reprogramming between human oncogenic viruses and oncogenesis.

  • Regulating cellular plasticity to persist: a way for tumor viruses to triumph
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2019-07-11
    Vural Yilmaz, Katerina Strati
  • The case for BK polyomavirus as a cause of bladder cancer
    Gabriel J Starrett, Christopher B Buck
  • How the gut microbiome regulates host immune responses to viral vaccines.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2019-06-05
    Anastasia N Vlasova,Sayaka Takanashi,Ayako Miyazaki,Gireesh Rajashekara,Linda J Saif

    The co-evolution of the microbiota and immune system has forged a mutually beneficial relationship. This relationship allows the host to maintain the balance between active immunity to pathogens and vaccines and tolerance to self-antigens and food antigens. In children living in low-income and middle-income countries, undernourishment and repetitive gastrointestinal infections are associated with the failure of oral vaccines. Intestinal dysbiosis associated with these environmental influences, as well as some host-related factors, compromises immune responses and negatively impacts vaccine efficacy. To understand how immune responses to viral vaccines can be optimally modulated, mechanistic studies of the relationship between the microbiome, host genetics, viral infections and the development and function of the immune system are needed. We discuss the potential role of the microbiome in modulating vaccine responses in the context of a growing understanding of the relationship between the gastrointestinal microbiota, host related factors (including histo-blood group antigens) and resident immune cell populations.

  • Hepatitis C NS5A protein: two drug targets within the same protein with different mechanisms of resistance.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2014-06-01
    Precious J Lim,Philippe A Gallay

    The era of interferon-free antiviral treatments for hepatitis C virus infection has arrived. With increasing numbers of approved antivirals, evaluating all parameters that may influence response is necessary to choose optimal combinations for treatment success. Targeting NS5A has become integral in antiviral combinations in clinical development. Daclatasvir and ledipasvir belong to the NS5A inhibitor class, which directly target the NS5A protein. Alisporivir, a host-targeting antiviral, is a cyclophilin inhibitor that indirectly targets NS5A by blocking NS5A/cyclophilin A interaction. Resistance to daclatasvir and ledipasvir differs from alisporivir, with mutations arising in NS5A domains I and II, respectively. Combining these two classes acting on distinct NS5A domains represents an attractive strategy for potentially effective interferon-free treatments for chronic hepatitis C infection.

  • Editorial overview: Viruses and cancer.
    Curr. Opin. Virol. (IF 5.400) Pub Date : null
    Marta M Gaglia,Karl Munger

  • Targeting HIV-1 proviral transcription.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2019-09-02
    Alex Olson,Binita Basukala,Wilson W Wong,Andrew J Henderson

    Despite the success of antiretroviral therapies, there is no cure for HIV-1 infection due to the establishment of a long-lived latent reservoir that fuels viral rebound upon treatment interruption. 'Shock-and-kill' strategies to diminish the latent reservoir have had modest impact on the reservoir leading to considerations of alternative approaches to target HIV-1 proviruses. This review explores approaches to target HIV-1 transcription as a way to block the provirus expression.

  • 更新日期：2019-11-01
  • Applications of CRISPR/Cas9 tools in deciphering the mechanisms of HIV-1 persistence.
    Roxane Verdikt,Gilles Darcis,Amina Ait-Ammar,Carine Van Lint

    HIV-1 infection can be controlled but not cured by combination antiretroviral therapy. Indeed, the virus persists in treated individuals in viral reservoirs, the best described of which consisting in latently infected central memory CD4+ T cells. However, other cell types in other body compartments than in the peripheral blood contribute to HIV-1 persistence. Addressing the molecular mechanisms of HIV-1 persistence and their cell-specific and tissue-specific variations is thus crucial to develop HIV-1 curative strategies. CRISPR/Cas9 editing technologies have revolutionized genetic engineering by their high specificity and their versatility. Multiple applications now allow to investigate the molecular mechanisms of HIV-1 persistence. Here, we review recent advances in CRISPR-based technologies in deciphering HIV-1 gene expression regulation during persistence.

  • Elimination of infectious HIV DNA by CRISPR-Cas9.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2019-08-27
    Atze T Das,Caroline S Binda,Ben Berkhout

    Current antiretroviral drugs can efficiently block HIV replication and prevent transmission, but do not target the HIV provirus residing in cells that constitute the viral reservoir. Because drug therapy interruption will cause viral rebound from this reservoir, HIV-infected individuals face lifelong treatment. Therefore, novel therapeutic strategies are being investigated that aim to permanently inactivate the proviral DNA, which may lead to a cure. Multiple studies showed that CRISPR-Cas9 genome editing can be used to attack HIV DNA. Here, we will focus on not only how this endonuclease attack can trigger HIV provirus inactivation, but also how virus escape occurs and this can be prevented.

  • The potential of engineered antibodies for HIV-1 therapy and cure.
    Marloes Grobben,Richard Al Stuart,Marit J van Gils

    Broadly neutralizing antibodies (bnAbs) are currently under investigation as a therapy for HIV-1 infection and recent clinical trials have shown prolonged viral suppression by bnAbs during antiretroviral treatment interruption. Interestingly, these bnAbs also showed the ability to activate the host immune system to clear HIV-1 infected cells. There are many possibilities to further increase the potential efficacy of bnAbs. Most notably, Fc domain engineering to improve half-life and increase engagement of effector cells will augment two advantages of bnAbs. Moreover, antibody engineering can improve affinity and recognition of conserved epitopes and allows the combination of multiple epitope specificities in a single molecule. These increasingly potent and broad antibodies may prove valuable as alternative HIV-1 therapeutic and possibly in curative approaches.

  • HIV-1 persistence in the central nervous system: viral and host determinants during antiretroviral therapy.
    E F Balcom,W C Roda,E A Cohen,M Y Li,C Power

    Despite remarkable therapeutic advances in the past two decades, the elimination of human immunodeficiency virus type 1 (HIV-1) from latent reservoirs constitutes a major barrier to eradication and preventing neurological disease associated with HIV/AIDS. Invasion of the central nervous system (CNS) by HIV-1 occurs early in infection, leading to viral infection and productive persistence in brain macrophage-like cells (BMCs) including resident microglia and infiltrating macrophages. HIV-1 persistence in the brain and chronic neuroinflammation occur despite effective treatment with antiretroviral therapy (ART). This review examines the evidence from clinical studies, in vivo and in vitro models for HIV-1 CNS persistence, as well as therapeutic considerations in targeting latent CNS reservoirs.

  • A broad drug arsenal to attack a strenuous latent HIV reservoir.
    Mateusz Stoszko,Enrico Ne,Erik Abner,Tokameh Mahmoudi

    HIV cure is impeded by the persistence of a strenuous reservoir of latent but replication competent infected cells, which remain unsusceptible to c-ART and unrecognized by the immune system for elimination. Ongoing progress in understanding the molecular mechanisms that control HIV transcription and latency has led to the development of strategies to either permanently inactivate the latent HIV infected reservoir of cells or to stimulate the virus to emerge out of latency, coupled to either induction of death in the infected reactivated cell or its clearance by the immune system. This review focuses on the currently explored and non-exclusive pharmacological strategies and their molecular targets that 1. stimulate reversal of HIV latency in infected cells by targeting distinct steps in the HIV-1 gene expression cycle, 2. exploit mechanisms that promote cell death and apoptosis to render the infected cell harboring reactivated virus more susceptible to death and/or elimination by the immune system, and 3. permanently inactivate any remaining latently infected cells such that c-ART can be safely discontinued.

  • 更新日期：2019-11-01
  • 更新日期：2019-11-01
  • Curr. Opin. Virol. (IF 5.400) Pub Date : 2017-08-30
    John P Carr,Peter Palukaitis

  • Mutually assured destruction: the cold war between viruses and natural killer cells.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2019-03-17
    Ayad Ali,Ivayla E Gyurova,Stephen N Waggoner

    Natural killer (NK) cells play a multitude of antiviral roles that are significant enough to provoke viral counterefforts to subvert their activity. As innate lymphocytes, NK cells provide a rapid source of pro-inflammatory antiviral cytokines and bring to bear cytolytic activities that are collectively meant to constrain viral replication and dissemination. Additionally, NK cells participate in adaptive immunity both by shaping virus-specific T-cell responses and by developing adaptive features themselves, including enhanced antibody-dependent effector functions. The relative importance of different functional activities of NK cells are poorly understood, thereby obfuscating clinical use of these cells. Here we focus on opposing efforts of NK cells and viruses to gain tactical superiority during infection.

  • Editorial overview: Viral immunology.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2019-04-23
    Juan C de la Torre,John Teijaro

  • Editorial overview: Emerging viruses: interspecies transmission: Expect the unexpected.
    Adolfo García-Sastre,Juergen A Richt

  • VH1-69 antiviral broadly neutralizing antibodies: genetics, structures, and relevance to rational vaccine design.
    Fang Chen,Netanel Tzarum,Ian A Wilson,Mansun Law

    Broadly neutralizing antibodies (bnAbs) are potential therapeutic molecules and valuable tools for studying conserved viral targets for vaccine and drug design. Interestingly, antibody responses to conserved epitopes can be highly convergent at the molecular level. Human antibodies targeting a number of viral antigens have often been found to utilize a restricted set of immunoglobulin germline genes in different individuals. Here we review recent knowledge on VH1-69-encoded antibodies in antiviral responses to influenza virus, HCV, and HIV-1. These antibodies share common genetic and structural features, and often develop neutralizing activity against a broad spectrum of viral strains. Understanding the genetic and structural characteristics of such antibodies and the target epitopes should help advance novel strategies to elicit bnAbs through vaccination.

  • Achieving cross-reactivity with pan-ebolavirus antibodies.
    Liam B King,Jacob C Milligan,Brandyn R West,Sharon L Schendel,Erica Ollmann Saphire

    Filoviruses are the causative agents of highly lethal outbreaks in sub-Saharan Africa. Although an experimental vaccine and several therapeutics are being deployed in the Democratic Republic of Congo to combat the ongoing Ebola virus outbreak, these therapies are specific for only one filovirus species. There is currently significant interest in developing broadly reactive monoclonal antibodies (mAbs) with utility against the variety of ebolaviruses that may emerge. Thus far, the primary target of these mAbs has been the viral spike glycoprotein (GP). Here we present an overview of GP-targeted antibodies that exhibit broad reactivity and the structural characteristics that could confer this cross-reactivity. We also discuss how these structural features could be leveraged to design vaccine antigens that elicit cross-reactive antibodies.

  • Successes and challenges for preventing measles, mumps and rubella by vaccination.
    Bettina Bankamp,Carole Hickman,Joseph P Icenogle,Paul A Rota

    The measles, mumps and rubella (MMR) vaccine has an outstanding safety record and is highly efficacious. High coverage with MMR has led to the elimination of endemic measles, rubella, and congenital rubella syndrome in the US. The biggest challenges to global measles and rubella control and elimination are insufficient vaccination coverage globally and increasing hesitancy. Despite high two dose coverage rates, mumps has made a resurgence in the US and other countries. Mumps outbreaks have occurred primarily in close contact, high-density settings and most cases had received a second dose 10 or more years previously. Waning humoral immunity and antigenic variation of circulating wild-type mumps strains may play a role in the mumps resurgence.

  • Virus recognition of glycan receptors.
    Andrew J Thompson,Robert P de Vries,James C Paulson

    Attachment of viruses to cell-surface receptors is the initial step in infection. Many mammalian viruses have evolved to recognize receptors that are glycans on cell-surface glycoproteins or glycolipids. Although glycans are a ubiquitous component of mammalian cells, the types of terminal structures expressed vary among different cell-types and tissues, and even between comparable cells and tissues from different species, frequently leading to specific tissue and species tropisms as a direct consequence of glycan receptor recognition. Covering the majority of known virus families, this review provides an overview of mammalian viruses that use glycans as receptors, and their roles in determining in host recognition and tropism.

  • Current small animal models for LASV hearing loss.
    Rachel A Sattler,Junki Maruyama,Nathan Y Shehu,Tomoko Makishima,Slobodan Paessler

    Lassa virus (LASV) is endemic in West Africa, causing an estimated 100000-300000 new infections and up to 5000-10000 deaths yearly. There are no vaccines and therapeutics are extremely limited. Typical case fatality rates are ∼1%, although a recent 2018 Nigerian outbreak featured an unprecedented 25.4% case fatality rate. Survivors of infection suffer a lifetime of sequelae with sudden onset sensorineural hearing loss (SNHL) being the most prevalent. The cause of this hearing loss remains unknown, and there is a critical need for further research on its mechanisms and potential therapeutics. The objective of this review is to outline the only currently available small animal model for LASV-induced hearing loss and to identify potential surrogate models.

  • A review of Lassa fever vaccine candidates.
    Kolawole Salami,Dimitrios Gouglas,Connie Schmaljohn,Melanie Saville,Nadia Tornieporth

    Lassa fever is a zoonotic disease caused by the Lassa virus, a rodent-borne arenavirus endemic to West Africa. Recent steady increase in reported cases of the disease in Nigeria, where 123 deaths occurred in 546 confirmed cases in 2019 has further underlined the need to accelerate the development of vaccines for preventing the disease. Intensified research and development of Lassa fever medical countermeasures have yielded some vaccine candidates with preclinical scientific plausibility using predominantly novel technology. The more advanced candidates are based on recombinant measles, Vesicular Stomatitis Virus or Mopiea and Lassa virus reassortants expressing Lassa virus antigens, and the deoxyribonucleic acid platform. However, the Lassa fever portfolio still lags behind other neglected tropical diseases', and further investments are needed for continued development and additional research, such as the safety and efficacy of these vaccine candidates in special populations.

  • Antibody therapy for Lassa fever.
    Robert W Cross,Kathryn M Hastie,Chad E Mire,James E Robinson,Thomas W Geisbert,Luis M Branco,Erica Ollmann Saphire,Robert F Garry

    Serum from convalescent Lassa fever patients was previously shown to be ineffective as a source of protective antibodies in some early studies. Subsequently, monoclonal antibodies (MAbs) to the Lassa virus (LASV) glycoprotein produced by memory B cells of West African patients who survived Lassa fever were identified. Development of MAbs as potential Lassa immunotherapeutics was facilitated by structural studies and mutational analyses that identified protective epitopes on the prefusion form of the LASV glycoprotein. Human mAbs were screened for reactivity to different neutralizing epitopes, potency, and broad reactivity against multiple lineages of LASV. MAbs were downselected in a guinea pig model of Lassa fever. A cocktail of three human MAbs designated Arevirumab-3 rescued 100% of Cynomolgus macaques at advanced stages of disease more than a week post-infection. Antibody therapeutics may be further developed in clinical trials in endemic areas potentially offering a key treatment option for Lassa fever.

  • Human immune system mouse models of Ebola virus infection.
    Jessica R Spengler,Joseph Prescott,Heinz Feldmann,Christina F Spiropoulou

    Human immune system (HIS) mice, immunodeficient mice engrafted with human cells (with or without donor-matched tissue), offer a unique opportunity to study pathogens that cause disease predominantly or exclusively in humans. Several HIS mouse models have recently been used to study Ebola virus (EBOV) infection and disease. The results of these studies are encouraging and support further development and use of these models in Ebola research. HIS mice provide a small animal model to study EBOV isolates, investigate early viral interactions with human immune cells, screen vaccines and therapeutics that modulate the immune system, and investigate sequelae in survivors. Here we review existing models, discuss their use in pathogenesis studies and therapeutic screening, and highlight considerations for study design and analysis. Finally, we point out caveats to current models, and recommend future efforts for modeling EBOV infection in HIS mice.

  • Polintons, virophages and transpovirons: a tangled web linking viruses, transposons and immunity.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2017-07-04
    Eugene V Koonin,Mart Krupovic

    Virophages are satellite DNA viruses that depend for their replication on giant viruses of the family Mimiviridae. An evolutionary relationship exists between the virophages and Polintons, large self-synthesizing transposons that are wide spread in the genomes of diverse eukaryotes. Most of the Polintons encode homologs of major and minor icosahedral virus capsid proteins and accordingly are predicted to form virions. Additionally, metagenome analysis has led to the discovery of an expansive family of Polinton-like viruses (PLV) that are more distantly related to bona fide Polintons and virophages. Another group of giant virus parasites includes small, linear, double-stranded DNA elements called transpovirons. Recent in-depth comparative genomic analysis has yielded evidence of the origin of the PLV and the transpovirons from Polintons. Integration of virophage genomes into genomes of both giant viruses and protists has been demonstrated. Furthermore, in an experimental coinfection system that consisted of a protist host, a giant virus and an associated virophage, the virophage integrated into the host genome and, after activation of its expression by a superinfecting giant virus, served as an agent of adaptive immunity. There is a striking analogy between this mechanism and the CRISPR-Cas system of prokaryotic adaptive immunity. Taken together, these findings show that Polintons, PLV, virophages and transpovirons form a dynamic network of integrating mobile genetic elements that contribute to the cellular antivirus defense and host-virus coevolution.

  • Vaccine development for respiratory syncytial virus.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2017-05-20
    Barney S Graham

    Respiratory syncytial virus (RSV) is an important and ubiquitous respiratory pathogen for which no vaccine is available notwithstanding more than 50 years of effort. It causes the most severe disease at the extremes of age and in settings of immunodeficiency. Although RSV is susceptible to neutralizing antibody, it has evolved multiple mechanisms of immune evasion allowing it to repeatedly infect people despite relatively little genetic diversity. Recent breakthroughs in determining the structure and antigenic content of the fusion (F) glycoprotein in its metastable untriggered prefusion form (pre-F) and the stable rearranged postfusion form (post-F) have yielded vaccine strategies that can induce potent neutralizing antibody responses and effectively boost pre-existing neutralizing activity. In parallel, novel live-attenuated and chimeric virus vaccine candidates and other novel approaches to deliver vaccine antigens have been developed. These events and activities have aroused optimism and a robust pipeline of potential vaccine products that promise to provide a means to reduce the public health burden of RSV infection.

  • Recent advances in human flavivirus vaccines.
    Iris Scherwitzl,Juthathip Mongkolsapaja,Gavin Screaton

    Dengue (DENV), West Nile (WNV) and Zika (ZIKV) viruses are mosquito-transmitted flaviviruses that cause thousands of human deaths and millions of illnesses each year. In the last decades, epidemic outbreaks of all three flaviviruses emerged and caused a major health and economical problem in many parts of the world. The increasing and expanding burden of flaviviruses has highlighted the need for effective human vaccines against all three viruses. This review provides an overview of the recent progress in DENV, WNV and ZIKV vaccines development with specific focus on candidates in human clinical development.

  • Determinants of early life immune responses to RSV infection.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2016-03-18
    Tracy J Ruckwardt,Kaitlyn M Morabito,Barney S Graham

    Respiratory syncytial virus causes significant morbidity and mortality in both developed and developing countries, and a vaccine that adequately protects from severe disease remains an important unmet need. RSV disease has an inordinate impact on the very young, and the physical and immunological immaturity of early life complicates vaccine design. Defining and targeting the functional capacities of early life immune responses and controlling responses during primary antigen exposure with selected vaccine delivery approaches will be important for protecting infants by active immunization. Alternatively, vaccination of older children and pregnant mothers may ameliorate disease burden indirectly until infants reach about six months of age, when they can generate more effective anti-RSV immune responses.

  • Animal models for SARS and MERS coronaviruses.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2015-07-18
    Lisa M Gretebeck,Kanta Subbarao

    The emergence of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome coronavirus (MERS-CoV), two strains of animal coronaviruses that crossed the species barrier to infect and cause severe respiratory infections in humans within the last 12 years, have taught us that coronaviruses represent a global threat that does not recognize international borders. We can expect to see other novel coronaviruses emerge in the future. An ideal animal model should reflect the clinical signs, viral replication and pathology seen in humans. In this review, we present factors to consider in establishing an animal model for the study of novel coronaviruses and compare the different animal models that have been employed to study SARS-CoV and MERS-CoV.

  • Strategies to guide the antibody affinity maturation process.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2015-04-29
    Nicole A Doria-Rose,M Gordon Joyce

    Antibodies with protective activity are critical for vaccine efficacy. Affinity maturation increases antibody activity through multiple rounds of somatic hypermutation and selection in the germinal center. Identification of HIV-1 specific and influenza-specific antibody developmental pathways, as well as characterization of B cell and virus co-evolution in patients, has informed our understanding of antibody development. In order to counteract HIV-1 and influenza viral diversity, broadly neutralizing antibodies precisely target specific sites of vulnerability and require high levels of affinity maturation. We present immunization strategies that attempt to recapitulate these natural processes and guide the affinity maturation process.

  • Targeting host-derived glycans on enveloped viruses for antibody-based vaccine design.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2015-03-10
    Max Crispin,Katie J Doores

    The surface of enveloped viruses can be extensively glycosylated. Unlike the glycans coating pathogens such as bacteria and fungi, glycans on viruses are added and processed by the host-cell during biosynthesis. Glycoproteins are typically subjected to α-mannosidase processing and Golgi-mediated glycosyltransferase extension to form complex-type glycans. In envelope viruses, exceptions to this default pathway are common and lead to the presence of oligomannose-type glycan structures on the virion surface. In one extreme example, HIV-1 utilises a high density of glycans to limit host antibody recognition of protein. However, the high density limits glycan processing and the resulting oligomannose structures can be recognised by broadly neutralising antibodies isolated from HIV-1 infected patients. Here we discuss how divergence from host-cell glycosylation can be targeted for vaccine design.

  • Viral diseases of the central nervous system.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2015-02-15
    Phillip A Swanson,Dorian B McGavern

    Virus-induced diseases of the central nervous system (CNS) represent a significant burden to human health worldwide. The complexity of these diseases is influenced by the sheer number of different neurotropic viruses, the diverse routes of CNS entry, viral tropism, and the immune system. Using a combination of human pathological data and experimental animal models, we have begun to uncover many of the mechanisms that viruses use to enter the CNS and cause disease. This review highlights a selection of neurotropic viruses that infect the CNS and explores the means by which they induce neurological diseases such as meningitis, encephalitis, and myelitis.

  • Evidence linking HHV-6 with multiple sclerosis: an update.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2014-12-03
    Emily C Leibovitch,Steven Jacobson

    Following reports of elevated antiviral antibodies in MS patient sera and viral DNA detection in MS plaques nearly two decades ago, the neurovirology community has actively explored how herpesviruses such as HHV-6 might be involved in MS disease pathogenesis. Though findings across the field are non-uniform, an emerging consensus of viral correlates with disease course and evidence of HHV-6-specific immune responses in the CNS provide compelling evidence for a role, direct or indirect, of this virus in MS. Ultimately, the only way to demonstrate the involvement, or lack thereof, of HHV-6 or other herpesviruses in this disease is through a controlled clinical trial of an efficacious antiviral drug.

  • Recent developments in animal models for human herpesvirus 6A and 6B.
    Branka Horvat,Bradford K Berges,Paolo Lusso

    Progress in the identification of suitable animal models for human herpesvirus (HHV)-6A and HHV-6B infections has been slow. Recently, new models have been established, mainly for HHV-6A, which reproduce some pathological features seen in humans. Neuroinflammatory signs were observed in infected marmosets and CD46-transgenic mice; although viral replication was not prominent, persistence of viral DNA and specific immunologic responses were detected, suggesting an immune-mediated pathogenic mechanism. Pig-tailed macaques showed robust viral replication concomitant with acute-phase symptoms, and provided a model to study the effects of HHV-6A on AIDS progression. In humanized mice, viral replication was less evident, but infection led to T-cell alterations. Altogether, these recent developments have opened new perspectives for studying the pathogenic role of HHV-6A in humans.

  • Regulation of rotavirus polymerase activity by inner capsid proteins.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2014-09-23
    Chelsea L Gridley,John T Patton

    Rotavirus, a cause of pediatric gastroenteritis, has a genome consisting of 11 segments of double-stranded (ds)RNA surrounded by a triple-layered protein capsid. The rotavirus RNA-dependent RNA polymerase, VP1, synthesizes both dsRNA and plus-strand RNA (+RNA) within subviral particles. Structural analyses of the rotavirus capsid and polymerase, combined with functional studies of purified capsid proteins, indicate that the inner capsid protein controls the initiation of RNA synthesis by VP1. Whether VP1 directs dsRNA versus +RNA synthesis may be regulated by the impact of the viral RNA capping enzyme on the position of the polymerase plug, a flexible element that inserts into one of the polymerase's RNA exit tunnels. This review discusses recent findings and ideas into the mechanisms used by rotavirus capsid proteins to control the activities of its viral polymerase and to coordinate RNA synthesis with the assembly of virus particles.

  • Viral microRNA genomics and target validation.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2014-04-26
    Joseph M Ziegelbauer

    A subset of viruses express their own microRNAs (miRNAs) and one way to understand the functions of these microRNAs is to identify the targets of these miRNAs. Sequence analysis and mRNA expression profiling were some of the first techniques to identify targets of viral miRNAs. More recently, proteomics and sequencing of RNA by crosslinking and immunoprecipitation (CLIP) methods have been insightful and discovered many miRNA targets that may be missed using other methods. We are now at a point where numerous validated miRNA targets have been described and integration of these genomic datasets will provide a richer understanding of miRNA targeting and viral infection, persistence, and pathogenesis.

  • Emerging phleboviruses.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2014-03-13
    Richard M Elliott,Benjamin Brennan

    The Bunyavidae family is the largest grouping of RNA viruses and arguably the most diverse. Bunyaviruses have a truly global distribution and can infect vertebrates, invertebrates and plants. The majority of bunyaviruses are vectored by arthropods and thus have the remarkable capability to replicate in hosts of disparate phylogeny. The family has provided many examples of emerging viruses including Sin Nombre and related viruses responsible for hantavirus cardiopulmonary syndrome in the Americas, first identified in 1993, and Schmallenberg virus which emerged in Europe in 2011, causing foetal malformations in ruminants. In addition, some well-known bunyaviruses like Rift Valley fever and Crimean-Congo haemorrhagic fever viruses continue to emerge in new geographical locations. In this short review we focus on newly identified viruses associated with severe haemorrhagic disease in humans in China and the US.

  • A model for cofactor use during HIV-1 reverse transcription and nuclear entry.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2014-02-15
    Laura Hilditch,Greg J Towers

    Lentiviruses have evolved to infect and replicate in a variety of cell types in vivo whilst avoiding the powerful inhibitory activities of restriction factors or cell autonomous innate immune responses. In this review we offer our opinions on how HIV-1 uses a series of host proteins as cofactors for infection. We present a model that may explain how the capsid protein has a fundamental role in the early part of the viral lifecycle by utilising cyclophilin A (CypA), cleavage and polyadenylation specificity factor-6 (CPSF6), Nup358 and TNPO3 to orchestrate a coordinated process of DNA synthesis, capsid uncoating and integration targeting that evades innate responses and promotes integration into preferred areas of chromatin.

  • Concepts of papillomavirus entry into host cells.
    Patricia M Day,Mario Schelhaas

    Papillomaviruses enter basal cells of stratified epithelia. Assembly of new virions occurs in infected cells during terminal differentiation. This unique biology is reflected in the mechanism of entry. Extracellularly, the interaction of nonenveloped capsids with several host cell proteins, after binding, results in discrete conformational changes. Asynchronous internalization occurs over several hours by an endocytic mechanism related to, but distinct from macropinocytosis. Intracellular trafficking leads virions through the endosomal system, and from late endosomes to the trans-Golgi-network, before nuclear delivery. Here, we discuss the existing data with the aim to synthesize an integrated model of the stepwise process of entry, thereby highlighting key open questions. Additionally, we relate data from experiments with cultured cells to in vivo results.

  • 更新日期：2019-11-01
  • HIV accessory proteins versus host restriction factors.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2013-11-20
    Klaus Strebel

    Primate immunodeficiency viruses, including HIV-1, are characterized by the presence of accessory genes such as vif, vpr, vpx, vpu, and nef. Current knowledge indicates that none of the primate lentiviral accessory proteins has enzymatic activity. Instead, these proteins interact with cellular ligands to either act as adapter molecules to redirect the normal function of host factors for virus-specific purposes or to inhibit a normal host function by mediating degradation or causing intracellular mislocalization/sequestration of the factors involved. This review aims at providing an update of our current understanding of how Vif, Vpu, and Vpx control the cellular restriction factors APOBEC3G, BST-2, and SAMHD1, respectively.

  • Evolution of different antiviral strategies in wild mouse populations exposed to different gammaretroviruses.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2013-09-03
    Christine A Kozak

    Laboratory mice carry three host range groups of gammaretroviruses all of which are linked to leukemia induction. Although polytropic mouse leukemia viruses (P-MLVs) are generally recognized as the proximate cause of MLV-induced leukemias in laboratory mice, wild mice that carry only endogenous P-MLVs do not produce infectious virus and are not prone to disease; these mice carry the permissive XPR1 retroviral receptor and an attenuated variant of the retroviral restriction factor, APOBEC3. In contrast, Eurasian mice carrying ecotropic and xenotropic MLVs have evolved multiple restrictive XPR1 variants, other factors that interfere with MLV entry, and more effectively antiviral variants of APOBEC3. These different antiviral restrictions in Mus musculus subspecies suggest that the different virus types found in these natural populations may pose different but largely uncharacterized survival risks in their host subspecies.

  • The virus-receptor interaction in the replication of feline immunodeficiency virus (FIV).
    Brian J Willett,Margaret J Hosie

    The feline and human immunodeficiency viruses (FIV and HIV) target helper T cells selectively, and in doing so they induce a profound immune dysfunction. The primary determinant of HIV cell tropism is the expression pattern of the primary viral receptor CD4 and co-receptor(s), such as CXCR4 and CCR5. FIV employs a distinct strategy to target helper T cells; a high affinity interaction with CD134 (OX40) is followed by binding of the virus to its sole co-receptor, CXCR4. Recent studies have demonstrated that the way in which FIV interacts with its primary receptor, CD134, alters as infection progresses, changing the cell tropism of the virus. This review examines the contribution of the virus-receptor interaction to replication in vivo as well as the significance of these findings to the development of vaccines and therapeutics.

  • A virocentric perspective on the evolution of life.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2013-07-16
    Eugene V Koonin,Valerian V Dolja

    Viruses and/or virus-like selfish elements are associated with all cellular life forms and are the most abundant biological entities on Earth, with the number of virus particles in many environments exceeding the number of cells by one to two orders of magnitude. The genetic diversity of viruses is commensurately enormous and might substantially exceed the diversity of cellular organisms. Unlike cellular organisms with their uniform replication-expression scheme, viruses possess either RNA or DNA genomes and exploit all conceivable replication-expression strategies. Although viruses extensively exchange genes with their hosts, there exists a set of viral hallmark genes that are shared by extremely diverse groups of viruses to the exclusion of cellular life forms. Coevolution of viruses and host defense systems is a key aspect in the evolution of both viruses and cells, and viral genes are often recruited for cellular functions. Together with the fundamental inevitability of the emergence of genomic parasites in any evolving replicator system, these multiple lines of evidence reveal the central role of viruses in the entire evolution of life.

  • Impact of host and virus genome variability on HCV replication and response to interferon.
    Cameron J Schweitzer,T Jake Liang

    Since the discovery of hepatitis C virus (HCV), treatment has proven difficult and the regimen of pegylated interferon-α and ribavirin is only effective for half of patients. Evidence suggests that host and viral genome variations play a role in either viral clearance or persistence. Powerful genomic technologies have made it possible to study genome-wide associations with treatment response, which yielded critical genetic polymorphisms that predict treatment response. This has important implications for treatment of HCV infection and opened the door to the possibility of genetic marker-guided treatment (personalized medicine). This review will focus on the recent advances in understanding host and viral genetic variations with regards to treatment and the importance for future therapeutic intervention.

  • To dream the impossible dream: universal influenza vaccination.
    Jonathan W Yewdell

    Year in and year out, influenza viruses exact a deadly and expensive toll on humanity. Current vaccines simply do not keep pace with viral immune evasion, providing partial protection, at best, among various age groups. A quantum leap in understanding the basic principles of the adaptive and innate immune responses to influenza viruses offers the opportunity to develop vaccines that forestall, and potentially ultimately defeat, influenza virus antigenic variation.

  • Vaccines for viral hemorrhagic fevers--progress and shortcomings.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2013-06-19
    Darryl Falzarano,Heinz Feldmann

    With a few exceptions, vaccines for viruses that cause hemorrhagic fever remain unavailable or lack well-documented efficacy. In the past decade this has not been due to a lack of the ability to develop vaccine platforms against highly pathogenic viruses, but rather the lack of will/interest to invest in platforms that have the potential to become successful vaccines. The two exceptions to this are vaccines against Dengue virus (DENV) and Rift Valley fever virus (RVFV), which recently have seen significant progress in putting forward new and improved vaccines, respectively. Experimental vaccines for filoviruses and Lassa virus (LASV) do exist but are hindered by a lack of financial interest and only partially or ill-defined correlates/mechanisms of protection that could be assessed in clinical trials.

  • Animal models for highly pathogenic emerging viruses.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2013-02-14
    David Safronetz,Thomas W Geisbert,Heinz Feldmann

    Exotic and emerging viral pathogens associated with high morbidity and mortality in humans are being identified annually with recent examples including Lujo virus in southern Africa, Severe Fever with Thrombocytopenia Syndrome virus in China and a SARS-like coronavirus in the Middle East. The sporadic nature of these infections hampers our understanding of these diseases and limits the opportunities to design appropriate medical countermeasures against them. Because of this, animal models are utilized to gain insight into the pathogenesis of disease with the overall goal of identifying potential targets for intervention and evaluating specific therapeutics and vaccines. For these reasons it is imperative that animal models of disease recapitulate the human condition as closely as possible in order to provide the best predictive data with respect to the potential efficacy in humans. In this article we review the current status of disease models for highly pathogenic and emerging viral pathogens.

  • Virus entry--an unwilling collaboration by the cell.
    Ari Helenius,Bernard Moss

  • Flaviviruses: braking the entering.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2013-01-29
    Theodore C Pierson,Margaret Kielian

    Flaviviruses are small spherical virus particles covered by a dense icosahedral array of envelope (E) proteins that mediate virus attachment to cells and the fusion of viral and cellular membranes. Our understanding of the mechanism by which flavivirus E proteins orchestrate entry into cells has been advanced by studies of E structure and arrangement on the virion at different steps of the virus entry/membrane fusion process. When combined with an increasingly clear (albeit still incomplete) view of the cell biology of virus entry, these advances suggest new antiviral strategies. Indeed, inhibitors that target cellular and viral processes involved in entry show promise as powerful tools to study this critical step of the viral lifecycle, and with luck, may ultimately lead to therapeutic advances.

  • Recombinant origin, contamination, and de-discovery of XMRV.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2012-07-24
    Krista Delviks-Frankenberry,Oya Cingöz,John M Coffin,Vinay K Pathak

    The discovery and de-discovery of the xenotropic murine leukemia virus-related virus (XMRV) has been a tumultuous roller-coaster ride for scientists and patients. The initial associations of XMRV with chronic fatigue syndrome and prostate cancer, while providing much hope and optimism, have now been discredited and/or retracted following overwhelming evidence that (1) numerous patient cohorts from around the world are XMRV-negative, (2) the initial reports of XMRV-positive patients were due to contamination with mouse DNA, XMRV plasmid DNA, or virus from the 22Rv1 cell line and (3) XMRV is a laboratory-derived virus generated in the mid 1990s through recombination during passage of a prostate tumor xenograft in immuno-compromised mice. While these developments are disappointing to scientists and patients, they provide a valuable road map of potential pitfalls to the would-be microbe hunters.

  • Pathogenesis of acute respiratory illness caused by human parainfluenza viruses.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2012-06-20
    Henrick Schomacker,Anne Schaap-Nutt,Peter L Collins,Alexander C Schmidt

    Human parainfluenza viruses (HPIVs) are a common cause of acute respiratory illness throughout life. Infants, children, and the immunocompromised are the most likely to develop severe disease. HPIV1 and HPIV2 are best known to cause croup while HPIV3 is a common cause of bronchiolitis and pneumonia. HPIVs replicate productively in respiratory epithelial cells and do not spread systemically unless the host is severely immunocompromised. Molecular studies have delineated how HPIVs evade and block cellular innate immune responses to permit efficient replication, local spread, and host-to-host transmission. Studies using ex vivo human airway epithelium have focused on virus tropism, cellular pathology and the epithelial inflammatory response, elucidating how events early in infection shape the adaptive immune response and disease outcome.

  • Interactions among capsid proteins orchestrate rotavirus particle functions.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2012-05-19
    Shane D Trask,Kristen M Ogden,John T Patton

    Rotaviruses are members of the Reoviridae family of non-enveloped viruses and important etiologic agents of acute gastroenteritis in infants and young children. In recent years, high-resolution structures of triple-layered rotavirus virions and the constituent proteins have provided valuable insights into functions. Of note, structural studies have revealed the position of the viral RNA-dependent RNA polymerase, VP1, within the inner capsid, which in turn provides clues about the location of the viral capping machinery and the route of viral transcript egress. Mechanisms by which the viral spike protein, VP4, mediates receptor binding and membrane penetration have also been aided by high-resolution structural studies. Future work may serve to fill the remaining gaps in understanding of rotavirus particle structure and function.

  • Ebolavirus vaccines for humans and apes.
    Hugues Fausther-Bovendo,Sabue Mulangu,Nancy J Sullivan

    Because of high case fatality proportions, person-to-person transmission, and potential use in bioterrorism, the development of a vaccine against ebolavirus remains a top priority. Although no licensed vaccine or treatment against ebolavirus is currently available, progress in preclinical testing of countermeasures has been made. Here, we will review ebolavirus vaccine candidates and considerations for their use in humans and wild apes.

  • Degrees of maturity: the complex structure and biology of flaviviruses.
    Curr. Opin. Virol. (IF 5.400) Pub Date : 2012-03-27
    Theodore C Pierson,Michael S Diamond

    Flaviviruses are small enveloped virions that enter target cells in a pH-dependent fashion. Virus attachment, entry, and membrane fusion are orchestrated by the envelope (E) and pre-membrane (prM) proteins, the two structural proteins displayed on the surface of virions. Flaviviruses assemble as an immature non-infectious form onto which prM and E form trimeric spikes. During egress from infected cells, flaviviruses undergo dramatic structural changes characterized by the formation of a herringbone arrangement of E proteins that lie flat against the surface of the virion and cleavage of the prM protein by the cellular protease furin. The result is a relatively smooth, infectious mature virion. This dynamic process is now understood in structural detail at the atomic level. However, recent studies indicate that many of the virions released from cells share structural features of both immature and mature virus particles. These mosaic partially mature virions are infectious and interact uniquely with target cells and the host immune response. Here, we will discuss recent advances in our understanding of the biology and significance of partially mature flaviviruses.

  • The genome-linked protein VPg of vertebrate viruses - a multifaceted protein.
    Ian Goodfellow

    Several vertebrate positive-sense RNA viruses, namely the Picornaviridae and Caliciviridae have evolved to use a protein-primed mechanism of genome replication. This results in the covalent linkage of a virus encoded protein, VPg (viral protein genome-linked), to the 5' end of viral RNA. Recent studies have highlighted the pivotal role VPg plays in the life cycle of these viruses, which in the case of the Caliciviridae, includes a role in viral protein synthesis. This article provides an overview of the current knowledge of the functions of vertebrate RNA virus VPg proteins, illustrating their diverse function and the parallels they share with plant virus VPg proteins.

  • The direct passage of animal viruses between cells.
    Quentin J Sattentau

    The paradigm that viruses can move directly, and in some cases covertly, between contacting target cells is now well established for several virus families. The underlying mechanisms of cell-to-cell spread, however, remain to be fully elucidated and may differ substantially depending on the viral exit/entry route and the cellular tropism. Here, two divergent cell-to-cell spread mechanisms are exemplified: firstly by human retroviruses, which rely upon transient adhesive structures that form between polarized immune cells termed virological synapses, and secondly by herpesviruses that depend predominantly on pre-existing stable cellular contacts, but may also form virological synapses. Plant viruses can also spread directly between contacting cells, but are obliged by the rigid host cell wall to move across pore structures termed plasmodesmata. This review will focus primarily on recent advances in our understanding of animal virus cell-to-cell spread using examples from these two virus families, and will conclude by comparing and contrasting the cell-to-cell spread of animal and plant viruses.

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