Annual Review of Virology - Volume 6, 2019

The human T cell leukemia virus persists in vivo in 10³ to 10⁶ clones of T lymphocytes that appear to survive for the lifetime of the host. The plus strand of the provirus is typically transcriptionally silent in freshly isolated lymphocytes, but the strong, persistently activated cytotoxic T lymphocyte (CTL) response to the viral antigens indicates that the virus is not constantly latent in vivo. There is now evidence that the plus strand is transcribed in intense intermittent bursts that are triggered by cellular stress, modulated by hypoxia and glycolysis, and inhibited by polycomb repressive complex 1 (PRC1). The minus-strand gene hbz is transcribed at a lower, more constant level but is silent in a proportion of infected cells at a given time. Viral genes in the sense and antisense strands of the provirus play different respective roles in latency and de novo infection: Expression of the plus-strand gene tax is essential for de novo infection, whereas hbz appears to facilitate survival of the infected T cell clone in vivo.

Viral diseases provide a major challenge to twenty-first century agriculture worldwide. Climate change and human population pressures are driving rapid alterations in agricultural practices and cropping systems that favor destructive viral disease outbreaks. Such outbreaks are strikingly apparent in subsistence agriculture in food-insecure regions. Agricultural globalization and international trade are spreading viruses and their vectors to new geographical regions with unexpected consequences for food production and natural ecosystems. Due to the varying epidemiological characteristics of diverent viral pathosystems, there is no one-size-fits-all approach toward mitigating negative viral disease impacts on diverse agroecological production systems. Advances in scientific understanding of virus pathosystems, rapid technological innovation, innovative communication strategies, and global scientific networks provide opportunities to build epidemiologic intelligence of virus threats to crop production and global food security. A paradigm shift toward deploying integrated, smart, and eco-friendly strategies is required to advance virus disease management in diverse agricultural cropping systems.

Viruses constitute the largest group of emerging pathogens, and geminiviruses (plant viruses with circular, single-stranded DNA genomes) are the major group of emerging plant viruses. With their high potential for genetic variation due to mutation and recombination, their efficient spread by vectors, and their wide host range as a group, including both wild and cultivated hosts, geminiviruses are attractive models for the study of the evolutionary and ecological factors driving virus emergence. Studies on the epidemiological features of geminivirus diseases have traditionally focused primarily on crop plants. Nevertheless, knowledge of geminivirus infection in wild plants, and especially at the interface between wild and cultivated plants, is necessary to provide a complete view of their ecology, evolution, and emergence. In this review, we address the most relevant aspects of geminivirus variability and evolution in wild and crop plants and geminiviruses’ potential to emerge in crops.

Since its discovery in 1976, Ebola virus (EBOV) has caused numerous outbreaks of fatal hemorrhagic disease in Africa. The biggest outbreak on record is the 2013–2016 epidemic in west Africa with almost 30,000 cases and over 11,000 fatalities, devastatingly affecting Guinea, Liberia, and Sierra Leone. The epidemic highlighted the need for licensed drugs or vaccines to quickly combat the disease. While at the beginning of the epidemic no licensed countermeasures were available, several experimental drugs with preclinical efficacy were accelerated into human clinical trials and used to treat patients with Ebola virus disease (EVD) toward the end of the epidemic. In the same manner, vaccines with preclinical efficacy were administered primarily to known contacts of EVD patients on clinical trial protocols using a ring-vaccination strategy. In this review, we describe the pathogenesis of EBOV and summarize the current status of EBOV vaccine development and treatment of EVD.

The circulation of Zika virus (ZIKV) in nearly 80 countries and territories poses a significant global threat to public health. ZIKV is causally linked to severe developmental defects in the brain, recognized as congenital Zika syndrome (CZS), which includes microcephaly and other serious congenital neurological complications. Since the World Health Organization declared the ZIKV outbreak a public health emergency of international concern, remarkable progress has been made in the generation of different ZIKV infection animal models to gain insight into cellular targets and pathogenesis and to explore the associated underlying mechanisms. Here we focus on summarizing our current understanding of the effects of ZIKV on mammalian brain development in different developmental stages and discuss the potential underlying mechanisms of ZIKV-induced CZS, as well as future perspectives.

Zika virus (ZIKV) and nonhuman primates have been inextricably linked since the virus was first discovered in a sentinel rhesus macaque in Uganda in 1947. Soon after ZIKV was epidemiologically associated with birth defects in Brazil late in 2015, researchers capitalized on the fact that rhesus macaques are commonly used to model viral immunity and pathogenesis, quickly establishing macaque models for ZIKV infection. Within months, the susceptibility of pregnant macaques to experimental ZIKV challenge and ZIKV-associated abnormalities in fetuses was confirmed. This review discusses key unanswered questions in ZIKV immunity and in the pathogenesis of thecongenital Zika virus syndrome. We focus on those questions that can be best addressed in pregnant nonhuman primates and lessons learned from developing macaque models for ZIKV amid an active epidemic.

Viruses are causative agents for many diseases and infect all living organisms on the planet. Development of effective therapies has relied on our ability to isolate and culture viruses in vitro, allowing mechanistic studies and strategic interventions. While this reductionist approach is necessary, testing the relevance of in vitro findings often takes a very long time. New developments in imaging technologies are transforming our experimental approach where viral pathogenesis can be studied in vivo at multiple spatial and temporal resolutions. Here, we outline a vision of a top-down approach using noninvasive whole-body imaging as a guide for in-depth characterization of key tissues, physiologically relevant cell types, and pathways of spread to elucidate mechanisms of virus spread and pathogenesis. Tool development toward imaging of infectious diseases is expected to transform clinical diagnosis and treatment.

Genetic alleles that contribute to enhanced susceptibility or resistance to viral infections and virally induced diseases have often been first identified in mice before humans due to the significant advantages of the murine system for genetic studies. Herein we review multiple discoveries that have revealed significant insights into virus-host interactions, all made using genetic mapping tools in mice. Factors that have been identified include innate and adaptive immunity genes that contribute to host defense against pathogenic viruses such as herpes viruses, flaviviruses, retroviruses, and coronaviruses. Understanding the genetic mechanisms that affect infectious disease outcomes will aid the development of personalized treatment and preventive strategies for pathogenic infections.

Defective viral genomes (DVGs) are generated during viral replication and are unable to carry out a full replication cycle unless coinfected with a full-length virus. DVGs are produced by many viruses, and their presence correlates with alterations in infection outcomes. Historically, DVGs were studied for their ability to interfere with standard virus replication as well as for their association with viral persistence. More recently, a critical role for DVGs in inducing the innate immune response during infection was appreciated. Here we review the role of DVGs of RNA viruses in shaping outcomes of experimental as well as natural infections and explore the mechanisms by which DVGs impact infection outcome.

In the absence of an intact interferon (IFN) response, mammals may be susceptible to lethal viral infection. IFNs are secreted cytokines that activate a signal transduction cascade leading to the induction of hundreds of interferon-stimulated genes (ISGs). Remarkably, approximately 10% of the genes in the human genome have the potential to be regulated by IFNs. What do all of these genes do? It is a complex question without a simple answer. From decades of research, we know that many of the protein products encoded by these ISGs work alone or in concert to achieve one or more cellular outcomes, including antiviral defense, antiproliferative activities, and stimulation of adaptive immunity. The focus of this review is the antiviral activities of the IFN/ISG system. This includes general paradigms of ISG function, supported by specific examples in the literature, as well as methodologies to identify and characterize ISG function.

Autism is a developmental disability that can cause significant social, communication, and behavioral challenges. A report published in 1998, but subsequently retracted by the journal, suggested that measles, mumps, and rubella (MMR) vaccine causes autism. However, autism is a neurodevelopmental condition that has a strong genetic component with genesis before one year of age, when MMR vaccine is typically administered. Several epidemiologic studies have not found an association between MMR vaccination and autism, including a study that found that MMR vaccine was not associated with an increased risk of autism even among high-risk children whose older siblings had autism. Despite strong evidence of its safety, some parents are still hesitant to accept MMR vaccination of their children. Decreasing acceptance of MMR vaccination has led to outbreaks or resurgence of measles. Health-care providers have a vital role in maintaining confidence in vaccination and preventing suffering, disability, and death from measles and other vaccine-preventable diseases.

The recent market approvals of recombinant adeno-associated virus (rAAV) gene therapies in Europe and the United States are landmark achievements in the history of modern science. These approvals are also anticipated to herald the emergence of a new class of therapies for monogenic disorders, which had hitherto been considered untreatable. These events can be viewed as stemming from the convergence of several important historical trends: the study of basic virology, the development of genomic technologies, the imperative for translational impact of National Institutes of Health–funded research, and the development of economic models for commercialization of rare disease therapies. In this review, these historical trends are described and the key developments that have enabled clinical rAAV gene therapies are discussed, along with an overview of the current state of the field and future directions.