Current opinion in virology最新文献

In the last few decades, several mosquito-borne arboviruses of zoonotic origin have established large-scale epidemic transmission cycles in the human population. It is often considered that arbovirus emergence is driven by adaptive evolution, such as virus adaptation for transmission by ‘domestic’ mosquito vector species that live in close association with humans. Here, I argue that although arbovirus adaptation to domestic mosquito vectors has been observed for several emerging arboviruses, it was generally not directly responsible for their initial emergence. Secondary adaptation to domestic mosquitoes often amplified epidemic transmission, however, this was more likely a consequence than a cause of arbovirus emergence. Considering that emerging arboviruses are generally ‘preadapted’ for transmission by domestic mosquito vectors may help to enhance preparedness toward future arbovirus emergence events.

Cytomegaloviruses (CMVs) are typically disseminated by cell-to-cell transfer, which requires reprogramming of cellular signaling pathways and restructuring of the cell architecture. Viral particles not only transfer genetic information between cells, but also tegument proteins that enable the virus to counteract cellular defense mechanisms immediately upon entering cells. The UL25 gene family of CMVs encodes such tegument proteins and also gives rise to related nonstructural proteins expressed early in infection. Herein, we report on the functions attributed to UL25 family members of several β-herpesviruses, particularly to the M25 proteins of mouse CMV that were found to interfere with the antiviral role of the p53 tumor suppressor protein and to mediate cytoskeleton rearrangement of infected cells.

Viral-associated cancers are a distinct group of malignancies with a unique pathogenesis and epidemiology. Liquid biopsy is a minimally invasive way to identify tumor-associated abnormalities in blood derivatives, such as plasma, to guide the diagnosis, prognosis, and treatment of patients with cancer. Liquid biopsy encompasses a multitude of circulating analytes with the most extensively studied being cell-free DNA (cfDNA). In recent decades, substantial advances have been made toward the study of circulating tumor DNA in nonviral-associated cancers. Many of these observations have been translated to the clinic to improve the outcomes of patients with cancer. The study of cfDNA in viral-associated cancers is rapidly evolving and reveals tremendous potential for clinical applications. This review provides an overview of the pathogenesis of viral-associated malignancies, the current state of cfDNA analysis in oncology, the current state of cfDNA analysis in viral-associated cancers, and perspectives for the future of liquid biopsies in viral-associated cancers.

Hepatitis C virus (HCV) is a hepatotropic virus that establishes a chronic infection in most individuals. Effective treatments are available; however, many patients are not aware of their infection. Consequently, they do not receive treatment and HCV transmission remains high, particularly among groups at high risk of exposure such as people who inject intravenous drugs. A prophylactic vaccine may reduce HCV transmission, but is currently not available. HCV has evolved immune evasion strategies, which facilitate persistence and complicate development of a protective vaccine. The peculiar association of HCV particles with human lipoproteins is thought to facilitate evasion from humoral immune response and viral homing to liver cells. A better understanding of these aspects provides the basis for development of protective vaccination strategies. Here, we review key information about the composition of HCV particles, the mechanisms mediating lipoprotein incorporation, and the functional consequences of this interaction.

Many flaviviruses are well-known pathogens, such as dengue, Zika, Japanese encephalitis, and yellow fever viruses. Among them, dengue viruses cause global epidemics and threaten billions of people. Effective vaccines and antivirals are in desperate need. In this review, we focus on the recent advances in understanding viral nonstructural (NS) proteins as antiviral drug targets. We briefly summarize the experimental structures and predicted models of flaviviral NS proteins and their functions. We highlight a few well-characterized inhibitors targeting these NS proteins and provide an update about the latest development. NS4B emerges as one of the most promising drug targets as novel inhibitors targeting NS4B and its interaction network are entering clinical studies. Studies aiming to elucidate the architecture and molecular basis of viral replication will offer new opportunities for novel antiviral discovery. Direct-acting agents against dengue and other pathogenic flaviviruses may be available very soon.

Despite decades of suppressive antiretroviral therapy, human immunodeficiency virus (HIV) reservoirs in infected individuals persist and fuel viral rebound once therapy is interrupted. The persistence of viral reservoirs is the main obstacle to achieving HIV eradication or a long-term remission. The last decade has seen a profound change in our understanding of the mechanisms behind HIV persistence, which appears to be much more complex than originally assumed. In addition to the persistence of transcriptionally silent proviruses in a stable latent reservoir that is invisible to the immune system, HIV is increasingly recognized to persist by resistance to the immune clearance, which appears to play a surprisingly prominent role in shaping the reservoir. In this review, we discuss some emerging insights into the mechanisms of HIV persistence, as well as their implications for the development of strategies towards an HIV cure.

Viral RNAs (vRNAs) are decorated by post-transcriptional modifications, including methylation of nucleotides. Methylations regulate biological functions linked to the sequence, structure, and protein interactome of RNA. Several RNA viruses were found to harbor 2′-O-methylations, affecting the ribose moiety of RNA. This mark was initially shown to target the first and second nucleotides of the 5′-end cap structure of mRNA. More recently, nucleotides within vRNA were also reported to carry 2′-O-methylations. The consequences of such methylations are still puzzling since they were associated with both proviral and antiviral effects. Here, we focus on the mechanisms governing vRNA 2′-O-methylation and we explore the possible roles of this epitranscriptomic modification for viral replication.

Acute hyperinflammatory virus infections, such as influenza or coronavirus disease-19, are still a major health burden worldwide. In these diseases, a massive overproduction of pro-inflammatory cytokines and chemokines (cytokine storm syndrome) determine the severity of the disease, especially in late stages. Direct-acting antivirals against these pathogens have to be administered very early after infection to be effective and may induce viral resistance. Here, we summarize data on a host-targeted strategy using inhibitors of the cellular Raf/MEK/ERK kinase cascade that not only block replication of different RNA viruses but also suppress the hyperinflammatory cytokine response upon infection. In the first phase-II clinical trial of that approach, the MEK inhibitor Zapnometinib shows evidence of clinical benefit.

While receptor binding is well recognized as a factor in influenza-A virus (IAV) and coronavirus (CoV) host adaptation, the role of viral glycoprotein cleavage has not been studied in detail so far. Interestingly, recent studies suggest that host species may differ in their protease repertoire available for cleavage. Furthermore, it was shown for certain bat-derived CoVs that proteolytic activation provides a critical barrier to infect human cells. Understanding the role of glycoprotein cleavage in different species and how IAV and CoVs adapt to a new protease repertoire may allow evaluating the zoonotic potential and risk posed by these viruses. Here, we summarize the current knowledge on the emergence of a multibasic cleavage site (CS) in the glycoproteins of IAVs and CoVs in different host species. Additionally, we discuss the role of transmembrane serine protease 2 (TMPRSS2) in virus activation and entry and a role of neuropilin-1 in acquisition of a multibasic CS in different hosts.

Multi-drug-resistant bacteria are associated with significantly higher morbidity and mortality. The possibilities for discovering new antibiotics are limited, but phage therapy — the use of bacteriophages (viruses infecting bacteria) to cure infections — is now being investigated as an alternative or complementary treatment to antibiotics. However, one of the major limitations of this approach lies in the antagonistic coevolution between bacteria and bacteriophages, which determines the ultimate success or failure of phage therapy. Here, we review the possible influence of the animal host on phage resistance and its consequences for the efficacy of phage therapy. We also discuss the value of in vitro assays for anticipating the dynamics of phage resistance observed in vivo.