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The SARS-CoV-2 pandemic and its unprecedented global societal and economic disruptive impact has marked the third zoonotic introduction of a highly pathogenic coronavirus into the human population. Although the previous coronavirus SARS-CoV and MERS-CoV epidemics raised awareness of the need for clinically available therapeutic or preventive interventions, to date, no treatments with proven efficacy are available. The development of effective intervention strategies relies on the knowledge of molecular and cellular mechanisms of coronavirus infections, which highlights the significance of studying virus–host interactions at the molecular level to identify targets for antiviral intervention and to elucidate critical viral and host determinants that are decisive for the development of severe disease. In this Review, we summarize the first discoveries that shape our current understanding of SARS-CoV-2 infection throughout the intracellular viral life cycle and relate that to our knowledge of coronavirus biology. The elucidation of similarities and differences between SARS-CoV-2 and other coronaviruses will support future preparedness and strategies to combat coronavirus infections.In this Review, Thiel and colleagues discuss the key aspects of coronavirus biology and their implications for SARS-CoV-2 infections as well as for treatment and prevention strategies.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an unprecedented global health crisis. However, therapeutic options for treatment are still very limited. The development of drugs that target vital proteins in the viral life cycle is a feasible approach for treating COVID-19. Belonging to the subfamily Orthocoronavirinae with the largest RNA genome, SARS-CoV-2 encodes a total of 29 proteins. These non-structural, structural and accessory proteins participate in entry into host cells, genome replication and transcription, and viral assembly and release. SARS-CoV-2 proteins can individually perform essential physiological roles, be components of the viral replication machinery or interact with numerous host cellular factors. In this Review, we delineate the structural features of SARS-CoV-2 from the whole viral particle to the individual viral proteins and discuss their functions as well as their potential as targets for therapeutic interventions.Elucidating the structure and function of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins is vital for understanding the molecular mechanisms of viral replication and COVID-19 pathogenesis, and could lead to the development of novel therapeutics. In this Review, Yang and Rao delineate the structural features of SARS-CoV-2 from the whole viral particle to the individual viral proteins and discuss their functions as well as their potential as targets for therapeutic interventions.

Phages differ substantially in the bacterial hosts that they infect. Their host range is determined by the specific structures that they use to target bacterial cells. Tailed phages use a broad range of receptor-binding proteins, such as tail fibres, tail spikes and the central tail spike, to target their cognate bacterial cell surface receptors. Recent technical advances and new structure–function insights have begun to unravel the molecular mechanisms and temporal dynamics that govern these interactions. Here, we review the current understanding of the targeting machinery and mechanisms of tailed phages. These new insights and approaches pave the way for the application of phages in medicine and biotechnology and enable deeper understanding of their ecology and evolution.

Herpesviruses are ubiquitous, double-stranded DNA, enveloped viruses that establish lifelong infections and cause a range of diseases. Entry into host cells requires binding of the virus to specific receptors, followed by the coordinated action of multiple viral entry glycoproteins to trigger membrane fusion. Although the core fusion machinery is conserved for all herpesviruses, each species uses distinct receptors and receptor-binding glycoproteins. Structural studies of the prototypical herpesviruses herpes simplex virus 1 (HSV-1), HSV-2, human cytomegalovirus (HCMV) and Epstein–Barr virus (EBV) entry glycoproteins have defined the interaction sites for glycoprotein complexes and receptors, and have revealed conformational changes that occur on receptor binding. Recent crystallography and electron microscopy studies have refined our model of herpesvirus entry into cells, clarifying both the conserved features and the unique features. In this Review, we discuss recent insights into herpesvirus entry by analysing the structures of entry glycoproteins, including the diverse receptor-binding glycoproteins (HSV-1 glycoprotein D (gD), EBV glycoprotein 42 (gp42) and HCMV gH–gL–gO trimer and gH–gL–UL128–UL130–UL131A pentamer), as well gH–gL and the fusion protein gB, which are conserved in all herpesviruses.Recent crystallography and electron microscopy studies have refined our model of herpesvirus entry into cells. In this Review, Connolly, Jardetzky and Longnecker discuss recent insights into herpesvirus entry by analysing the structures of entry glycoproteins, including the diverse receptor-binding glycoproteins and conserved fusion proteins.

The envelope spike (S) proteins of MERS-CoV and SARS-CoV determine the virus host tropism and entry into host cells, and constitute a promising target for the development of prophylactics and therapeutics. Here, we present high-resolution structures of the trimeric MERS-CoV and SARS-CoV S proteins in its pre-fusion conformation by single particle cryo-electron microscopy. The overall structures resemble that from other coronaviruses including HKU1, MHV and NL63 reported recently, with the exception of the receptor binding domain (RBD). We captured two states of the RBD with receptor binding region either buried (lying state) or exposed (standing state), demonstrating an inherently flexible RBD readily recognized by the receptor. Further sequence conservation analysis of six human-infecting coronaviruses revealed that the fusion peptide, HR1 region and the central helix are potential targets for eliciting broadly neutralizing antibodies. Host tropism and cell entry of pathogenic coronaviruses are mediated by their envelope spike (S) proteins. Here the authors present structural analyses of trimeric MERS-CoV and SARS-CoV S proteins in pre-fusion conformation, and reveal two states of the receptor binding domain that suggest new avenues for the generation of neutralizing antibodies.

SARS-CoV-2 carries the largest single-stranded RNA genome and is the causal pathogen of the ongoing COVID-19 pandemic. How the SARS-CoV-2 RNA genome is folded in the virion remains unknown. To fill the knowledge gap and facilitate structure-based drug development, we develop a virion RNA in situ conformation sequencing technology, named vRIC-seq, for probing viral RNA genome structure unbiasedly. Using vRIC-seq data, we reconstruct the tertiary structure of the SARS-CoV-2 genome and reveal a surprisingly “unentangled globule” conformation. We uncover many long-range duplexes and higher-order junctions, both of which are under purifying selections and contribute to the sequential package of the SARS-CoV-2 genome. Unexpectedly, the D614G and the other two accompanying mutations may remodel duplexes into more stable forms. Lastly, the structure-guided design of potent small interfering RNAs can obliterate the SARS-CoV-2 in Vero cells. Overall, our work provides a framework for studying the genome structure, function, and dynamics of emerging deadly RNA viruses. Secondary structures and long-range RNA interactions of the SARS-CoV-2 genome have been investigated by various sequencing methods. Here the authors use an RNA-RNA hybrid sequencing method to predict the secondary and tertiary structure of the SRAS-CoV-2 RNA genome in the virion.

Key Points The HIV-1 Gag polyprotein precursor is necessary and sufficient for the formation of virus-like particles in Gag-expressing cells. Gag contains domains that are required for virus assembly and release: the matrix (MA) domain directs Gag to the plasma membrane and promotes the incorporation of the viral envelope (Env) glycoproteins; the capsid (CA) domain drives Gag–Gag interactions during assembly; the nucleocapsid (NC) domain packages the viral genomic RNA; and the p6 domain is required for efficient particle release. HIV-1 recruits several host factors to promote virus assembly and release. For example, the endosomal sorting complex required for transport (ESCRT) machinery is recruited by the p6 domain of Gag to mediate the pinching off of virus particles from the cell. Shortly after virus release from the cell, the viral protease cleaves the Gag precursor into the mature Gag proteins MA, CA, NC and p6. Gag processing is a highly ordered multistep sequential process that triggers the morphological rearrangement of viral protein structure, which is known as maturation. The Gag protein has been the focus of drug discovery efforts aimed at developing inhibitors that are distinct from those targeting the viral enzymes protease, reverse transcriptase and integrase. Of particular promise are small-molecule inhibitors of capsid function, and maturation inhibitors, which target a late step in Gag processing. In this article, Eric Freed reviews recent progress in elucidating the steps involved in HIV-1 assembly, release and maturation, highlighting how these events are orchestrated by the viral Gag precursor protein and how this information is being used to develop novel anti-HIV-1 therapeutics. Major advances have occurred in recent years in our understanding of HIV-1 assembly, release and maturation, as work in this field has been propelled forwards by developments in imaging technology, structural biology, and cell and molecular biology. This increase in basic knowledge is being applied to the development of novel inhibitors designed to target various aspects of virus assembly and maturation. This Review highlights recent progress in elucidating the late stages of the HIV-1 replication cycle and the related interplay between virology, cell and molecular biology, and drug discovery.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease in young children and elderly people. Although the virus was isolated in 1955, an effective RSV vaccine has not been developed, and the only licensed intervention is passive immunoprophylaxis of high-risk infants with a humanized monoclonal antibody. During the past 5 years, however, there has been substantial progress in our understanding of the structure and function of the RSV glycoproteins and their interactions with host cell factors that mediate entry. This period has coincided with renewed interest in developing effective interventions, including the isolation of potent monoclonal antibodies and small molecules and the design of novel vaccine candidates. In this Review, we summarize the recent findings that have begun to elucidate RSV entry mechanisms, describe progress on the development of new interventions and conclude with a perspective on gaps in our knowledge that require further investigation.Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease in young children and elderly people. In this Review, Battles and McLellan summarize our current understanding of RSV entry, describe progress on the development of new interventions and conclude with a perspective on gaps in our knowledge that require further investigation.

Key Points In a mature, infectious HIV-1 virion, the viral genome is housed within a conical capsid core made up of the viral capsid (CA) protein. During infection, the CA protein interacts with several cellular factors to enable efficient HIV-1 genome replication, timely core disassembly, nuclear import and the integration of the viral genome into the genome of the target cell. Several models of capsid core uncoating have been proposed, including immediate uncoating, cytoplasmic uncoating and uncoating at nuclear pores. The first model suggests that the HIV-1 capsid core dissociates almost immediately on viral entry; the second is a model of gradual uncoating as the virus travels through the cytoplasm until it reaches the nucleus; and the final model suggests that an intact capsid core reaches the nuclear pore complexes (NPCs). These models may not be mutually exclusive and could depend on the type of cell infected and its status of activation. Both viral and cellular factors are important for regulating viral uncoating. For example, the activity of viral integrase has been shown to affect the stability of the viral capsid core. The stability of the capsid core is also influenced by interactions between CA and the host protein cyclophilin A and microtubule motor proteins, such as dynein and kinesin-1. The viral capsid also influences nuclear import via interactions with host proteins, such as cleavage and polyadenylation specificity factor 6 (CPSF6), transportin 3 (TNPO3) and proteins that are part of NPCs. Understanding the viral uncoating process and the role of CA during infection will enable the design of new therapeutic strategies against HIV-1, including the development of compounds that affect the stability of the capsid core. In this Review, Campbell and Hope describe the interactions between the HIV-1 capsid core and several cellular factors that enable efficient HIV-1 genome replication, timely core disassembly, nuclear import and viral integration into the genome of the target cell. In a mature, infectious HIV-1 virion, the viral genome is housed within a conical capsid core made from the viral capsid (CA) protein. The CA protein and the structure into which it assembles facilitate virtually every step of infection through a series of interactions with multiple host cell factors. This Review describes our understanding of the interactions between the viral capsid core and several cellular factors that enable efficient HIV-1 genome replication, timely core disassembly, nuclear import and the integration of the viral genome into the genome of the target cell. We then discuss how elucidating these interactions can reveal new targets for therapeutic interactions against HIV-1.

Traditionally, the viral replication cycle is envisioned as a single, well-defined loop with four major steps: attachment and entry into a target cell, replication of the viral genome, maturation of viral proteins and genome packaging into infectious progeny, and egress and dissemination to the next target cell. However, for many viruses, a growing body of evidence points towards extreme heterogeneity in each of these steps. In this Review, we reassess the major steps of the viral replication cycle by highlighting recent advances that show considerable variability during viral infection. First, we discuss heterogeneity in entry receptors, followed by a discussion on error-prone and low-fidelity polymerases and their impact on viral diversity. Next, we cover the implications of heterogeneity in genome packaging and assembly on virion morphology. Last, we explore alternative egress mechanisms, including tunnelling nanotubes and host microvesicles. In summary, we discuss the implications of viral phenotypic, morphological and genetic heterogeneity on pathogenesis and medicine. This Review highlights common themes and unique features that give nuance to the viral replication cycle.The textbook view of the viral life cycle depicts uniform, discrete steps. However, growing evidence shows considerable phenotypic and morphological heterogeneity during viral infection. In this Review, Lakdawala and colleagues highlight host and viral heterogeneity and its causes and consequences.