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HBV covalently closed circular DNA (cccDNA) enables and persists in chronic infection, but the molecular mechanism of its formation is unclear. Here, Wei and Ploss elucidate the detailed kinetics and biochemical steps by which the relaxed circular DNA is converted into cccDNA.

The human genome includes a large amount of repetitive sequence, such as human satellite II (HSATII), but their function remains largely unknown. Here, Nogalski et al. show that herpesvirus infection induces HSATII RNA expression, which in turn affects virus replication and cell motility.

The entire hepatitis C virus life cycle can be recapitulated in an inbred mouse model, allowing preclinical assessment of antiviral therapeutics and vaccines.

Amino acid changes in the envelope and non-structural 2A protein attenuate the virulent yellow fever virus (YFV) and enhance host antiviral responses upon infection in vivo. These traits explain the potency of the YFV vaccine.

Hepatitis B virus is an almost uniquely human-tropic pathogen for which model systems are scarce. Here, the authors determine key residues within the HBV receptor that form a barrier in the HBV life cycle in primates and identify marmosets as a model candidate for infection with simian-tropic HBV.

The replication of hepatitis B virus involves the formation of covalently closed circular DNA (cccDNA), which relies on a set of undefined host factors. Here, the authors use a cell-free system to reconstitute cccDNA formation and identify the minimal set of host factors required, which are components of the lagging-DNA-strand replication machinery.

Analysis of virus replication on a single-cell level is often hampered by a lack of specific or sensitive enough reagents. Here, Douamet al. use RNA-flow technique to track (+) and (−) strand RNA of yellow fever virus in hematopoietic cells in mouse models and identify virus-host interactions that affect disease outcome.

The lack of models that mimic hepatitis B virus (HBV) infection in a physiologically relevant context has hampered drug development. Here, Winer et al. establish a self-assembling, primary hepatocyte co-culture system that can be infected with patient-derived HBV without further modifications.

This report identifies the gap junction protein occludin as the fourth and final key component of the hepatitis C virus cell-entry receptor, paving the way towards the development of a small animal model for hepatitis C virus.

In this study, the authors identify genetic insertions in the population of hepatitis E virus analyzed in serum samples of a patient with ribavirin treatment failure. They show that these genomic rearrangements promote viral replication without affecting ribavirin sensitivity.

Humanized mice are an enabling technology to explore human immunity and disease. Here, Douam et al. provide an in-depth comparison of immune responses to yellow fever vaccine in human vaccinees, conventional and second-generation humanized mice and define a workflow to evaluate and refine these models.

Here, Biswas et al. present and characterize a second-generation model of HBV infection in rhesus macaques, showing that extended infection requires suppression of host immunity.

Patagia—the mammalian gliding membrane—repeatedly originated through a process of convergent genomic evolution, whereby the regulation of Emx2 was altered by distinct cis-regulatory elements in independently evolved species.

Combining transcriptomics, mathematical modelling and in vivo gene editing, this study shows that Sfrp2 contributes to stripe formation and hair colour in the African striped mouse.

Pierre Guermonprez and colleagues have worked out how a subset of dendritic cells expands in individuals with severe malaria. Plasmodium infection causes an accumulation of xanthine in infected red blood cells. The researchers found that type I interferon triggers an increase in the enzyme that metabolizes xanthine to uric acid. Uric acid then acts on mast cells to release Flt3 ligand, an important regulator of dendritic cells, which in turn stimulate T cells to respond to the infection.

Hepatitis E virus (HEV) is a public health concern in both developing and developed countries. Here, the authors describe advances in understanding HEV biology, clinical infection and the challenges still to be overcome in HEV research, particularly with respect to cell culture and animal models.

Passive immunotherapy with a combination of neutralizing monoclonal antibodies is shown to be effective in suppressing HIV replication in a humanized mouse model.

Hepatitis C virus research is hampered by the inability to detect individual infected cells. Jones et al. achieve this by imaging the translocation of a fluorescent reporter protein after cleavage by a viral protease in living or fixed cells.

The new entry inhibitor eCD4-Ig, consisting of the immunoadhesin form of CD4 (CD4-Ig) fused to a small CCR5-mimetic sulfopeptide, avidly binds two highly conserved sites of the HIV-1 Env protein; the inhibitor has high potency and breadth and can neutralize 100% of a diverse panel of neutralization-resistant HIV-1 viruses, and when delivered to macaques using an adeno-associated virus vector, it can provide effective long-term protection from multiple challenges with simian/human immunodeficiency virus.

This Review highlights some of the advances that have been made towards understanding the complexity of differential interferon (IFN) signalling inputs and outputs as well as some of the strategies viruses use to interfere with or circumvent IFN-induced antiviral responses.