This review describes the diverse array of pathways and molecular targets that are used by viruses to elude immune detection and destruction. These include targeting of pathways for major histocompatibility complex-restricted antigen presentation, apoptosis, cytokine-mediated signaling, and humoral immune responses. The continuous interactions between host and pathogens during their coevolution have shaped the immune system, but also the counter measures used by pathogens. Further study of their interactions should improve our ability to manipulate and exploit the various pathogens.

One antibody for all and all antibodies for one: Antibodies against related flavi-viruses such as dengue (DENV) and West Nile (WNV) can cross-react with Zika virus (ZIKV) and could thereby increase disease severity. Bardina et al. tested whether DENV and WNV antibodies from humans, or even yellow fever vaccination, could enhance ZIKV infection. In a mouse model, low titers of DENV and WNV antibodies enhanced ZIKV viremia, especially in the spinal cord and testes, whereas high titers remained protective. Generally, WNV antibodies were less disease-enhancing than DENV antibodies, and, in macaques, yellow fever vaccination had very little effect. Science , this issue p. 175

The proteasome is a multicatalytic protease complex that plays a key role in diverse cellular functions. The peptide vinyl sulfone, carboxybenzyl-leucyl-leucyl-leucine vinyl sulfone (Z-L₃VS) covalently inhibits the trypsin-like, chymotrypsin-like and, unlike lactacystin, also the peptidylglutamyl peptidase activity in isolated proteasomes, and blocks their function in living cells. Although described as a class of mechanism-based inhibitors for cysteine proteases, the peptide vinyl sulfone Z-L₃VS and a¹²⁵I-labeled nitrophenol derivative (¹²⁵I-NIP-L₃VS) covalently modify the active site threonine of the catalytic β subunits of the proteasome. Modification of Thermoplasma proteasomes demonstrates the requirement for a hydroxyl amino acid (threonine, serine) as nucleophile at the β subunit’s NH₂terminus.¹²⁵I-NIP-L₃VS covalently modifies the HslV subunit of theEscherichia coliprotease complex HslV/HslU, a reaction that requires ATP, and supports a catalytic mechanism shared with that of the eukaryotic proteasome.

ISG15 is an interferon (IFN)-α/β-induced ubiquitin-like protein. It exists as a free molecule, intracellularly and extracellularly, and conjugated to target proteins. Studies in mice have demonstrated a role for Isg15 in antiviral immunity. By contrast, human ISG15 was shown to have critical immune functions, but not in antiviral immunity. Namely, free extracellular ISG15 is crucial in IFN-γ-dependent antimycobacterial immunity, while free intracellular ISG15 is crucial for USP18-mediated downregulation of IFN-α/β signalling. Here we describe ISG15-deficient patients who display no enhanced susceptibility to viruses in vivo, in stark contrast to Isg15-deficient mice. Furthermore, fibroblasts derived from ISG15-deficient patients display enhanced antiviral protection, and expression of ISG15 attenuates viral resistance to WT control levels. The species-specific gain-of-function in antiviral immunity observed in ISG15 deficiency is explained by the requirement of ISG15 to sustain USP18 levels in humans, a mechanism not operating in mice.

Antigenic variation promotes neutralizing antibodies to both seasonal and pandemic influenza A strains in humans.