The central nervous system (CNS) necessitates intricately coordinated immune responses to prevent neurological disease. However, the emergence of viruses capable of entering the CNS and infecting neurons threatens this delicate balance. Our CNS is protected from foreign invaders and excess solutes by a semipermeable barrier of endothelial cells called the blood–brain barrier. Thereby, viruses have implemented several strategies to bypass this protective layer and modulate immune responses within the CNS. In this review, we outline these immune regulatory mechanisms and provide perspectives on future questions in this rapidly expanding field.

Hepatitis C virus (HCV) assembly and envelopment are coordinated by a complex protein interaction network that includes most of the viral structural and nonstructural proteins. While the nonstructural protein 4A (NS4A) is known to be important for viral particle production, the specific function of NS4A in this process is not well understood. We performed mutagenesis of the C-terminal acidic domain of NS4A and found that mutation of several of these amino acids prevented the formation of the viral envelope, and therefore the production of infectious virions, without affecting viral RNA replication. In an overexpression system, we found that NS4A interacted with several viral proteins known to coordinate envelopment, including the viral E1 glycoprotein. One of the NS4A C-terminal mutations, Y45F, disrupted the interaction of NS4A with E1. Specifically, NS4A interacted with the first hydrophobic region of E1, a region previously described as regulating viral particle production. Indeed, we found that an E1 mutation in this region, D72A, also disrupted the interaction of NS4A with E1. Supernatants from HCV NS4A Y45F transfected cells had significantly reduced levels of HCV RNA, however they contained equivalent levels of Core protein. Interestingly, the Core protein secreted from these cells formed high order oligomers with a density matching the infectious virus secreted from wild-type cells. These results suggest that this Y45F mutation in NS4A causes secretion of low-density Core particles lacking genomic HCV RNA. These results corroborate previous findings showing that the E1 D72A mutation also causes secretion of Core complexes lacking genomic HCV RNA, and therefore suggest that the interaction between NS4A and E1 is involved in the incorporation of viral RNA into infectious HCV particles. Our findings define a new role for NS4A in the HCV lifecycle and help elucidate the protein interactions necessary for production of infectious virus. RNA viruses, which encompass both established and emerging pathogens, pose significant public health challenges. Viruses in the family Flaviviridae, including Dengue virus, Zika virus, and hepatitis C virus (HCV), continue to cause morbidity and mortality worldwide. One HCV protein, NS4A, acts in several steps of the viral lifecycle; however, how it contributes to viral particle production is not understood. Here, we investigated the role of one region of NS4A, the C-terminal acidic domain, in regulating the viral lifecycle. We found that amino acids within this domain are important for viral envelopment and the production infectious particles, specifically through interaction with the E1 glycoprotein. NS4A interacts with the first hydrophobic domain of E1. Disruption of this interaction, by either mutation of E1 or NS4A, prevents the production of infectious virus particles and instead results in release of low-density Core protein complexes that lack HCV RNA into the cellular supernatant. Overall, our results reveal that NS4A is important for late stages of the HCV lifecycle and suggest that the interaction between NS4A and E1 may regulate the incorporation of viral RNA into the virion for the formation of infectious HCV particles.

Viruses and hosts must navigate environments in which each tries to outcompete the other for survival or to coexist within the same spaces. In Lewis Carrol’s Through the Looking Glass, the Red Queen tells Alice, “Now, here, you see, it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that!” Borrowing from this idea, the Red Queen hypothesis asserts that organisms, such as viruses, must continuously adapt to environmental pressures to survive. In this commentary, we draw parallels between the Red Queen hypothesis and the experiences scientists of color navigate to thrive in academic spaces. In both phenomena, adapting to environmental pressures is necessary for survival. We identify the various pressures and bottlenecks faced by historically underrepresented groups in academia, as well as the adaptation strategies they must implement to persist in academia.