SummaryAedes aegypti mosquitoes are responsible for transmitting many medically important viruses such as those that cause Zika and dengue. The inoculation of viruses into mosquito bite sites is an important and common stage of all mosquito-borne virus infections. We show, using Semliki Forest virus and Bunyamwera virus, that these viruses use this inflammatory niche to aid their replication and dissemination in vivo. Mosquito bites were characterized by an edema that retained virus at the inoculation site and an inflammatory influx of neutrophils that coordinated a localized innate immune program that inadvertently facilitated virus infection by encouraging the entry and infection of virus-permissive myeloid cells. Neutrophil depletion and therapeutic blockade of inflammasome activity suppressed inflammation and abrogated the ability of the bite to promote infection. This study identifies facets of mosquito bite inflammation that are important determinants of the subsequent systemic course and clinical outcome of virus infection.

Mosquito-borne infections are increasing in number and are spreading to new regions at an unprecedented rate. In particular, mosquito-transmitted viruses, such as those that cause Zika, dengue, West Nile encephalitis, and chikungunya, have become endemic or have caused dramatic epidemics in many parts of the world. Aedes and Culex mosquitoes are the main culprits, spreading infection when they bite. Importantly, mosquitoes do not act as simple conduits that passively transfer virus from one individual to another. Instead, host responses to mosquito-derived factors have an important influence on infection and disease, aiding replication and dissemination within the host. Here, we discuss the latest research developments regarding this fascinating interplay between mosquito, virus, and the mammalian host.

Several large studies in Europe and the USA revealed that approximately 10% of all newly diagnosed patients harbour HIV-1 variants with at least one major resistance-associated mutation. In this review we discuss the underlying mechanisms that drive the evolution of drug-resistant viruses after transmission to the new host. In a comprehensive literature search 12 papers describing the evolution of 58 cases of transmitted resistant HIV-1 variants were found. Based on observations in the literature we propose three pathways describing the evolution of resistant HIV-1 after transmission to a new host. Firstly, reversion of the resistance mutation towards wild-type may rapidly occur when drug resistance mutations severely impact replicative capacity. Alternatively, a second pathway involves replacement of transmitted drug resistance mutations by atypical amino acids that also improve viral replication capacity. In the third evolutionary pathway the resistance mutations persist either because they do not significantly affect viral replication capacity or evolution is constrained by fixation through compensatory mutations. In the near future ultra-sensitive resistance tests may provide more insight into the presence of archived and minority variants and their clinical relevance. Meanwhile, clinical guidelines advise population sequence analysis of the baseline plasma sample to identify transmission of resistance. Given the limited sensitivity of this technique for minority populations and the delay between the moment of infection and time of analysis, knowledge of the described evolutionary mechanisms of transmitted drug resistance patterns is essential for clinical management and public health strategies.

The encephalitic response to viral infection requires local chemokine production and the ensuing recruitment of immune and inflammatory leukocytes. Accordingly, chemokine receptors present themselves as plausible therapeutic targets for drugs aimed at limiting encephalitic responses. However, it remains unclear which chemokines are central to this process and whether leukocyte recruitment is important for limiting viral proliferation and survival in the brain or whether it is predominantly a driver of coincident inflammatory pathogenesis. Here we examine chemokine expression and leukocyte recruitment in the context of avirulent and virulent Semliki Forest virus (SFV) as well as West Nile virus infection and demonstrate rapid and robust expression of a variety of inflammatory CC and CXC chemokines in all models. On this basis, we define a chemokine axis involved in leukocyte recruitment to the encephalitic brain during SFV infection. CXCR3 is the most active; CCR2 is also active but less so, and CCR5 plays only a modest role in leukocyte recruitment. Importantly, inhibition of each of these receptors individually and the resulting suppression of leukocyte recruitment to the infected brain have no effect on viral titer or survival following infection with a virulent SFV strain. In contrast, simultaneous blockade of CXCR3 and CCR2 results in significantly reduced mortality in response to virulent SFV infection. In summary, therefore, our data provide an unprecedented level of insight into chemokine orchestration of leukocyte recruitment in viral encephalitis. Our data also highlight CXCR3 and CCR2 as possible therapeutic targets for limiting inflammatory damage in response to viral infection of the brain. IMPORTANCEBrain inflammation (encephalitis) in response to viral infection can lead to severe illness and even death. This therefore represents an important clinical problem and one that requires the development of new therapeutic approaches. Central to the pathogenesis of encephalitis is the recruitment of inflammatory leukocytes to the infected brain, a process driven by members of the chemokine family. Here we provide an in-depth analysis of the chemokines involved in leukocyte recruitment to the virally infected brain and demonstrate that simultaneous blockade of two of these receptors, namely, CXCR3 and CCR2, does not alter viral titers within the brain but markedly reduces inflammatory leukocyte recruitment and enhances survival in a murine model of lethal viral encephalitis. Our results therefore highlight chemokine receptors as plausible therapeutic targets in treating viral encephalitis.