Evolution of inflammation and immunity in a dengue virus 1 human infection model

Abstract

Dengue virus (DENV) infections are major causes of morbidity and mortality throughout the tropics and subtropics. More than 400 million infections are estimated to occur every year, resulting in nearly 100 million symptomatic infections and more than 20,000 deaths. Early immune response kinetics to infection remain unclear, in large part due to the variable incubation period exhibited by the DENVs after introduction into a susceptible host. To fill this knowledge gap, we performed a comprehensive virologic and immunologic analysis of individuals experimentally infected with the underattenuated DENV-1 strain 45AZ5. This analysis captured both the kinetics and composition of the innate, humoral, and cellular immune responses elicited by experimental DENV-1 infection, as well as virologic and clinical features. We observed a robust DENV-specific immunoglobulin A (IgA) antibody response that manifested between the appearance of DENV-specific IgM and IgG in all challenged individuals, as well as the presence of a non-neutralizing/NS1-specific antibody response that was delayed relative to the appearance of DENV virion–specific humoral immunity. RNA sequencing analysis revealed discrete and temporally restricted gene modules that correlated with acute viremia and the induction of adaptive immunity. Our analysis provides a detailed description, in time and space, of the evolving matrix of DENV-elicited human inflammation and immunity and reveals several previously unappreciated immunological aspects of primary DENV-1 infection that can inform countermeasure development and evaluation.

Blocking NS3–NS4B interaction inhibits dengue virus in non-human primates

“…Some of the main challenges for dengue therapeutics are the rapid decline in patient viraemia during the febrile phase and the hesitancy of patients to seek medical attention early on. As viraemia lasts for only around 1 week in the blood of an individual with DENV infection before it gets resolved by the immune system 39,40 , the treatment window is limited. Thus, early, rapid and sensitive diagnostics are indispensable to identify and treat patients early on during the critical treatment window so that the antiviral can exert its maximal effect 41 .…”

“…This suggests that such highly resistant mutants most likely do not occur naturally in the population. Considering that viraemia typically lasts for about 1 week, resulting in a short treatment period 39,40 , it can be assumed that such a short time frame may not allow for the selection of drug-resistant variants.…”

Subcapsular sinus macrophages maximize germinal center development in non-draining lymph nodes during blood-borne viral infection

“…For example, the nonstructural protein NS1 is secreted by infected cells and can reach serum concentrations of 1 to 2 μg/ml during human dengue virus infection (63,64). Both mice and humans develop strong anti-NS1 Ab responses during flavivirus infection (65)(66)(67). Our data suggest that macrophage infection in non-draining LNs can provide a local source of viral proteins like NS1 that are not included in virions.…”

TV005 dengue vaccine protects against dengue serotypes 2 and 3 in two controlled human infection studies

“…The opportunities for DENV CHIMs as an integrated component of global dengue vaccine development are still being realized. Additional dengue serotypes and strains from different viral backgrounds have been described (25,26,32,33); each model has distinct features, including various degrees of viral titer (viremia) and clinical signs and symptoms. Of particular interest are opportunities for vaccine CHIMs in dengue-endemic settings in which the documentation of efficacy in populations with varying degrees of baseline immunity would increase confidence before the large-scale introduction of dengue vaccines or phase III efficacy trials in new populations.…”