Influenza A viruses (IAVs)
Influenza A viruses (IAVs) pose a major threat to the human population, contributing to over 36,000 deaths each year in the United States alone. The Hensley laboratory uses basic virology and immunology techniques to understand how seasonal IAVs escape pre-existing immune responses.
In particular the laboratory is interested in how seasonal influenza changes from year-to-year, as proteins on the surface of the virus accumulate mutations, a phenomena known as antigenic drift. Since antigenic drift is often unpredictable, one goal of the Hensley laboratory is to create a universal flu vaccine that will essentially attack viral coat proteins in places that cannot be easily mutated.
There are three primary research efforts in the Hensley Laboratory:
- Mechanisms of IAV antigenic drift
- Characterization of IAV antibody responses
- Development of a broadly-neutralizing IAV vaccine based on the induction of anti-fusion antibodies
Antigenic drift of IAVs is driven by the accumulation of mutations in the viral surface proteins hemagglutinin (HA) and neuraminidase (NA). Revisiting a mouse model of antigenic drift established in the 1950’s, Hensley found that IAV rapidly accumulates HA mutations that increase the virus’s ability to bind to cell surface receptors – a necessary step before infection – when confronted with antibodies. Importantly and surprisingly, many receptor-modulating mutations are located in antigenic sites of HA, in many cases at a considerable distance from the defined receptor binding pocket. Therefore, a major driving force of IAV antigenic drift is likely related to how the virus interacts with cellular receptors rather than how the virus interacts with individual antibodies.
The Hensley laboratory will focus on additional aspects of viral fitness that may impact antigenic drift of IAVs, and will continue using the mouse model to study the evolution of other viruses. It will be pivotal to study gastroenteritis-promoting Norwalk viruses, which similar to IAV, are constantly mutating at antigenic sites while utilizing many different molecules for viral attachment. It will also be informative to analyze other viruses that do not undergo extensive amounts of antigenic drift, such as parainfluenza viruses, which are a common cause of lower respiratory tract disease. Ultimately, a better understanding of the mechanisms of antigenic drift will lead to the development of monitoring systems that can better predict viral strains with epidemic potential.
During IAV infection, the B cells of the human immune system primarily produce antibodies against HA, NA, and nucleoprotein (NP).
The Hensley laboratory is building several tools that may determine the fine specificity of IAV-specific B cell responses. These assays include ELISA-based competition assays and FACs-based binding assays that quantify site specific antibody responses in sera, as well as other FACs-based assays that identify IAV-specific B cells at the single cell level. These new assays can begin to address many basic questions. How diverse is the IAV antibody response? Do IAV antibody responses vary greatly in specificity between individuals? Can antigenic drift be accelerated in individuals with limited antibody responses? These assays can also be used to evaluate the types of antibodies that are induced by novel vaccine platforms which is the basis of the laboratory’s third major area of focus as outlined below.
It is necessary to start the process of manufacturing vaccines well before the arrival of seasonal IAV. Unfortunately, due to antigenic drift, the chosen vaccine strain is not necessarily the IAV strain that dominates during the flu season. That is why the Hensley laboratory takes part in the Wistar Vaccine Center’s efforts to create a universal influenza vaccine, an IAV vaccine that induces the immune system to make broadly-neutralizing antibodies against the virus.
During natural IAV infection some antibodies are elicited against the conserved regions of HA and a small subset of these antibodies can inhibit the fusion step of viral entry, which is a critical component of the viral lifecycle. An IAV vaccine that induces fusion-inhibiting antibodies is particularly attractive since these antibodies bind to sections of the protein that generally do not mutate. However, it is difficult to elicit antibodies against these regions of the HA because they are hidden until the virus enters the cell. The Hensley laboratory is focusing on making a vaccine where these conserved components are freely exposed to the immune system.