Influenza A viruses have broad host tropism, being able to infect a range of hosts from wild fowl to swine to humans. This broad tropism makes highly pathogenic influenza A strains, such as H5N1, potentially dangerous to humans if they gain the ability to jump from an animal reservoir to humans. How influenza A viruses are able to jump the species barrier is incompletely understood due to the complex genetic nature of the viral surface glycoprotein, hemagglutinin, which mediates entry, combined with the virus's ability to use various receptor linkages. Current therapeutics against influenza A include those that target the uncoating process after entry as well as those that prevent viral budding. While there are therapeutics in development that target entry, currently there are none clinically available. We review here the genetics of influenza A viruses that contribute to entry tropism, how these genetic alterations may contribute to receptor usage and species tropism, as well as how novel therapeutics can be developed that target the major surface glycoprotein, hemagglutinin. 1. Introduction Influenza viruses belong to the Orthomyxoviridae family, which consists of several genera. The first includes both influenza A and B viruses, while another is comprised of influenza C virus [1]. These classifications are based on the distinct antigenic nature of the internal nucleoprotein and matrix proteins of each virus. Infection with influenza subtypes B and C is mostly restricted to humans [2, 3], while subtype A is able to infect a wide range of hosts including but not limited to humans, swine, horses, domestic and wild birds, fowl, and dogs [4–8]. This broad spectrum of hosts plays a pivotal role in the ability of the virus to reassort, mutate, and spread, all of which contribute to the ever-present global threat of influenza. Influenza A virus poses the most serious hazard of the three subtypes, causing global economic losses as well as severe health concerns. Influenza A virus is the causative agent of severe respiratory illness infecting nearly 15% of the world’s population with upwards of 250,00–500,000 deaths estimated by the World Health Organization. Infections are characterized by upper respiratory distress along with high fever, myalgia, headache and severe malaise, nonproductive cough, sore throat, and rhinitis. Severe illness and death are mainly associated with the young, elderly, and those with compromised immune systems [2]. Influenza viruses have ravaged human and poultry populations around the world for centuries, causing serious illness and
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