Abstract
Influenza A viruses (IAV) can infect a broad range of animal hosts, including humans. In humans, IAV causes seasonal annual epidemics and occasional pandemics, representing a serious public health and economic problem, which is most effectively prevented through vaccination. The defense mechanisms that the host innate immune system provides restrict IAV replication and infection. Consequently, to successfully replicate in interferon (IFN)-competent systems, IAV has to counteract host antiviral activities, mainly the production of IFN and the activities of IFN-induced host proteins that inhibit virus replication. The IAV multifunctional proteins PA-X and NS1 are virulence factors that modulate the innate immune response and virus pathogenicity. Notably, these two viral proteins have synergistic effects in the inhibition of host protein synthesis in infected cells, although using different mechanisms of action. Moreover, the control of innate immune responses by the IAV NS1 and PA-X proteins is subject to a balance that can determine virus pathogenesis and fitness, and recent evidence shows co-evolution of these proteins in seasonal viruses, indicating that they should be monitored for enhanced virulence. Importantly, inhibition of host gene expression by the influenza NS1 and/or PA-X proteins could be explored to develop improved live-attenuated influenza vaccines (LAIV) by modulating the ability of the virus to counteract antiviral host responses. Likewise, both viral proteins represent a reasonable target for the development of new antivirals for the control of IAV infections. In this review, we summarize the role of IAV NS1 and PA-X in controlling the antiviral response during viral infection.
Highlights
We have described that recombinant live-attenuated influenza vaccines (LAIV) pH1N1 viruses encoding Non-Structural 1 (NS1) and PA-X proteins that simultaneously inhibit or do not inhibit host gene expression are impaired in viral growth properties in cultured cells, correlating with virus attenuation in vivo, in comparison to recombinant pH1N1 viruses in which only one of the viral proteins (NS1 or PA-X) inhibited host gene expression [174] (Table 3)
In order to replicate in the host, Influenza A Virus (IAV) encode two viral proteins, NS1 and PA-X, that have developed distinct mechanisms to counteract innate immune responses and the antiviral state produced in the infected and neighboring cells [60,70,160]
One synergistic mechanism used by IAV NS1 and PA-X proteins to counteract the immune response consists in their ability to block host protein synthesis, using different mechanisms [70,74,155,160,161]
Summary
IAV are members of the Orthomyxoviridae family of enveloped viruses, which contain an eight-segmented, single-stranded (ss), negative-sense RNA genome [1]. IAV can infect multiple hosts, including birds, pigs, dogs, horses, bats, and humans [2,3,4,5] These viruses undergo reassortment in wild hosts, leading to the emergence of novel strains with epidemic or pandemic potential in humans. The first IAV pandemic in the 21st century started in 2009 with the emergence of a quadruple-reassortant swine-origin H1N1 IAV (pH1N1) [15,16], which, in less than one year, infected more than 600,000 individuals around the world, this number is likely underestimated This virus is efficiently transmitted among humans and continues circulating seasonally [12,17,18]. Organization (WHO) [7,19], leading to a significant worldwide economic impact
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