Temperature Sensitive Mutations in Influenza A Viral Ribonucleoprotein Complex Responsible for the Attenuation of the Live Attenuated Influenza Vaccine

Abstract

Live attenuated influenza vaccines (LAIV) have prevented morbidity and mortality associated with influenza viral infections for many years and represent the best therapeutic option to protect against influenza viral infections in humans. However, the development of LAIV has traditionally relied on empirical methods, such as the adaptation of viruses to replicate at low temperatures. These approaches require an extensive investment of time and resources before identifying potential vaccine candidates that can be safely implemented as LAIV to protect humans. In addition, the mechanism of attenuation of these vaccines is poorly understood in some cases. Importantly, LAIV are more efficacious than inactivated vaccines because their ability to mount efficient innate and adaptive humoral and cellular immune responses. Therefore, the design of potential LAIV based on known properties of viral proteins appears to be a highly appropriate option for the treatment of influenza viral infections. For that, the viral RNA synthesis machinery has been a research focus to identify key amino acid substitutions that can lead to viral attenuation and their use in safe, immunogenic, and protective LAIV. In this review, we discuss the potential to manipulate the influenza viral RNA-dependent RNA polymerase (RdRp) complex to generate attenuated forms of the virus that can be used as LAIV for the treatment of influenza viral infections, one of the current and most effective prophylactic options for the control of influenza in humans.

Functional Characterization and Direct Comparison of Influenza A, B, C, and D NS1 Proteins in vitro and in vivo

“…Influenza viruses belong to the Orthomyxoviridae family and are enveloped viruses which contain a segmented genome of singlestranded RNA molecules of negative polarity (Wright et al, 2007;Nogales and Martinez-Sobrido, 2016;Martinez-Sobrido et al, 2018;Blanco-Lobo et al, 2019). Currently, there are four recognized influenza virus types: A, B, C, and D (IAV, IBV, ICV, and IDV, respectively) (Wright et al, 2007;Chen and Holmes, 2008;Wanitchang et al, 2012;Tong et al, 2013;Baker et al, 2014;Yoon et al, 2014;Hengrung et al, 2015;Matsuzaki et al, 2016;Wang et al, 2016;Foni et al, 2017;Nogales et al, 2017c;Su et al, 2017;Nakatsu et al, 2018;Asha and Kumar, 2019;Zhang et al, 2019).…”

“…IAV and IBV contain eight genomic viral (v)RNA segments (Wright et al, 2007), and two major glycoproteins in the virion surface, the hemagglutinin (HA) and neuraminidase (NA), which are responsible for viral binding and release, respectively, of the virus from infected cells (Wright et al, 2007). Moreover, HA and NA glycoproteins are also the major antigenic determinants of IAV and IBV and they are used to further classify them in subtypes (IAV) or lineages (IBV) (Martinez-Sobrido et al, 2018;Blanco-Lobo et al, 2019). IAV have a broad species tropism, infecting multiple avian and mammalian species, including humans (Parrish et al, 2015;Mostafa et al, 2018;Long et al, 2019), while IBV are primarily limited to infect humans (Osterhaus et al, 2000;Chen and Holmes, 2008;Piepenbrink et al, 2019).…”

Host Single Nucleotide Polymorphisms Modulating Influenza A Virus Disease in Humans

“…Moreover, the packaging signals playing a role in the efficient encapsidation of the viral segments into nascent virions, are located at the 3 and 5 end of the coding regions ( Figure 1B) [1]. Structurally, vRNAs form viral ribonucleoprotein complexes (vRNPs), where vRNAs are coated with multiple subunits of the viral nucleoprotein (NP) and are associated with the heterotrimeric polymerase, which contains the polymerase basic 2 and 1 (PB2 and PB1, respectively) and acidic (PA) proteins ( Figure 1A) [2][3][4]. Each vRNP acts as an independent transcription-replication unit using an uncommon mechanism among negative-sense RNA viruses, given that viral RNA synthesis occurs in the infected-cells nucleus.…”

“…Each vRNP acts as an independent transcription-replication unit using an uncommon mechanism among negative-sense RNA viruses, given that viral RNA synthesis occurs in the infected-cells nucleus. vRNAs are used as templates by the viral polymerase to synthesize two positive-sense RNA molecules, the complementary RNAs (cRNAs), from which the same viral polymerase synthesizes more copies of genomic vRNA, and the mRNAs for viral protein synthesis [1][2][3][4][5][6]. The small IAV genome encodes for up to 16 viral proteins through The ion channel M2 (red) protein is also located in the membrane.…”

A Luciferase-fluorescent Reporter Influenza Virus for Live Imaging and Quantification of Viral Infection

“…Influenza A virus (IAV) is an enveloped single-stranded negative-sense segmented RNA virus of the Orthomyxoviridae family 1,2,3 . The World Health Organization (WHO) estimates 3-5 million annual influenza cases and over 250,000 deaths from influenza worldwide 4,5,6 .…”