FLU VIRUS RNP COMPLEX

Baylor College Of Medicine, Houston TX

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Influenza is a major public health concern each year, and influenza A virus can cause widespread pandemics with high mortality rates. Currently, there are grave concerns that the avian H5N1 influenza A virus, which has spread from Asia to Europe and Africa, may gain the ability to be transmitted efficiently between humans, resulting in a worldwide pandemic that could claim a large number of human lives. For better prevention and treatment of human influenza virus infections, it is critical that we obtain a comprehensive understanding of the basic molecular biology of influenza viruses. Influenza viruses are a group of negative-strand (-) RNA viruses that transcribe and replicate their viral RNAs in the cell nucleus. Like other (-)-strand RNA viruses, the segmented genome of influenza A viruses, eight segments in total, is encapsidated in the form of ribonucleoprotein (RNP) complexes. The nucleoprotein (NP), the major protein component of RNPs, binds along the entire length of each genomic RNA segment, forming the double-helical RNP structures found in mature virus. The viral polymerase, consisting of PA, PB1, and PB2 subunits, is bound to the two RNA termini of the RNP. As one of the most abundant proteins made in infected cells, influenza virus NP has essential roles in many important viral processes, including intracellular trafficking of viral genome, viral RNA replication, and the assembly and packaging of viral genome in progeny viruses. The crystal structure of influenza A virus NP has recently been determined in our laboratory [1]. Organized as trimers in the crystal, NP folds into a two-domain structure with a topology completely different from that of the rhabdovirus NP (Fig. 2). A short tail loop, consisting of residues 402 to 428, is likely to play an important role in NP oligomerization, as single-residue mutation in this region causes a total loss of oligomerization. A large positively charged groove was identified at the exterior of the NP trimer at the interface between the two domains. An external RNA binding site indicates that RNA is likely to be exposed in the influenza virus RNPs, different from the situation in non-segmented RNA viruses [2]. This structural difference explains previous results that showed fundamental differences between influenza RNPs and the RNPs of non-segmented (-)-strand RNA viruses like VSV and rabies virus. For example, the viral RNA in influenza virus RNPs is digested by RNase treatment, whereas the viral RNA in the RNPs of parainfluenza viruses and rhabdoviruses is completely resistant to RNase digestion [3-5]. In addition, polyvinylsufate (PVS), a negatively charged polymer, is able to completely displace RNA from influenza virus RNP, whereas it has no effect on RNPs from VSV [6].