The PB2 Polymerase Host Adaptation Substitutions Prime Avian Indonesia Sub Clade 2.1 H5N1 Viruses for Infecting Humans.

Pui Wang,Siu-Ying Lau,Conor Cremin,Wenjun Song,Min Zheng,Pin Chen,Honglian Liu,Xiaofeng Huang,Bobo Mok,Honglin Chen,Siwen Liu

doi:10.3390/v11030292

Pui Wang, Siu-Ying Lau + Show 9 more

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https://doi.org/10.3390/v11030292

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Abstract

Significantly higher numbers of human infections with H5N1 virus have occurred in Indonesia and Egypt, compared with other affected areas, and it is speculated that there are specific viral factors for human infection with avian H5N1 viruses in these locations. We previously showed PB2-K526R is present in 80% of Indonesian H5N1 human isolates, which lack the more common PB2-E627K substitution. Testing the hypothesis that this mutation may prime avian H5N1 virus for human infection, we showed that: (1) K526R is rarely found in avian influenza viruses but was identified in H5N1 viruses 2–3 years after the virus emerged in Indonesia, coincident with the emergence of H5N1 human infections in Indonesia; (2) K526R is required for efficient replication of Indonesia H5N1 virus in mammalian cells in vitro and in vivo and reverse substitution to 526K in human isolates abolishes this ability; (3) Indonesian H5N1 virus, which contains K526R-PB2, is stable and does not further acquire E627K following replication in infected mice; and (4) virus containing K526R-PB2 shows no fitness deficit in avian species. These findings illustrate an important mechanism in which a host adaptive mutation that predisposes avian H5N1 virus towards infecting humans has arisen with the virus becoming prevalent in avian species prior to human infections occurring. A similar mechanism is observed in the Qinghai-lineage H5N1 viruses that have caused many human cases in Egypt; here, E627K predisposes towards human infections. Surveillance should focus on the detection of adaptation markers in avian strains that prime for human infection.

Highlights

Human infection with avian H5N1 subtype virus was first documented in Hong Kong in 1997, where it caused 18 infections and six deaths [1,2]
Apart from human cases infected with Qinghai-like viruses, which harbor 627K PB2 in avian species, and Indonesian viruses the later which rarely contain 627K PB2, about 30% of human isolates from rest of the affected areas mainly from China, Vietnam and Thailand contain 627K, with the E627K
While H5N1 virus was first detected in Indonesia in 2003, it is suggested that the first introduction may have occurred as early as 2002 [33]

Summary

Introduction

Human infection with avian H5N1 subtype virus was first documented in Hong Kong in 1997, where it caused 18 infections and six deaths [1,2]. Regional dissemination occurred subsequently and human infections with H5N1 have been identified in Southeast Asian countries, including Thailand, Vietnam, Laos and Indonesia, since 2003 [4]. Following a major outbreak in migratory wild birds at Lake Qinghai, China, in 2005, H5N1 virus spread further to Europe, Africa. According to a World Health Organization report, 860 human cases, including 454 deaths, have been confirmed in 16 countries between 2003 and July 2015 (http://www.who.int/influenza/). While human infections have been identified in several countries, two genetic variants of avian H5N1 virus have caused nearly 70% of all human infections; one, a descendant of the Qinghai-lineage virus (or subclade 2.2), is currently circulating in

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