Virulence and Genetic Compatibility of Polymerase Reassortant Viruses Derived from the Pandemic (H1N1) 2009 Influenza Virus and Circulating Influenza A Viruses

ABSTRACTWe have previously shown that 11 patients became naturally coinfected with seasonal H1N1 (A/H1N1) and pandemic H1N1 (pdm/H1N1) during the Southern hemisphere winter of 2009 in New Zealand. Reassortment of influenza A viruses is readily observed during coinfection of host animals andin vitro; however, reports of reassortment occurring naturally in humans are rare. Using clinical specimen material, we show reassortment between the two coinfecting viruses occurred with high likelihood directly in one of the previously identified patients. Despite the lack of spread of these reassortants in the community, we did not find them to be attenuated in several model systems for viral replication and virus transmission: multistep growth curves in differentiated human bronchial epithelial cells revealed no growth deficiency in six recovered reassortants compared to A/H1N1 and pdm/H1N1 isolates. Two reassortant viruses were assessed in ferrets and showed transmission to aerosol contacts. This study demonstrates that influenza virus reassortants can arise in naturally coinfected patients.IMPORTANCEReassortment of influenza A viruses is an important driver of virus evolution, but little has been done to address humans as hosts for the generation of novel influenza viruses. We show here that multiple reassortant viruses were generated during natural coinfection of a patient with pandemic H1N1 (2009) and seasonal H1N1 influenza A viruses. Though apparently fit in model systems, these reassortants did not become established in the wider population, presumably due to herd immunity against their seasonal H1 antigen.

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Early findings of oseltamivir-resistant pandemic (H1N1) 2009 influenza A viruses in Taiwan

Antiviral Research ◽

10.1016/j.antiviral.2010.09.014 ◽

2010 ◽

Vol 88 (3) ◽

pp. 256-262 ◽

Cited By ~ 22

Author(s):

Ji-Rong Yang ◽

Yuan-Pin Huang ◽

Yu-Cheng Lin ◽

Chun-Hui Su ◽

Chuan-Yi Kuo ◽

...

Keyword(s):

Influenza A ◽

Pandemic H1n1 ◽

Influenza A Viruses ◽

Pandemic H1n1 2009

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Cross-Reactive Neuraminidase-Inhibiting Antibodies Elicited by Immunization with Recombinant Neuraminidase Proteins of H5N1 and Pandemic H1N1 Influenza A Viruses

Journal of Virology ◽

10.1128/jvi.00585-15 ◽

2015 ◽

Vol 89 (14) ◽

pp. 7224-7234 ◽

Cited By ~ 31

Author(s):

Wen-Chun Liu ◽

Chia-Ying Lin ◽

Yung-Ta Tsou ◽

Jia-Tsrong Jan ◽

Suh-Chin Wu

Keyword(s):

Influenza Virus ◽

Sialic Acid ◽

Influenza Vaccine ◽

Influenza A ◽

Expression System ◽

Influenza Viruses ◽

Pandemic H1n1 ◽

Influenza A Viruses ◽

Homologous Virus ◽

Universal Influenza Vaccine

ABSTRACTNeuraminidase (NA), an influenza virus envelope glycoprotein, removes sialic acid from receptors for virus release from infected cells. For this study, we used a baculovirus-insect cell expression system to construct and purify recombinant NA (rNA) proteins of H5N1 (A/Vietnam/1203/2004) and pandemic H1N1 (pH1N1) (A/Texas/05/2009) influenza viruses. BALB/c mice immunized with these proteins had high titers of NA-specific IgG and NA-inhibiting (NI) antibodies against H5N1, pH1N1, H3N2, and H7N9 viruses. H5N1 rNA immunization resulted in higher quantities of NA-specific antibody-secreting B cells against H5N1 and heterologous pH1N1 viruses in the spleen. H5N1 rNA and pH1N1 rNA immunizations both provided complete protection against homologous virus challenges, with H5N1 rNA immunization providing better protection against pH1N1 virus challenges. Cross-reactive NI antibodies were further dissected via pH1N1 rNA protein immunizations with I149V (NA with a change of Ile to Val at position 149), N344Y, and I365T/S366N NA mutations. The I365T/S366N mutation of pH1N1 rNA enhanced cross-reactive NI antibodies against H5N1, H3N2, and H7N9 viruses. It is our hope that these findings provide useful information for the development of an NA-based universal influenza vaccine.IMPORTANCENeuraminidase (NA) is an influenza virus enzymatic protein that cleaves sialic acid linkages on infected cell surfaces, thus facilitating viral release and contributing to viral transmission and mucus infection. In currently available inactivated or live, attenuated influenza vaccines based on the antigenic content of hemagglutinin proteins, vaccine efficacy can be contributed partly through NA-elicited immune responses. We investigated the NA immunity of different recombinant NA (rNA) proteins associated with pH1N1 and H5N1 viruses. Our results indicate that H5N1 rNA immunization induced more potent cross-protective immunity than pH1N1 rNA immunization, and three mutated residues, I149V, I365T, and S366N, near the NA enzyme active site(s) are linked to enhanced cross-reactive NA-inhibiting antibodies against heterologous and heterosubtypic influenza A viruses. These findings provide useful information for the development of an NA-based universal influenza vaccine.

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Cross-reactive CD8+T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1007270107 ◽

2010 ◽

Vol 107 (28) ◽

pp. 12599-12604 ◽

Cited By ~ 119

Author(s):

Stephanie Gras ◽

Lukasz Kedzierski ◽

Sophie A. Valkenburg ◽

Karen Laurie ◽

Yu Chih Liu ◽

...

Keyword(s):

T Cell ◽

Influenza A ◽

Cd8 T Cell ◽

T Cell Immunity ◽

Pandemic H1n1 ◽

Influenza A Viruses ◽

Cell Immunity ◽

Pandemic H1n1 2009 ◽

1918 Influenza

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Virulence of pandemic (H1N1) 2009 influenza A polymerase reassortant viruses

Virulence ◽

10.4161/viru.2.5.17267 ◽

2011 ◽

Vol 2 (5) ◽

pp. 422-426 ◽

Cited By ~ 5

Author(s):

Min-Suk Song ◽

Philippe Noriel Q. Pascua ◽

Young Ki Choi

Keyword(s):

Influenza A ◽

Pandemic H1n1 ◽

Pandemic H1n1 2009 ◽

Reassortant Viruses

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Validation of commercial real-time RT-PCR kits for detection of influenza A viruses in porcine samples and differentiation of pandemic (H1N1) 2009 virus in pigs

Journal of Virological Methods ◽

10.1016/j.jviromet.2010.11.007 ◽

2011 ◽

Vol 171 (1) ◽

pp. 241-247 ◽

Cited By ~ 11

Author(s):

Françoise Pol ◽

Stéphane Quéguiner ◽

Stéphane Gorin ◽

Céline Deblanc ◽

Gaëlle Simon

Keyword(s):

Real Time ◽

Influenza A ◽

Pandemic H1n1 ◽

Rt Pcr ◽

Influenza A Viruses ◽

Pandemic H1n1 2009

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Cross-Reactive Neutralizing Antibodies Directed against Pandemic H1N1 2009 Virus Are Protective in a Highly Sensitive DBA/2 Mouse Influenza Model

Journal of Virology ◽

10.1128/jvi.02444-09 ◽

2010 ◽

Vol 84 (15) ◽

pp. 7662-7667 ◽

Cited By ~ 52

Author(s):

Adrianus C. M. Boon ◽

Jennifer deBeauchamp ◽

Scott Krauss ◽

Adam Rubrum ◽

Ashley D. Webb ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Influenza A ◽

Influenza Pandemic ◽

Small Animal ◽

High Dose ◽

Suitable Model ◽

Pandemic H1n1 ◽

Influenza A Viruses ◽

Pandemic H1n1 2009

ABSTRACT Our ability to rapidly respond to an emerging influenza pandemic is hampered somewhat by the lack of a susceptible small-animal model. To develop a more sensitive model, we pathotyped 18 low-pathogenic non-mouse-adapted influenza A viruses of human and avian origin in DBA/2 and C57BL/6 mice. The majority of the isolates (13/18) induced severe morbidity and mortality in DBA/2 mice upon intranasal challenge with 1 million infectious doses. Also, at a 100-fold-lower dose, more than 50% of the viruses induced severe weight loss, and mice succumbed to the infection. In contrast, only two virus strains were pathogenic for C57BL/6 mice upon high-dose inoculation. Therefore, DBA/2 mice are a suitable model to validate influenza A virus vaccines and antiviral therapies without the need for extensive viral adaptation. Correspondingly, we used the DBA/2 model to assess the level of protection afforded by preexisting pandemic H1N1 2009 virus (H1N1pdm) cross-reactive human antibodies detected by a hemagglutination inhibition assay. Passive transfer of these antibodies prior to infection protected mice from H1N1pdm-induced pathogenicity, demonstrating the effectiveness of these cross-reactive neutralizing antibodies in vivo.

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A Prospective Comparison of the Epidemiological and Clinical Characteristics of Pandemic (H1N1) 2009 Influenza A Virus and Seasonal Influenza A Viruses in Guangzhou, South China in 2009

Japanese Journal of Infectious Diseases ◽

10.7883/yoken.65.208 ◽

2012 ◽

Vol 65 (3) ◽

pp. 208-214 ◽

Cited By ~ 13

Author(s):

Zi-feng Yang ◽

Yang-qing Zhan ◽

Rong-chang Chen ◽

Rong Zhou ◽

Yu-tao Wang ◽

...

Keyword(s):

Influenza A Virus ◽

South China ◽

Influenza A ◽

Clinical Characteristics ◽

Seasonal Influenza ◽

Pandemic H1n1 ◽

Influenza A Viruses ◽

Prospective Comparison ◽

Pandemic H1n1 2009

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Continual Reintroduction of Human Pandemic H1N1 Influenza A Viruses into Swine in the United States, 2009 to 2014

Journal of Virology ◽

10.1128/jvi.00459-15 ◽

2015 ◽

Vol 89 (12) ◽

pp. 6218-6226 ◽

Cited By ~ 59

Author(s):

Martha I. Nelson ◽

Jered Stratton ◽

Mary Lea Killian ◽

Alicia Janas-Martindale ◽

Amy L. Vincent

Keyword(s):

Influenza Virus ◽

Influenza A ◽

The United States ◽

Influenza Viruses ◽

Pandemic H1n1 ◽

Influenza A Viruses ◽

Virus Diversity ◽

Swine Population ◽

The U.S

ABSTRACTThe diversity of influenza A viruses in swine (swIAVs) presents an important pandemic threat. Knowledge of the human-swine interface is particularly important for understanding how viruses with pandemic potential evolve in swine hosts. Through phylogenetic analysis of contemporary swIAVs in the United States, we demonstrate that human-to-swine transmission of pandemic H1N1 (pH1N1) viruses has occurred continuously in the years following the 2009 H1N1 pandemic and has been an important contributor to the genetic diversity of U.S. swIAVs. Although pandemic H1 and N1 segments had been largely removed from the U.S. swine population by 2013 via reassortment with other swIAVs, these antigens reemerged following multiple human-to-swine transmission events during the 2013-2014 seasonal epidemic. These findings indicate that the six internal gene segments from pH1N1 viruses are likely to be sustained long term in the U.S. swine population, with periodic reemergence of pandemic hemagglutinin (HA) and neuraminidase (NA) segments in association with seasonal pH1N1 epidemics in humans. Vaccinating U.S. swine workers may reduce infection of both humans and swine and in turn limit the role of humans as sources of influenza virus diversity in pigs.IMPORTANCESwine are important hosts in the evolution of influenza A viruses with pandemic potential. Here, we analyze influenza virus sequence data generated by the U.S. Department of Agriculture's national surveillance system to identify the central role of humans in the reemergence of pandemic H1N1 (pH1N1) influenza viruses in U.S. swine herds in 2014. These findings emphasize the important role of humans as continuous sources of influenza virus diversity in swine and indicate that influenza viruses with pandemic HA and NA segments are likely to continue to reemerge in U.S. swine in association with seasonal pH1N1 epidemics in humans.

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