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Historical Perspective Emergence of Influenza A (H1N1) Viruses Shanta M. Zimmer, M.D., and Donald S. Burke, M.D. On April 17, 2009, Officials at the Centers for Disease Control and Prevention (CDC) confirmed two cases of swine influenza in children living in neighboring counties in California. Here we take a perspective from systems biology to review the series of evolutionary and epidemiologic events, starting in 1918, that led to the emergence of the current swine-origin influenza A (H1N1) strain (S-OIV), which is widely known as swine flu. This article is one of two historical articles on influenza A(H1N1) viruses in this issue of the Journal. Our review focuses on the key steps that characterize this viral evolution. Emergence of a Virus Simultaneous Appearance in Humans and Swine (1918) Before 1918, influenza in humans was well known, but the disease had never been described in pigs.3 For pig farmers in Iowa, everything changed after the Cedar Rapids Swine Show, which was held from September 30 to October 5 of that year.4 Just as the 1918 pandemic spread the human influenza A (H1N1) virus worldwide and killed 40 million to 50 million people, herds of swine were hit with a respiratory illness that closely resembled the clinical syndrome affecting humans. Similarities in the clinical presentations and pathologic features of influenza in humans and swine suggested that pandemic human influenza in 1918 was actually adapted to the pig, and the search for the causative agent began. The breakthrough came in 1931 when Robert Shope, a veterinarian, transmitted the infectious agent of swine influenza from sick pigs, by filtering their virus containing secretions, to healthy animals.7 Infectivity of the filtrate was subsequently confirmed by Smith, Andrewes, and Laidlaw,8 who used the ferret model of influenza infection to document transmissibility for both human and swine viruses. Shope furthered the notion that the human pandemic strain of influenza A(H1N1) and the infectious agent of swine influenza were closely related by showing that human adult serum could neutralize the swine flu virus.4 In a mouse model, samples from patients ranging from newborn infants to 76-year-olds were tested for their ability to neutralize a swine influenza virus strain. This work showed that nearly all serum samples from subjects who were at least 12 years of age were able to protect mice from challenge with a virus isolated from pigs in 1930, whereas those from children older than 1 month but under the age of 12 years had no neutralizing antibody.4 These experiments suggested that the swine influenza virus, or an antigenically similar one, had been in circulation in the human population and had originated from the 1918 pandemic strain. Advanced virologic and molecular studies of viral relatedness support Shopes early hypotheses.

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PERSPECTIVA HISTRICA APARICIN DE LOS VIRUS DE LA INFLUENZA A (H1N1) El 17 de abril del ao 2009, funcionarios del Centro para el Control y la Prevencin de Enfermedades (CDC, por sus siglas en ingls) confirmaron dos casos de gripe porcina en nios residenciados en dos condados de California. En este artculo se toma la perspectiva de la biologa de sistemas, para revisar las caractersticas histricas y epidemiolgicas del virus, empezando en 1918, lo que permiti la aparicin de la cepa SOIV de influenza A (H1N1), conocida como gripe porcina. Este artculo es uno de los dos artculos histricos sobre influenza A (H1N1) dentro de esta revista. La revisin se enfoca en los pasos crticos que caracterizaron la evolucin del virus. APARICIN DEL VIRUS Aparicin simultanea en humanos y cerdos (1918) Antes de 1918, la influenza haba sido conocida en humanos pero jams se haba visto en cerdos. Todo cambi en Iowa despus que se llevara a cabo el Cedar Rapids Swine Show, el cual se desarroll del 30 de septiembre al 5 de octubre de ese ao. En 1918, la pandemia de influenza A (H1N1) fue la causante de 50 millones de muertes aproximadamente, las manadas de cerdos presentaron enfermedades respiratorias muy parecidas a las de los humanos. Lo cual indujo a bsqueda del agente causante. En 1931, el veterinario Robert Shope, transmiti el agente infeccioso de la influenza de cerdos enfermos a cerdos sanos, a travs de un filtrado de secreciones. Smith, Andrewes y Laidlaw comprobaron la transmisin del virus, a travs del uso del model ferret, tanto en humanos como en animales. Shope contribuy con la idea de que la cepa de la pandemia humana de la influenza A (H1N1) y el agente infeccioso de la gripe porcina estn muy relacionados, al probar que el suero de los humanos adultos tena la capacidad de neutralizar el virus. Realizando diferentes estudios con ratones, las muestras de los pacientes con edades comprendidas entre 0 y 76 aos fueron analizadas para probar su capacidad de neutralizar la cepa del virus de la gripe porcina. Este trabajo mostr que aproximadamente todas las muestras de suero de los pacientes que tenan al menos de 12 aos de edad pudieron proteger a los ratones de la infeccin con el virus aislado en cerdos en 1930, mientras que las muestras de los nios mayores a un mes pero menores de 12 aos de edad no lograron neutralizar el anticuerpo. Estos experimentos sugirieron que el virus de la influenza porcina o uno similar haba estado en circulacin en la poblacin humana y se origin en la pandemia de 1918. Estudios virolgicos y moleculares avanzados han ratificado la hiptesis temprana de Shope.