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Molecular Epidemiology of 2005 H5N1 Cleavage Site Deletion

Recombinomics Commentary

July 2, 2005

Ten 2005 HA sequences have now been made available to the public at the flu database at Los Alamos National Labs and although the isolates came from both northern and southern Vietnam, all 10 have a three nucleotide deletion in the HA cleavage site that results in a protein product that is a amino acid shorter than the wild type protein.  The lost amino acid is an arginine residue in the HA cleavage site.

Although 2003 and 2004 isolates from Yunnan are missing an ARG in the protein, the three missing nucleotides are slight different in the Yunnan isolates than the 2005 isolates in Vietnam.  However, exact matches are found in isolates from Hong Kong (A/Duck/Hong Kong/573.4/01,
A/Ck/HK/2133.1/2003), South Korea (A/duck/Korea/ESD1/03, A/chicken/Korea/ES/03) Japan (A/chicken/Oita/8/2004, A/chicken/Koyoto/3/2004, .A/chicken/Yamaguchi/7/2004, A/crow/Osaka/102/2004, A/crow/Kyoto/53/2004), Guangdong (A/duck/Guangdong/173/04), and Hau Giang (A/chicken/Viet Nam/HauGiang-617/2004) in Vietnam's Mekong Delta.  All of these isolates have 3 adenosine residues deleted at positions 1058-1060.

These isolates provide a genetic trail of the deletion.  The earliest H5N1 isolate with the exact match is from a duck in Hong Kong from 2001.  The deletion is exact, but the isolate has one nucleotide difference in the immediate vicinity of the deletion, T1070C.

The deletion is then found in two 2003 South Korean isolates from a duck and chicken. Both of these isolates have an additional polymorphism at G1050A.  The same sequence is found in one of the 2004 isolates from Oita, Japan.  The remaining four isolates from Japan all match the 2001 Hong Kong isolate.  This sequence is also found in the 2003 isolate from the Hong Kong chicken and the 2004 isolate from a duck in Guangdong, which is not surprising because a survey of live markets in 2003 in South Korea identified several recombinants and reassortants and the sequences acquires matched isolates from Hong Kong and Guangdong indicating frequent dual infections between viruses from China and South Korea.

The other isolate with the three nucleotide deletion was isolated in the summer of 2004 from a chicken in Hau Giang.  This isolate was an exact match for the 10 2005 HA sequences.  The isolate is a clear recombinant because the three nucleotide deletion is in a HA gene that is clearly from Vietnam or Thailand and not from China, Japan, or Korea.

Recombination requires dual infections and human data indicate there was considered H5N1 activity in the summer of 2004. Four Vietnamese from Hau Giang died at the end of July and beginning of August.  Although samples were not collected from the first four clustered fatalities, two of the fatalities were cousins.  The older sister of one of the cousins then developed bird flu symptoms right after her brother died and she tested positive for H5N1.  At the same time, two young children from Ha Tay province in northern Vietnam also died and tested positive for H5N1.  Thus, there were clusters of H5N1 confirmed fatalities in both northern and southern Vietnam at the same time as the recombinant was being isolated in Hau Giang.

Recently there have been a number of respiratory disease in southern Vietnam, central Vietnam, Guangdong, Cambodia, and Malaysia.  These outbreaks have been attributed to hot weather and have been characterized as diseases of unknown origin or human influenza.  However, conditions that would lead to outbreaks of human influenza would also trigger avian influenza and there have been reports of many new suspected and confirmed cases of H5N1 in northern Vietnam last month.  Details have been lacking in the larger human outbreaks, but it is during these outbreaks that the likelihood of dual infections are increased, leading to new reassortants and recombinants.

It would seem that the lack of data on the human cases is overlooking potential recombinants being formed during these outbreaks, which are the precursors of larger outbreaks in the fall.

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