Commentary
Indonesian H5N1 Sequence Hoarding Raises Concerns
Recombinomics Commentary 16:07
June 20, 2008
The National Institute for Health Research and Development of the Ministry of Health and the Eijkman Institute of Molecular Biology in Jakarta announced Thursday that based on the genetic sequencing tests, the H5N1 avian influenza virus in Indonesia remains a poultry virus and has not yet mutated into forms that could easily transmitted between humans.
The above comments on recent human H5N1 sequences in Indonesia are vague at best. It is unclear what definition of “mutated into forms that could easily transmit to humans” is. In the past, WHO consultants have focused of the acquisition of human gene segments via reassortment. However, there is no evidence that H5N1 requires reassortment with human gene segments to achieve easy transmission.
Experimental attempts to create such a virus by construction of such reassortants in the lab have been a dismal failure. Many constructs are unable to replicate. Some can replicate in cell culture or experimental mice, but the vast majority fail to produce pathological symptoms in mice. In the most recent report, only three combinations were associated with significant weight loss. In contrast H5N1 with all eight gene segments originating from birds can kill experimental mice in three days. Similarly, earlier constructs failed to transmitted ferret to ferret in a lab model.
The speculation that H5N1 reassortants could transmitted between humans more efficiently was based on prior pandemics in 1957 and 1968 which involved reassortment. However, these pandemics were relatively mild when compared to the 1918 pandemic, which did not involve reassortment. The 1918 pandemic strain was clearly due to recombination in all eight gene segments based on polymorphism tracing. This analysis identified human and swine H1N1 genes as the parental sequences.
However, unlike the pandemics of 1918, 1957, and 1968, H5N1 has a polybasic cleavage site, which is diagnostic for highly pathogenic avian influenza (HPAI), which is define by the effect of infections on experimental chickens. H5N1 can clearly replicate well in mammalian hosts and has been linked to fatal infections in domestic and wild cats, dogs, stone martens, civet cats, and foxes in addition to humans. In humans the case fatality rate is approximately 10 fold high than the 1918 pandemic and is above 80% in Indonesia.
H5N1 infections in humans have also been associated with human to human (H2H) transmission in family members or close contacts. In the Qinghai strain of H5N1, these clusters have been associated with single nucleotide changes in the receptor binding domain. Although such changes have not been reported for human isolates from Indonesia, the isolates developed by WHO consultants in Hong Kong and Atlanta have involved selection in chicken eggs, which is known to select against receptor binding domain changes that increase affinity for mammalian receptors.
Moreover, the most recent public human H5N1 sequences from Indonesia were collected at the beginning of 2007. There are no public sequences representing infections in the past 1 ½ years, although media reports have suggested samples representing a handful of more recent cases have been sent to WHO affiliated labs in the US and Japan, but none of these sequences have been made public.
Thus, the above comments by labs in Indonesia provide little information on H2H changes in Indonesia. Although H2H has been frequently denied in Indonesia, the number of reported and unreported clusters is large. Such clusters include the first confirmed case in Indonesia in 2005, the large Karo cluster, as well as clusters linked to three of the five most recent confirmed cases in Indonesia. False negatives and misdiagnosed H5N1 cases in Indonesia are common, leading to significant under representation of H2H transmissions in Indonesia.
The release of sequences from isolates collected in the past 1 ½ years is long overdue, and the hoarding of these Indonesian human H5N1 sequences remains hazardous to the world’s health.
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