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D225G Lung Tropism Driving H1N1 False Negatives?
Recombinomics Commentary 23:17
November 19, 2009

The recently released H1N1 Ukraine sequences by Mill Hill provide additional insight into the evolution of H1N1.  Ten isolates were sequenced, including HA from all 10.  Four had the predicted receptor binding domain change D225G, which has been found on multiple H1N1 genetic backgrounds.  All four of the sequences with D225G were from the four fatal cases.  Although it is possible that there are two distinct H1N1 viruses in circulation, it is more likely that the virus is present as a mixture and those with higher concentration of D225G produce high concentrations of virus in lungs, leading to cytokine storms and deaths.  Isolates with mixed signals coding for position 225 in H1N1 have been deposited at Genbank, supporting the mixture hypothesis.

These mixtures could be generating false negatives in cases where the level of D225G is high.  Virus with D225G would quickly move to the lower respiratory tract and the low levels of wild type in the upper respiratory tract would be clear by the host's immune response.  These patients would be infected and seriously ill, but the reduction or absence of virus in the upper respiratory tract would test negative.  The CDC has warned that rapid tests have  a sensitivity of  10-70% .  Thus, in some circumstances only 10% of H1N1 infected sample test positive.  This low sensitivity seems to be somewhat linked to H1N1 samples.

The negative data would lead to more testing for other respiratory viruses, which may explain the data reported for rhinoviruses in the Philadelphia area.  No unusual strain has emerged, suggesting that the viruses may simply represent opportunistic infections associated with the H1N1 infection that is testing negative.

The detection of such opportunistic infections is similar to results generated when SARS first emerged.  Since there was no direct test for the SARS CoV initially, many additional tests were run, and different labs would find different candidate respiratory viruses.  However, after the SARS CoV was discovered and developed into a diagnostic test it was clear that SARS was cause by SARS CoV and the other viruses were just opportunistic passengers.

The rapid movement of influenza virus to the lungs has parallels with the H5N1 outbreak in Turkey in late 2005/early 2006.  In that outbreak another receptor binding domain change, S227N was predicted and it was found in the first confirmed H5N1 cases.  However, the index case had initially tested negative, as did his sibling, on nose and throat swab.  H5N1 was confirmed from lung samples in each case.  However, that infection also appeared to involve mixtures.  Although the index case was positive for S227N, his sister was negative.  Eventually 4 sequences were released and one of the two subsequent isolates also had S227N, further suggesting that mixtures were in circulation and collection/isolation issues determined if S227N was detected.

A tissue specific D225G in swine H1N1 could be generating higher frequencies of false negatives if the ratio of D225G to wild type was high.

More testing of post-mortem samples would be useful to better understand the true level of D225G in circulation.

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