1918 and 2009 Pandemic Influenza Viruses Lack a Sugar = Topping

From: Subject: 1918 and 2009 Pandemic Influenza Viruses Lack a Sugar Topping Date: Sat, 27 Mar 2010 09:30:56 -0700 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0001_01CACD90.349D01D0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0001_01CACD90.349D01D0 Content-Type: text/html; charset="utf-8" Content-Transfer-Encoding: quoted-printable Content-Location: http://www3.niaid.nih.gov/news/newsreleases/2010/pandemicflusugar.htm =EF=BB=BF 1918 and 2009 Pandemic Influenza Viruses Lack a Sugar = Topping

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	National Institute of Allergy = and Infectious=20 Diseases (NIAID) http://www3.niaid.nih.gov/
FOR IMMEDIATE = RELEASE Wednesday, March=20 24, 2010	Media Contact: Anne A. = Oplinger (301)=20 402-1663 niaidnews@niaid.nih.gov

1918 and 2009 Pandemic Influenza Viruses = Lack a=20 Sugar Topping

Finding Could Aid Vaccine = Design

Although they emerged more than 90 years = apart, the=20 influenza viruses responsible for the pandemics = of 1918=20 and 2009 share a structural detail that makes = both=20 susceptible to neutralization by the same = antibodies.=20 Scientists led by Gary J. Nabel, M.D., Ph.D., of = the=20 National Institute of Allergy and Infectious = Diseases=20 (NIAID), part of the National Institutes of = Health,=20 describe the molecular basis for this shared=20 vulnerability and suggest how it might be = exploited to=20 design vaccines matched to future pandemic = influenza=20 virus strains. The research appears online today = in the=20 journal Science Translational = Medicine.

=E2=80=9CThis study defines an unexpected = similarity between=20 two pandemic-causing strains of = influenza,=E2=80=9D says NIAID=20 Director Anthony S. Fauci, M.D. =E2=80=9CIt = gives us a new=20 understanding of how pandemic viruses evolve = into=20 seasonal strains, and, importantly, provides = direction=20 for developing vaccines to slow or prevent that=20 transformation.=E2=80=9D

In one set of experiments, the NIAID = scientists and=20 their colleagues including Terrence M. Tumpey, = Ph.D., of=20 the Centers for Disease Control and Prevention, = injected=20 mice with a vaccine made from inactivated 1918 = influenza=20 virus. Then they exposed the mice to high levels = of 2009=20 H1N1 virus. All of the vaccinated mice survived. = The=20 reverse was also true: Mice vaccinated with = inactivated=20 2009 H1N1 virus and then exposed to 1918 virus = were=20 protected from death. The researchers concluded = that=20 vaccination with either pandemic virus caused = the mice=20 to produce antibodies capable of neutralizing = the other=20 virus.

=E2=80=9CThis is a surprising = result,=E2=80=9D notes Dr. Nabel. =E2=80=9CWe=20 wouldn=E2=80=99t have expected that = cross-reactive antibodies=20 would be generated against viruses separated by = so many=20 years.=E2=80=9D

Ordinarily, he explains, antibodies made in = response=20 to one year=E2=80=99s seasonal flu strain do not = fully react=20 with, or cross-neutralize, seasonal flu strains = that=20 come along just a few years later. This is due = in part=20 to slight, yearly changes in the amino acid = sequence of=20 hemagglutinin (HA), a viral surface protein. The = amino=20 acid sequences of the 1918 and 2009 H1N1 = influenza=20 viruses in a portion of HA called the globular = head=20 differ by about 20 percent. That difference is = on a par=20 with amino acid divergence in the HA head region = among=20 seasonal strains, so the researchers reasoned = that=20 antibody cross-neutralization in the pandemic = viruses=20 must be due to some feature besides simply the = degree of=20 amino acid variation.

In a series of experiments and computer = modeling=20 studies, Dr. Nabel and his team determined that = both=20 pandemic viruses lack a cap of sugar (glycan) = molecules=20 at two specific spots on the top of HA=E2=80=99s = globular=20 head. Without these sugars, both the 1918 = and 2009=20 pandemic viruses have unfettered access to the = receptors=20 that HA uses to enter human cells. This viral = advantage=20 quickly diminishes as immunity provided by = neutralizing=20 antibodies arises in people who have been = infected (and=20 recovered) or when people are vaccinated.

In contrast to the 1918 and 2009 viruses, = when the=20 investigators analyzed the structure of seasonal = flu=20 strains that had circulated between 1977 and = 2008, they=20 found that 97.8 percent had one glycan molecule = covering=20 the HA=E2=80=99s head, while 87.8 percent of the = strains had two=20 glycans. =E2=80=9CThe glycans act like an = umbrella that shields=20 the virus from the immune system,=E2=80=9D says = Dr. Nabel. =E2=80=9CThey=20 create a physical barrier over the virus and = prevent=20 antibody neutralization.=E2=80=9D

Further analysis of influenza sequences = collected=20 prior to 1977 revealed that the HA protein in = the=20 descendants of the 1918 influenza virus acquired = glycans=20 by the early 1940=E2=80=99s. =E2=80=9COur study = points to the key role=20 played by glycans in protecting hemagglutinin = from=20 neutralization as pandemic viruses evolve into = seasonal=20 ones,=E2=80=9D says Dr. Nabel.

Next, the researchers engineered mutant = pandemic flu=20 viruses by placing sugar molecules on the two = critical=20 regions at the top of the globular head. Once = covered,=20 antibodies could no longer recognize and = neutralize the=20 virus. However, says Dr. Nabel, the sugar-capped = viruses=20 did perform well as vaccines.

In their last series of experiments, the=20 investigators added sugar molecules to a 1918 = influenza=20 virus and vaccinated mice with it. The mice = produced=20 antibodies able to neutralize the original, = sugar-free=20 version of the 1918 virus. =E2=80=9CWe can use = this knowledge to=20 preemptively design vaccines with glycosylated = versions=20 of the newly emerged 2009 H1N1 pandemic = influenza=20 virus,=E2=80=9D says Dr. Nabel. Such a vaccine, = he adds, would=20 protect against the pandemic virus and might = also limit=20 the virus=E2=80=99s chances of acquiring a sugar = shield that=20 would allow it to entrench itself as a seasonal=20 variant.

Visit http://www.flu.gov/ for=20 one-stop access to U.S. government influenza. = Also,=20 visit NIAID=E2=80=99s= =20 flu Web portal.

UPDATE: On March 19, = 2010, Dr.=20 Nabel and his colleagues examined genetic = sequence data=20 recently deposited in a public database of flu = strains=20 and found four isolates of the pandemic 2009 = H1N1 virus=20 with a mutation in the HA protein that allows = attachment=20 of a sugar molecule in the region that would = give the=20 virus a shield from neutralizing antibodies. The = clinical and public health implications of this = finding=20 are yet to be determined.

NIAID conducts and supports = research=E2=80=94at NIH,=20 throughout the United States, and = worldwide=E2=80=94to study the=20 causes of infectious and immune-mediated = diseases, and=20 to develop better means of preventing, = diagnosing and=20 treating these illnesses. News releases, fact = sheets and=20 other NIAID-related materials are available on = the NIAID=20 Web site at http://www.niaid.nih.gov.=20

The National Institutes of Health = (NIH)=E2=80=94The Nation's=20 Medical Research Agency=E2=80=94includes 27 = Institutes and=20 Centers and is a component of the U. S. = Department of=20 Health and Human Services. It is the primary = federal=20 agency for conducting and supporting basic, = clinical and=20 translational medical research, and it = investigates the=20 causes, treatments and cures for both common and = rare=20 diseases. For more information about NIH and its = programs, visit http://www.nih.gov.

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Reference:

C-J Wei et al. Cross-neutralization = of 1918=20 and 2009 influenza viruses: Role of glycans in = viral=20 evolution and vaccine design. Science = Translational=20 Medicine. DOI: 10.1126/scitranslmed.3000799 = (2010).

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