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SIV gives up structural secrets of gp120
Newsdesk
Mortality benefits of influenza vaccine questioned USA has climbed from a fifth to twothirds. Yet estimates of winter deaths suggest that flu-related mortality has risen during this period. To try to reconcile this apparent contradiction, Simonsen’s team applied a cyclical regression model to estimate flu-related mortality from 1968 to 2001 and adjusted the results to compensate for an ageing population and the higher incidence of the virulent A(H3N2) virus in the 1990s. “The trends were not declining as much as we had hoped. But our strong conclusion, when considering excess mortality, is that we could never attribute more than 10% of all winter deaths to influenza, even in the pandemic seasons. The cohort studies must be overestimating the mortality benefit of vaccination”, she states. The study’s publication provoked strong reactions. The Centers for Disease Control and Prevention (CDC)
A study by researchers at the National Institutes of Health (NIH), Bethesda, MD, USA, concludes that influenza vaccinations in the USA have prevented fewer deaths than indicated by previous research (Arch Intern Med 2005; 165: 265–72). “It’s really hard to find out who died of influenza because it’s not a reportable disease and few people are tested”, says first author Lone Simonsen. Clinical trials have tested the efficacy of flu vaccines on mild morbidity but not resulting mortality in elderly people. “To estimate the winter-seasonal increases in mortality attributable to influenza, indirect approaches are required”, she adds. Cohort studies that compared mortality rates in vaccinated and unvaccinated groups of elderly people have shown that flu vaccination reduces all winter deaths by 50%. Over the past 25 years the proportion of those aged 65 years or over receiving flu jabs in the
reiterated its faith in existing studies, and questioned the methodology of the NIH study. Concerned by the impact of official disagreements on public confidence, the CDC and NIH released a joint statement, saying that annual vaccinations continue to provide the best protection for elderly people. Ira Longini (Emory University, Atlanta, GA) notes that an ecological analysis cannot infer causality. “However, it is clear that increasing vaccination of the elderly has not resulted in a decrease in pneumonia and influenza mortality on a population level in that age group.” He points to the distribution of robust and frail immune systems as an explanation. “As we increase vaccine coverage, a proportion of the elderly do not respond to vaccination and get sick and die from flu whether they are vaccinated or not.”
Claudia Orellana
SIV gives up structural secrets of gp120
204
and changing the orientation of parts of the protein. These are unusually extensive conformational rearrangements.” The structure of the unbound form sheds light on how HIV resists host immune attack. Although the immune
system produces anti-HIV antibodies, many of the antibodies can not neutralise the virus, and those that do block only a narrow range of variants. “There can be various reasons for the failure to neutralise”, explains Harrison. “The high degree of glycosylation of gp120 is probably one reason, as an extensive glycan coat covers much of the accessible surface in the unliganded conformation. Surfaces that must interact with [the] receptor and co-receptor are partly concealed and partly spread apart on the unliganded molecule, so only when the receptor binds and the conformation switches are those sites properly formed at all. The new structure will allow us to design experiments to pin down the mode of action of those rare antibodies that do neutralise many different isolates of HIV-1.”
Approach of HIV gp120/gp41 to a CD4 receptor
Adrian Burton
Steven Harrison
After nearly two decades of research, the unliganded structure of gp120— the protein that allows HIV and simian immunodeficiency virus (SIV) to attach to their target cells—has finally been unravelled, possibly opening a door to the development of new drugs and vaccine strategies (Nature 2005; 433: 834–41). The bound structure of gp120—ie, after it has attached to a CD4 receptor on the host cell membrane—has been known since 1998, but the unbound form has resisted attempts to determine its structure. “Comparison of the two forms shows that gp120 is substantially refolded when it attaches to a CD4 receptor”, explains Stephen Harrison (Harvard Medical School/Howard Hughes Medical Institute, Boston, MA, USA). “A large portion of the protein is reshuffled, leaving some pieces more than 40 Å [4 nm] from their original position
http://infection.thelancet.com Vol 5 April 2005
Mortality benefits of influenza vaccine questioned USA has climbed from a fifth to twothirds. Yet estimates of winter deaths suggest that flu-related mortality has risen during this period. To try to reconcile this apparent contradiction, Simonsen’s team applied a cyclical regression model to estimate flu-related mortality from 1968 to 2001 and adjusted the results to compensate for an ageing population and the higher incidence of the virulent A(H3N2) virus in the 1990s. “The trends were not declining as much as we had hoped. But our strong conclusion, when considering excess mortality, is that we could never attribute more than 10% of all winter deaths to influenza, even in the pandemic seasons. The cohort studies must be overestimating the mortality benefit of vaccination”, she states. The study’s publication provoked strong reactions. The Centers for Disease Control and Prevention (CDC)
A study by researchers at the National Institutes of Health (NIH), Bethesda, MD, USA, concludes that influenza vaccinations in the USA have prevented fewer deaths than indicated by previous research (Arch Intern Med 2005; 165: 265–72). “It’s really hard to find out who died of influenza because it’s not a reportable disease and few people are tested”, says first author Lone Simonsen. Clinical trials have tested the efficacy of flu vaccines on mild morbidity but not resulting mortality in elderly people. “To estimate the winter-seasonal increases in mortality attributable to influenza, indirect approaches are required”, she adds. Cohort studies that compared mortality rates in vaccinated and unvaccinated groups of elderly people have shown that flu vaccination reduces all winter deaths by 50%. Over the past 25 years the proportion of those aged 65 years or over receiving flu jabs in the
reiterated its faith in existing studies, and questioned the methodology of the NIH study. Concerned by the impact of official disagreements on public confidence, the CDC and NIH released a joint statement, saying that annual vaccinations continue to provide the best protection for elderly people. Ira Longini (Emory University, Atlanta, GA) notes that an ecological analysis cannot infer causality. “However, it is clear that increasing vaccination of the elderly has not resulted in a decrease in pneumonia and influenza mortality on a population level in that age group.” He points to the distribution of robust and frail immune systems as an explanation. “As we increase vaccine coverage, a proportion of the elderly do not respond to vaccination and get sick and die from flu whether they are vaccinated or not.”
Claudia Orellana
SIV gives up structural secrets of gp120
204
and changing the orientation of parts of the protein. These are unusually extensive conformational rearrangements.” The structure of the unbound form sheds light on how HIV resists host immune attack. Although the immune
system produces anti-HIV antibodies, many of the antibodies can not neutralise the virus, and those that do block only a narrow range of variants. “There can be various reasons for the failure to neutralise”, explains Harrison. “The high degree of glycosylation of gp120 is probably one reason, as an extensive glycan coat covers much of the accessible surface in the unliganded conformation. Surfaces that must interact with [the] receptor and co-receptor are partly concealed and partly spread apart on the unliganded molecule, so only when the receptor binds and the conformation switches are those sites properly formed at all. The new structure will allow us to design experiments to pin down the mode of action of those rare antibodies that do neutralise many different isolates of HIV-1.”
Approach of HIV gp120/gp41 to a CD4 receptor
Adrian Burton
Steven Harrison
After nearly two decades of research, the unliganded structure of gp120— the protein that allows HIV and simian immunodeficiency virus (SIV) to attach to their target cells—has finally been unravelled, possibly opening a door to the development of new drugs and vaccine strategies (Nature 2005; 433: 834–41). The bound structure of gp120—ie, after it has attached to a CD4 receptor on the host cell membrane—has been known since 1998, but the unbound form has resisted attempts to determine its structure. “Comparison of the two forms shows that gp120 is substantially refolded when it attaches to a CD4 receptor”, explains Stephen Harrison (Harvard Medical School/Howard Hughes Medical Institute, Boston, MA, USA). “A large portion of the protein is reshuffled, leaving some pieces more than 40 Å [4 nm] from their original position
http://infection.thelancet.com Vol 5 April 2005