The mechanisms of the antibody-dependent enhancement (ADE) of viral infection are presented, particularly within the Picornaviridae family. The ADE of infection has been described in both human and animal models, worsens viral infections and compromises vaccine safety. The ADE of coxsackievirus B infection can also be implied in the pathogenesis of diseases like chronic dilated cardiomyopathy or insulin-dependent type 1 diabetes.

Researchers are reporting that a new antiviral strategy powerfully protects monkeys from SIV, the simian cousin of HIV. The approach combines elements of vaccines and gene therapy, and experts say the development could eventually lead to a vaccinelike weapon against AIDS--a goal that has thus far proved elusive. Vaccines work by priming the "adaptive" immune system to recognize and attack a specific invader. But despite 2 decades of research, several potential AIDS vaccines have failed to teach the immune system to produce antibodies that can stop HIV. Still, some progress has been made: Researchers have isolated a handful of antibodies from HIV-infected humans that stymie HIV in test-tube studies. Intensive efforts have attempted to find the proteins or peptides that could teach the immune system to produce these powerful antibodies, yet none has made progress. AIDS vaccine researcher Philip Johnson came up with a workaround: Bypass the immune response and just deliver the antibodies. "We're taking what Mother Nature has given us in terms of molecules and antibodies, and we're leapfrogging the adaptive immune system, which is not very effective against HIV," he says. Johnson's group at Children's Hospital of Philadelphia in Pennsylvania decided to test the idea in the monkey SIV model to see if it had promise. The researchers first created what amounts to designer antibodies: They linked together pieces of antibody to construct "immunoadhesins." These molecules derailed SIV in test-tube studies and can remain in the blood at high concentrations. They then stitched the genes for these immunoadhesins into an adeno-associated virus (AAV), a "vector" used in human gene therapy experiments to deliver foreign DNA into the body's cells. Nine monkeys received injections into their muscles of AAVs that carried three different immunoadhesins. Four weeks later, the researchers "challenged" the monkeys with injections of SIV. Six of the nine animals did not become infected, whereas all six control animals, which did not receive the immunoadhesins, did. The team reports its findings online this week in Nature Medicine. "It's a great paper," says Nobel Prize-winning virologist David Baltimore, whose own lab at the California Institute of Technology in Pasadena is doing similar work. "Phil Johnson has gone for the throat with these anti-SIV immunoadhesins rather than natural antibodies. It's a hopeful opportunity to make a vaccine by a very different principle than what we've seen before." Several practical questions still loom large. The three monkeys that were not protected by the immunoadhesins all had immune responses that attacked these artificial antibodies. Why did some monkey immune systems go after the designer antibodies whereas others did not? "We don't have a clue," says Johnson. What's more, unlike a vaccine, which builds long-lasting immunological memory against a pathogen, the designer antibody approach depends on the viral vector persisting and continuing to pump out the immunoadhesins. Although Johnson says the monkeys continue to produce the immunoadhesins 80 weeks out, it's unclear how long the AAV will survive. Another potential problem is that prolonged exposure to the immunoadhesins or the vector itself could lead to immune responses against them later. Then there's the question of SIV compared with HIV. Immunologist Dennis Burton of the Scripps Research Institute in San Diego, California, notes that the particular SIV used to challenge the monkeys is "very, very sensitive" to antibodies. "With HIV, it would be quite difficult to get those levels of neutralization with the antibodies we know about," he says. Johnson recognizes the limitations, including the substantial regulatory hurdles that must be cleared before the new approach can be tested in humans, but he is confident that it will move forward. "Some people think it's nice monkey work but not translatable," says Johnson. "My favorite line is, 'Okay, so what's your idea?'"

Lab results could explain why young patients are hardest hit by current H1N1 strain ... Antibodies against some seasonal flu strains from prior years may be active against the new H1N1 swine flu currently circulating the globe, a recent study reports. The findings suggest an explanation for why swine flu appears to infect the young more often than the elderly, who are normally more susceptible to seasonal flu viruses. The study, published today in the Morbidity and Mortality Weekly Report, analyzed blood samples taken from 359 participants in flu vaccine studies conducted from 2005 to 2009. 33% of the samples from people over 60 years old had antibodies that reacted with the swine flu virus, as compared to 6%-9% of the samples from people aged 18–64 years, and none of the samples taken from children 1. The results match the apparent current epidemiology of swine flu infection, says Anne Schuchat, interim deputy director for the Science and Public Health Program at the Centers for Disease Control and Prevention (CDC) in Atlanta. Most cases of swine flu have occurred in people who are under 60 years old, and only 1% of confirmed swine flu infections in the United States were in patients over the age of 65. Nevertheless, the results should be interpreted with caution, Schuchat urged in a press briefing today. Researchers have shown that the antibodies react with the virus in test-tube assays, but they have not yet shown that the antibodies can fend off the virus in animals or people. "Whether this particular assay will pan out over time as predictive of clinical protection, we can't say," Schuchat said.

Confirming the first impressions of many American and Mexican doctors, federal health officials said on Wednesday that people born before 1957 appear to have some immunity to the swine flu virus now circulating. Tests on blood serum from older people showed that they had antibodies that attacked the new virus, Dr. Daniel Jernigan, chief flu epidemiologist at the Centers for Disease Control and Prevention, said in a telephone news conference. That does not mean that everyone over 52 is immune, since some Americans and Mexicans older than that have died of the new flu. But it bears out what doctors in the field have noticed: that the new flu infects and hospitalizes many more young people than seasonal flus, which tend to sicken and kill the very old ... The protection theory, Dr. Jernigan explained, is that from 1918 to 1957, all circulating seasonal type-A flus were weakened descendants of the 1918 Spanish flu, which was an H1N1, as the current swine is. (All flus are named for the shapes of hemagglutinin and neuraminidase displayed on the virus’s shell. Hemagglutinin is sometimes called the “spike”: the virus uses to enter a cell, while neuraminidase is the “helicopter blade” that chops off receptors, allowing newly made virus to escape.) Then in 1957, an H2N2, the Asian flu, emerged and displaced it. It was replaced in 1968 by the H3N2, called Hong Kong flu, which has persisted as a seasonal strain. A different and milder H1N1 emerged in 1977. It was isolated in China but is called the Russian flu because of a suspicion it escaped from a Soviet laboratory. That H1N1, the 1968 H3N2 and a B strain have all circulated in humans ever since, and the seasonal flu shot is aimed at them. Neither those shots nor the 40 million flu shots dispensed during the 1976 swine-flu scare are known to provide any protection against the new swine flu.

An unusual pattern of avian flu cases in Egypt — almost all are in toddlers, all of whom have survived — has led some flu-tracking Web sites to speculate that dozens of silent cases are circulating there. That would be an alarming development, but other experts, including those at the World Health Organization, say such fears are exaggerated. Although thousands of Egyptians have rushed their children to hospitals this flu season, there is no evidence yet of asymptomatic avian flu cases or any significant mutation in the H5N1 virus. “Right now, it’s all hot air,” said Dr. Robert G. Webster, a flu expert at St. Jude Children’s Research Hospital in Memphis. “I hope to hell it’s not happening, because it would mean the virus is adapting to humans. But there’s not a shred of data.” Bird flu has faded from world headlines because it has not caused a pandemic. But the disease is still circulating in poultry in Egypt, Indonesia, China, Vietnam and along the India-Bangladesh border. It has mutated into at least 10 strains and occasionally infects humans. An April 8 Reuters article from Cairo quoted a visiting W.H.O. expert saying his agency feared “something strange happening in Egypt” and would help the government test the blood of healthy people for antibodies this summer.

PMID: 18054840

PMID: 15685144

DA - 20080627 IS - 1549-4918 (Electronic) LA - ENG PT - JOURNAL ARTICLE