AIDS vaccine delivers
Cellular attack tactic keeps virus at bay.
17 January 2002
HELEN PEARSON
The HIV virus: killing cells laden with these particles may form a key part of future AIDS vaccination strategies.
A new AIDS vaccine could be one of the most promising yet. The drug's effects in monkeys suggest that killing virus-laden cells may form a key part of future vaccination strategies.
Vaccinated monkeys survived a usually lethal infection with a monkey-human hybrid virus, SHIV. Their primed immune system kept virus levels below detection, Emilio Emini of Merck Research Laboratories in West Point, Pennsylvania, and his team now report1. The results are some of the most encouraging to come out of AIDS vaccine research.
But doubts have already been voiced. Low-lying virus can change to elude the immune response, argue Dan Barouch of Harvard Medical School in Boston and his team. A year after they gave eight animals a similar vaccination, a mutant form of the virus emerged, killing one of the monkeys2 .
"This finding should be a reality check rather than a death knell," Barouch says, adding that the technique can be modified to block the emergence of mutant viruses. Future attempts could hit several different SIV proteins to prevent the virus escaping. Both of the latest vaccines targeted a single protein.
Emini is already pursuing this goal. But like multi-drug-resistant bacteria, HIV could conceivably outwit even a broadly targeted vaccine, although this is less likely. Whether the vaccines tested in the monkeys will be as effective in humans, however, is unknown.
Troubled history
AIDS is notoriously difficult to vaccinate against. Initial attempts took a conventional approach by injecting a single HIV surface protein to trigger the animals' immune system into producing antibodies that would attack the virus during a subsequent infection. But HIV evades antibodies by hiding the proteins that the antibodies latch onto and by evolving new strains.
AIDS is notoriously difficult to vaccinate against
"HIV turned out to be much more complicated," says vaccine researcher Jeffrey Lifson of the National Cancer Institute at Frederick, Maryland. In the past few years, vaccine hunters have switched to a different tack that simulates the way the body naturally attempts to deal with HIV infection - namely, stimulating the immune system to strike virus-infected cells.
Emini's team achieved this by using a harmless virus to deliver SIV DNA direct to specific immune cells. "It looks encouraging," says Lifson.
Unfortunately, as with any vaccine that keeps virus levels in check, rather than preventing infection, there is the risk that the pathogen will re-emerge. "It's an ominous question to ask about the whole strategy," comments Lifson. Nonetheless, such a vaccine could in theory defer the onset of AIDS and cut the risk of HIV spreading.
The antibody approach may still bear fruit if it can hit essential, unchanging parts of the virus. Meanwhile, the ultimate ideal remains a vaccine that triggers both arms of the immune system - antibodies and cell attack.
References
Shiver, J. W. et al. Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature, 415, 331 - 335, (2002).
Barouch, D. H. et al. Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature, 415, 335 - 339, (2002).
© Nature News Service / Macmillan Magazines Ltd 2002
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Hitting HIV-1 where it hurts
KIMBERLY CARR
A new drug against HIV-1 – the virus that causes AIDS – has been shown to be effective in preliminary trials, according to a report in Nature Medicine. Most importantly, the new drug represents a new class of drugs, with a mechanism of action completely different from those of the drugs now used.
'Combination' therapy for HIV-1 has had a great impact on the health and prognosis of AIDS patients. It's based on the same idea as combined chemotherapy for cancer. Combining several drugs (usually three for HIV-1) that attack the virus in different ways, makes it more difficult for the offender to 'escape' and develop resistance to treatment. It's hard for an army to defend itself on more than one front.
HIV-1 is a complicated virus, with a number of important steps in its life cycle. The first step is simply getting into the cell in order to infect it. The virus uses receptors on the cell's surface as gateways into the cell. The most famous 'gateway' is CD4, and there have been a number of attempts to block virus entry simply by blocking CD4. Unfortunately, they have all been unsuccessful.
Once the virus is in the cell, it makes a DNA copy of itself which it inserts into the host cell's DNA. To make the copy of itself, it uses an enzyme called reverse transcriptase. Until recently, all HIV-1 drugs targeted this step of the life-cycle, preventing the reverse transcriptase from making a copy of the virus. In the last few years, however, drugs against another target have proven successful, and the combination of drugs with different targets has revolutionized HIV-1 treatment.
The other major target of drugs is a protease – an enzyme that chops up proteins. When the DNA plans for the virus have been read, the proteins necessary to make new entire virus particles are made. But they're not made as separate proteins at first; one long multi-protein chain is made. The HIV-1 protease's job is to cut this chain into the necessary building blocks of a new viral particle. Protease inhibitors prevent this step and so prevent the production of new infective viruses.
Now J. Michael Kilby and Michael S. Saag of the University of Alabama at Birmingham, Alabama and colleagues have shown that a drug against a completely different target can reduce concentrations of HIV-1 in patients, and it's as effective as existing drugs.
In their paper in Nature Medicine, they show that a new drug, T-20, can stop HIV-1 from infecting cells. T-20 actually does what other drugs have tried (and failed at) before – it blocks HIV-1's entry into cells. By binding to a protein in the virus's outer envelope, it prevents the virus from fusing its membrane with that of the cell to be infected, and the virus simply cannot get in. Another target means a potentially better combined therapy for HIV-1.
For the virus, fighting on two fronts against the present combined therapies is hard; fighting on three fronts will be even more difficult. Unfortunately, such a new improved triple-therapy is not for tomorrow.
A number of other tests still need to be done to determine the effects of long-term treatment with T-20. And the drug cannot be given orally; twice-daily intravenous treatments were used in the trial. That simply isn't practical for HIV-1 patients without symptoms. But showing that it is possible to block viral entry with T-20 should make it easier to design other drugs to do the same thing, and then HIV-1 had better watch out.
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