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A Weak Spot in H.I.V.’s Armor Raises Hope for a Vaccine

October 30, 2012

(New York Times) The search for a vaccine against AIDS has been long and fruitless — mostly because the virus mutates so fast.
As is well known, flu vaccines have to be reformulated every year because influenza viruses mutate so steadily. But the human immunodeficiency virus, which causes AIDS, mutates as much in a single day as flu virus does in a year, presenting scientists with an almost insurmountable challenge.

This month, South African researchers announced that they had found a vulnerable spot on the virus’s outer shell that might present a good vaccine target, and that they had also learned, for the first time, at what stage of an infection it develops. They found only two women whose virus had the vulnerability — and it wasn’t the same virus that first infected them, but a mutant that developed a few months later.

The research, published by Nature Medicine on Oct. 21, was praised as “very interesting” by several AIDS experts.

“It’s a combination of good science and ‘Boy, did we get lucky,’ ” said Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases. “They had all these blood samples and virus samples.”

The researchers, led by Dr. Salim Abdool Karim, president of South Africa’s Medical Research Council and best known for pioneering work on vaginal microbicides, screened hundreds of blood samples given at regular intervals by 79 women who had been in earlier clinical trials at his Durban clinic and had become infected during the trials.

“What we have that’s unique,” Dr. Karim said, “is that for the first time, we understand how a person can make broadly neutralizing antibodies.”

The virus’s vulnerable spot — open to antibody attack — was created when a sugarlike surface compound called a glycan shifted positions.

Antibodies are Y-shaped proteins produced by the immune system that attach to a virus and block its outer receptors — sort of the way sweater fuzz attaches to Velcro and renders it unsticky.

There are many strains of H.I.V., and no known antibody incapacitates all of them. But in the last few years, several teams of scientists have isolated about a dozen that each can shut down up to 80 percent of all virus strains. These are said to be “broadly neutralizing.”

Less than 20 percent of all patients naturally develop such antibodies in their blood, and even those who do aren’t fully protected. One of the women whose blood was crucial to Dr. Karim’s study has died of AIDS-related tuberculosis, and the other is on antiretroviral drugs.

Nonetheless, experts hope it will eventually be possible to manufacture cocktails with large doses of several kinds of antibodies to treat patients — or even to induce the immune system to make those particular antibodies, which would amount to a vaccine.

But that will take more work, and more luck.

Dr. John P. Moore, an AIDS researcher at Weill Cornell Medical School, called the South African paper “good solid science, but not enough to know if you have the right target.”

“It’s like looking at a castle and saying: ‘I can see a weak point, but I don’t know what kind of battering ram to get,’ ” he added.

Normally, H.I.V. repels antibodies by mutating its Velcro hooks into different shapes. But some spots on the viral shell don’t change shape easily. Scientists from the National Institute for Communicable Diseases in South Africa and universities in KwaZulu/Natal, Cape Town and North Carolina, as well as from Harvard, screened multiple blood samples looking for previously known antibodies. They found them in the two women, and noted how long into their infections those antibodies appeared — around six months, it turned out, after their infections were first detected.

Then the scientists looked to see what exactly had changed in the virus circulating in their blood at that time.

They found that a sugarlike glycan had moved from Position 334 to Position 332 on one of the lumpy spikes that stud the virus. That tiny change allows the antibody to attach and alert the body that the whole round virus is an invader, Dr. Karim said.

Antibodies neutralize viruses by blocking their receptors and by attracting white blood cells that will engulf the virus.

Most of the work was done by South Africans and paid for by the South African government, Dr. Karim said proudly, although additional money came from the United States National Institutes of Health and the Bill & Melinda Gates Foundation.

Dr. Karim, who also teaches at Columbia University in New York, particularly praised one local researcher, Penny L. Moore of the National Health Laboratory Service in Johannesburg.

“She’s one of our up-and-coming stars,” he said. “Old fogies like myself are quickly becoming redundant.”

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