Latest Research on HIV/AIDS:

Recent studies found that Immune system might be revived to fight AIDS.

A spirited race between top immunology teams is set to culminate with the publication of two scientific papers reaching broadly similar conclusions about the AIDS virus: It exploits the human body’s natural mechanism for shutting down the immune system, and the process can be reversed.

The findings raise the tantalizing possibility that doctors one day could switch a patient’s immune system back on, so that it could resume its fight against HIV, or even cancer cells, certain parasites or the virus that causes hepatitis C. Those very different diseases “have one common denominator,” says Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases. “They persist. They’re chronic.”

The studies, published in the journal Nature and its sister journal, Nature Medicine, build on almost 15 years of work by other researchers, including Kyoto University Prof. Tasuku Honjo, who in the early 1990s discovered a molecule, which he named PD-1, on the surface of disease-fighting T-cells. Subsequent research revealed that PD-1 is a natural regulator of the human immune system, acting like a brake on rampaging T-cells and potentially preventing them from attacking the body itself.

The latest findings are preliminary, and there isn’t any way to predict whether this avenue of research will ever yield new treatments. And there’s one more blazing caveat: Switching the immune system back on — the most obvious treatment strategy — might trigger autoimmune disease. Scientists currently studying PD-1 are sobered by the shocking experience of a German drug company’s clinical trial conducted in London in March, in which six healthy volunteer patients received an experimental drug to stimulate the immune system and landed in intensive care, their lives in the balance, because the drug sent their immune systems into massive overdrive.

Nevertheless, research in this area is exploding. The Bill and Melinda Gates Foundation is funding a team researching how to turn the immune system back on in hepatitis C patients. Researchers at the National Institutes of Health are studying PD-1 in tuberculosis, one of the world’s leading killers.

“This isn’t just HIV,” says Harvard University immunologist Bruce Walker, the lead researcher on the study published in Nature. “This is much broader.”

Research has progressed furthest in cancer, where scientists have shown that PD-1 can shut down immune responses when it is activated by certain types of tumor cells. Last month, the U.S. Food and Drug Administration approved human testing of an experimental antibody designed to reverse the shutdown and permit the immune system to resume fighting cancer cells.

When a virus or other pathogen enters the body, immune-system cells multiply furiously and send out potent chemicals, called cytokines, which cause inflammation. “When you get the flu, for example, you feel sick not so much because of the virus, but because of the immune system — that’s what gives you the aches and fevers,” explains Drew Pardoll, an immunologist at Johns Hopkins University who has studied PD-1. Left unchecked, the raging immune response, including an excess of cytokines, could damage the body.

In a simple infection, such as the flu, the immune system apparently does its job and subsides. But if a pathogen isn’t quickly cleared out, as in the case of chronic disease, then PD-1 goes to work and shuts down production of key types of immune-system cells. Much of this basic understanding was achieved only late last year in a study published in Nature and led by Emory University Prof. Rafi Ahmed and a student of his at the time, Daniel Barber.

The research published goes further to address one of the most vexing mysteries in the biology of AIDS. Key immune-system cells known as HIV-specific CD8 killer T-cells exist in high numbers in many HIV-infected patients. Early in the course of the infection, these cells kill other cells carrying the virus. But in long-term patients, these cells barely fight the virus at all. The reigning theory was that HIV somehow disabled them. That may still be true in part, but studies reveal that HIV actually exploits the body’s own mechanism for shutting the cells down.

The PD-1 molecule buds on the surface of the killer T-cells that target HIV. By itself, PD-1 is inert and does nothing. But when PD-1 encounters a partner molecule, or ligand, the interaction sets off a chain reaction inside the killer T-cells. The T-cells multiply much more slowly or not at all, and overall they secrete far less of their powerful cytokines, the researchers found. Essentially, they abandon the fight.

The most dramatic finding is that the process can be reversed, at least in a test tube. When researchers added an antibody that blocked the interaction between PD-1 and its ligand, then the killer T-cells revived. They started multiplying again, and cytokine production increased. “I’ve never seen something as black and white,” said Rafick Sékaly, a professor at Canada’s Université de Montréal and a leader of the team whose study was published in Nature Medicine.

The team, led by Harvard’s Dr. Walker and researchers Cheryl Day and Daniel Kaufmann, made a further finding: Not only can PD-1 shut down the killer CD8 T-cells, but it also can affect command-and-control cells, known as CD4 cells. In other words, PD-1 acts on both the infantry and the generals. In one particularly striking bit of research, Dr. Kaufmann revived CD4 cells in five of six AIDS patients whose CD4 cells had shown zero activity against HIV. Taken together, studies suggest that two critical types of immune system cells — CD8 and CD4 — can in most patients be rescued and remobilized to fight HIV.

The Walker and Sékaly research teams both are keen to test the hypothesis by giving patients an antibody that blocks the interaction between PD-1 and its ligand. The two researchers have initiated discussions with Medarex, developer of the experimental antibody about to be tested in cancer patients. Dr. Sékaly has even sent blood samples to Medarex so that it can run laboratory experiments on them.

In addition, Harvard University researcher Gordon Freeman has made his own antibodies to PD-1 and its ligands. He is busy planning tests of them in monkeys, with an eye to testing them in humans infected with HIV and hepatitis C. Recently, Dr. Walker launched a new study of what he terms “elite controllers,” the 0.33% of HIV patients who keep the virus in check for many years without drugs. Dr. Walker believes that one reason these rare patients stay healthy may be that their immune cells lack PD-1, or that the interaction between PD-1 and its ligand might somehow be short-circuited. He has already begun to test these theories but doesn’t yet have results.

A third scientific team, led by Richard Koup, chief of the immunology laboratory at the National Institutes of Health’s Vaccine Research Center, also has been researching PD-1 in HIV. Dr. Koup’s team found that the interaction between PD-1 and its ligand appears to cause CD8 cells to die, not merely to stop functioning.

December 26, 2006:

New study in Africa has shown that Male circumcision decrease the chances of contracting HIV. Circumcision has emerged as a new tool in the battle against AIDS following results in three African studies which showed it cuts the chances of HIV infection by as much as 60%. Researchers who conducted one of the studies in Orange Farm outside of Johannesburg concluded that circumcising 1,000 men would prevent an estimated 300 new HIV infections over 20 years.

Caution: It only decrease the chances of contracting HIV, circumcision does not protect the person from HIV all the time.

March 1, 2007:

Emerging Drugs Show Promise Against HIV: After a dearth of new drugs for people infected with HIV, this year promises a bumper crop of medicines that may help combat rising resistance to older therapies.

Two of the experimental medicines take entirely new approaches in thwarting the HIV virus; a third overcomes resistant viruses by taking a new tack on an enzyme many older drugs target.

Amid scores of drugs in the pipeline presented this week at the annual Conference on Retroviruses and Opportunistic Infections in Los Angeles, several drugs look promising in pivotal efficacy studies including Merck & Co.’s MK-518 and Pfizer Inc.’s maraviroc. University of Pittsburgh researcher John Mellors called the drugs’ performance “a really remarkable development” and the best he’d seen since the debut of AIDS cocktail therapy over a decade ago. They, and another that’s garnering attention, Johnson & Johnson’s TMC125, are heading for review by the Food and Drug Administration this year.

Because HIV mutates quickly to outwit drugs, cocktails of two or three drugs are used to simultaneously attack the virus in different spots. The effectiveness of these cocktails is greater than the sum of their parts.

But doctors estimate tens of thousands of patients are infected with viruses that have become resistant to at least one class of HIV drug, weakening the cocktail approach. Some patients who have fought HIV for years have now run through the roughly two dozen drugs available. In these patients, the mutant HIV is rebounding, suppressing their immune systems and making them vulnerable to infections from other viruses, bacteria and fungi. So the need for fresh medicines is growing more acute. Now years of research and testing appear ready to pay off.

Data on clinical tests of the new drugs buoyed spirits at the conference. “It’s very exciting,” said Houston-based activist Nelson Vergel, who has wrestled with HIV since 1983. “This is the first time we’ve had so many agents for multidrug resistance from one meeting,” he said.

The arrival of new medicines at the same time is especially heartening, doctors say. Introducing new drugs one at a time can make it easier for the virus to fight them off. Cocktails with two new ingredients, for instance, could remain potent longer.

The new drugs may all be on the market by the end of 2007, and some patients in need can get access already.

Among the most advanced and promising of the new drugs is one from Merck, known until now by the code name MK-518. The company yesterday announced it will carry the generic name raltegravir and the tentative brand name Isentress, under review by the FDA. The drug, which inhibits an enzyme that HIV uses to copy itself into the DNA of white blood cells, is the first in a new class called integrase inhibitors.

Mr. Vergel, a 48-year-old retired chemical engineer, started taking the drug last May as part of an antiviral cocktail in a trial, and three weeks later his virus dropped to an undetectable level. The HIV rebounded after six months, but a rise in his infection-fighting white blood cells, called CD-4 cells, has persisted.

Robin Isaacs, Merck’s executive director of infectious-disease clinical development, said the two latest studies show the drug, taken twice a day, helped drive virus levels down to undetectable in slightly more than 60% of volunteers when added to an antiviral cocktail. Only 33% to 36% of patients receiving a placebo had similar reductions. Volunteers taking the new drug also saw higher levels of CD-4 cells than patients receiving placebo. A Merck spokesman said the company expects to file for FDA approval in the second quarter of this year.

Gilead Sciences Inc. is testing a once-a-day integrase inhibitor dubbed GS-9137, which might make it easier to combine with other medicines taken on the same schedule.

Another class of drugs, called entry inhibitors, may also debut this year. These medicines keep HIV out of white blood cells. One door to these cells, called CCR5, has been the object of research by several drug companies, but side effects have marred some of the early work. Pfizer’s maraviroc is beginning to convert some skeptics and is on a fast track for FDA approval. “Though this class has gotten beaten up a bit over the last year, the data on maraviroc is substantially better than anyone was expecting,” said Martin Delaney, a founder of the treatment advocacy group Project Inform in San Francisco, USA.

Two new studies at the meeting found that maraviroc taken with an antiviral cocktail was twice as likely to suppress HIV virus to undetectable levels as a placebo taken with the cocktail. It also doubled the rise in disease-fighting CD-4 cells.

The ranks of patients resistant to existing drugs are growing. With about one million Americans infected with HIV, and roughly 400,000 patients in treatment, Harvard University researcher Daniel Kuritzkes says 40,000 people harbor multidrug-resistant HIV.

But fewer than half of all such patients could expect to benefit from maraviroc, because most patients on long-term treatment harbor HIV strains that enter through a different portal, known as CXCR4, which is unaffected by the drug, said Dr. Steven Deeks, an HIV specialist at the University of California, San Francisco.

For Pfizer’s clinical trials, South San Francisco-based Monogram Biosciences tested potential patients to determine which portal HIV used to enter the cell. Only patients whose HIV entered through CCR5 were admitted to the trial. In a first for AIDS drugs, FDA approval might require doctors to ship samples to Monogram’s headquarters for testing before prescribing maraviroc.

Another compound, TMC125, from Johnson & Johnson’s Tibotec unit, has been developed to overcome viruses that have become resistant to other drugs in a class known as non-nucleoside reverse transcriptase inhibitors. The company expects to file for FDA approval in the second half of 2007.