Based on a study of more than 1,900 American men and women who have been in AIDS-related studies for more than a decade and who have been exposed to the human immunodeficiency virus repeatedly without becoming infected or who are HIV-positive but after years of infection haven't progressed to AIDS, O'Brien made another finding: There is a state of partial genetic protection that slows the course of illness.
The Caucasian people who have this gene are far less likely to progress rapidly to AIDS after infection and they live AIDS-free lives an average of two years longer than infected individuals who don't carry the gene.
O'Brien's findings are so strong - the statistical evidence so powerful - that the odds that this genetic protective effect is a matter of coincidence or other factors are 1 in 40 million. In the statistical world of biology, that constitutes virtual certainty.
O'Brien's findings were announced last week in Baltimore at the annual meeting of the Institute of Human Virology. Startling as his findings may seem, they are merely one piece of a constellation of revelations that during the past six months has turned AIDS research topsy-turvy.
"It's been exhilarating, the pace of discovery," Dr. Anthony Fauci, director of the NIH's National Institute of Allergy and Infectious Diseases in Bethesda, Md., told his assembled colleagues. "But it also gives me a migraine headache because of the difficulty of keeping up. We're at that stage that is both very exciting and frustrating."
O'Brien's findings amplify work in the Aaron Diamond AIDS Research Center's discovery of three genetically resistant New Yorkers. The Manhattan-based center's study, reported last month in Newsday, found that the men were missing 32 bits of genetic information involved in the production of a cellular receptor called CKR-5, the most important receptor used by HIV as a doorway to human white blood cells.
Ned Landau's laboratory at the Aaron Diamond Center showed that people who had genetically defective CKR-5 also had nonfunctional "doorways," so HIV couldn't get inside cells. This genetic protection is absolute if individuals are homozygous, meaning they inherited the trait from both parents. Just one month ago, fewer than five such individuals were known. But O'Brien and several others announced identification of dozens - perhaps hundreds - more.
Curiously, no one has found an African individual who is either heterozygous or homozygous for the anti-HIV gene. (Heterozygous individuals inherit a normal CKR-5 gene from one parent and the abnormal, protective gene from their other parent.) A Belgian study described at the meeting looked hard, and found none. And O'Brien found that even among blacks, many of whom have some Caucasian ancestors or parents, fewer than 2 percent carry the gene (vs. 24 percent of whites).
So why does this gene exist? It has to be relatively new because of its racial segregation. Scientists speculated the mutant form of CKR-5 protected against some scourge that afflicted Europeans but not Africans. The obvious candidate would be the Black Death of 1346, or plague. If the mutant CKR-5 blocked plague bacteria, the survivors would be more likely to carry the trait.
Why are heterozygotes slower to get AIDS? They have HIV "doorways," so their cells clearly can be infected. It turns out that when HIV attaches itself to the CKR-5 "doorways" a series of helpful chemicals is blocked. These chemicals, called chemokines, help the immune system fight off HIV. Several European laboratories, as well as that of Richard Koup of the Aaron Diamond AIDS Research Center, reported at this meeting that people who have the mutant CKR-5 genes make more of those protective chemokines. Dr. Ed Berger of the National Institute of Allergy and Infectious Diseases was among those who discovered CKR-5 and another HIV doorway dubbed fusin. "Are these the only two co-factors that are important?" he asked. "Clearly they are not."
Knowing some people are capable of battling HIV through these receptors and chemokines has fueled a long-standing debate: Is it the amount and type of virus in the body that dictates whether an individual will live years of disease-free life or succumb months after infection? Or is it something in that individual's immune system? If the virus is the key, the new triple-combination drug treatments that knock down HIV levels could eventually be curative. But if the immune system's weaknesses are key, there is little hope these therapies will work.
The evidence is contradictory. Dr. David Ho, director of the Aaron Diamond AIDS Research Center, says the body of an infected person makes 10 billion HIVs every day and 100 million CD4 lymphocytes daily to combat the virus. If the viral "factory" is shut down with drugs, Ho says, the immune system ought to be able to rev itself up.
But at this meeting, Dr. Frank Miedema of the Red Cross Transfusion Laboratory in Amsterdam, the Netherlands, presented contradictory evidence on the CD4 levels.
Miedema showed that those cells aren't dying or being replenished at the feverish pace described by Ho. It's hard to know for sure, because most CD4 cells are hidden in lymph nodes and other tissues where they can't be counted or tested for infection.
The University of Minnesota's Dr. Ashley Haas has studied the CD4 cells that may hide latent HIV deep in nodes and tissues. He told the gathering that "98 to 99 percent of all virus is in the lymphoid tissue ... and only 1 to 2 percent is in blood." If Haas is correct that would be terrible news for drug treatment because the new combination therapies can't reach viruses hidden in those lymph tissues.
Dr. Robert Siliciano of the University of Maryland has said that of the roughly 1 billion CD4 cells normally present in a person's body, fewer than one in every 30,000 are making HIV viruses. In his view, the numbers of latently infected T cells in hidden areas are orders of magnitude smaller than argued by Haas.
Who is right? Dr. Jacques Leibowich of the Hospital Raymond Poincare in Garches, France, told colleagues to concentrate on what's happening in patients. Leibowich declared, "I can say when they are on triple combination therapy, I see virus go away, CD4s go up and the patient is better."