In the 25 years that Ron Rosenes has lived with HIV, he has always suspected something more than good fortune shielded him from the worst of the disease.
Mr. Rosenes feels he contracted the AIDS virus before anyone knew it existed and "safe sex" became the mantra of a generation. "I was sexually very active in the late seventies," he said.
He has lost several friends and a close cousin to AIDS. In 1990, he watched his partner of 15 years die in the home they shared.
But even as he lost weight, left his job and made do with the "sub-optimal therapies" of the early nineties, Mr. Rosenes held on.
He never suffered the opportunistic infections others endured. He never picked up anything life threatening. Although his viral load soared and certain immune cells plummeted, blood test after blood test showed a healthy presence of other immune cells.
"It became more obvious to me, especially after [my partner]died, that I was being spared."
The 59-year-old Toronto man may well have his family history to thank. Mr. Rosenes carries a gift in his genes - a mutation that confers a natural resistance to HIV. In all likelihood, it was passed down to him from his ancestors in Europe, where the protective trait is most prevalent.
From the earliest days of the epidemic, doctors have puzzled over long-term HIV patients who show little progression from infection to full-blown AIDS. Some have never had to take even a single drug to keep the virus in check. Others, despite repeated exposure, have never contracted it.
The question now is whether their good fortune truly is inherited.
The mutation Mr. Rosenes carries is the best-known example of genetic resistance to the AIDS virus. It offers not immunity, but a form of protection that drug makers are keen to mimic. But there are most certainly other genetic traits that confer resistance or susceptibility to HIV, and the race to find them has begun in earnest. An effective treatment, perhaps even a vaccine, hangs in the balance.
In the United States, two separate research groups have recently identified traits linked to HIV susceptibility. Scientists at the British Columbia Centre for Excellence in HIV/AIDS are recruiting HIV patients considered to be "long-term non-progressors" who have never actually developed AIDS.
This spring, an international consortium of universities launched an ambitious project to scan the whole genomes of hundreds of HIV-positive Europeans and Africans for mutations that might be linked to the disease. Some scientists even suspect genes may partly explain why HIV has hammered certain regions more than others, sub-Saharan Africa in particular.
"My hypothesis is that there are biological differences in susceptibility, and knowing them will be crucial for the development of a vaccine," said Jacques Pépin, a professor of microbiology and infectious diseases at the University of Sherbrooke. "If we don't know why some people get infected and others don't, why some people get sick and others don't, we'll never understand how the virus works or how to stop it."
Mr. Rosenes has made good use of his time. He's been chair of the AIDS Committee of Toronto, a board member of the Canadian Treatment Action Council and the willing subject of research.
In the mid-nineties, he submitted his blood for an experiment at McGill University investigating ways to boost the immune system. Not long after, the lab called to tell him about the protective quirk they'd found in a gene called CCR5.
"I really found out about it in a fluky kind of way," Mr. Rosenes recalled.
CCR5 is a gene that produces tiny keyhole-like entry points on the surface of the immune system's T cells. They're known as chemokine receptors. HIV, like a savvy burglar, happens to have the right set of molecular keys to unlock them and break into the cell to cause infection. There are about 23 different mutated versions of the CCR5 gene. But the most common and best understood is one called CCR5-Delta32. People with this mutation have 32 bits of genetic code deleted in the CCR5 gene. The missing bits result in fewer entry points on the cell surface, upping the chances of shutting out HIV.
People who have one Delta32 copy - as Mr. Rosenes does - have partial resistance, with a two- to four-year delay in the progression of HIV. Those who inherit two copies of the Delta32 mutation - one from mom and the other from dad - have almost absolute protection.
"If they have one copy, we call them lucky. If they have two copies, we call them really very lucky," said Richard Harrigan, director of the research lab at the B.C. Centre for Excellence in HIV/AIDS.
Mr. Rosenes, vice-chair of the Local Host board of directors of the 2006 International AIDS Conference in Toronto this week, feels that his mutation "helped to bridge the gap" between the time he contracted the disease and when effective drugs became available in 1996.
"I understand it as a key factor in my long-term survival," he said.
Since its discovery in 1996, studies have piled up showing the protective mutation is more common in certain places in the world. In Europe and West Asia, the prevalence rate runs as high as 10 to 15 per cent, and the numbers rise the farther north you go. In Southern Europe, it's roughly 4 per cent or less. A 1998 study that tested 2,500 people from 16 European countries found the highest frequency in Denmark and the lowest in Corsica.
One per cent of Caucasians are estimated to have the two copies that confer near-immunity to HIV. In particular populations, such as Ashkenazi Jews of Eastern Europe, a group that includes the ancestors of Mr. Rosenes, estimates peg the rate as high as 15 per cent. But in native Indians, East Asians and people in sub-Saharan Africa, home to two-thirds of the world's AIDS cases, the mutation is rare to non-existent.
To Dr. Pépin, the pattern supports his view that certain populations face a higher biological risk of contracting HIV.
"Everybody in the field knows the prevalence in Africa is higher than the rest of the world," he said. HIV rates in parts of sub-Saharan Africa are higher by 400-fold compared with Scandinavia, he noted.
Most people accept that most of the gap can be explained by socio-economic differences that have nothing to do with DNA, said Dr. Pépin, who worked in Africa during the 1980s. These include the region's poor state of nutrition and lack of access to hygiene, health care and education. The urbanization of Africa has also brought men to the cities, leading to more transient sex, more commercial sex and a higher prevalence of other sexually transmitted diseases. All of these things increase the risk of spreading HIV.
"If you look at a map of the world, you see the regions with the highest prevalence are sub-Saharan Africa and the Caribbean, places where there are populations who came from Africa as slaves," Dr. Pépin said.
To investigate this, Dr. Pépin decided to look at a place of mixed populations and determine if there was any correlation between a person's geographical ancestry and HIV prevalence. He picked 34 countries in the Americas, including Haiti, largely populated by descendents from sub-Saharan Africa; the Dominican Republic, with its blend of Spanish, European and African descendants; Cuba, with a 10 per cent African and 30 per -cent mixed European population; and Argentina, which imported relatively few African slaves.
He then relied on HIV prevalence rates in the countries of origin to predict the prevalence rates among population groups in the countries of mixed populations - and they closely matched.
"What I observed is not due solely to behavioural factors," he said of the work, published last summer in the journal of Tropical Medicine and International Health.
The pattern, he pointed out, is also what you might expect to see when something like a CCR5 protective mutation is present at such low levels in one population and higher levels in another.
"But there is not a single factor that explains it all," he said.
The CCR5 gene mutation sprung up as most do: a one-time, random event in a single person. Initially, scientists thought it happened fairly recently, popping up just 1,000 years ago and then spreading rapidly across Europe, helped by the Viking raids of the 8th to 10th centuries, but more so because the mutation offered some form of a survival advantage.
"There must have been some kind of an epidemic in Europe, which extended to North Africa, that wiped out the people who [did not have the mutation]" Dr. Pépin said. "It's possible that populations in Africa suffered a little bit, but maybe [that epidemic]didn't reach portions of sub-Saharan Africa."
A number of candidates have been suggested: the bubonic plague, typhus, influenza. But to Montgomery Slatkin, a population geneticist at the University of California at Berkeley, none of these fit the bill.
These historical infections, he explained, did not result in enough deaths in a short enough time period to change the frequency of the CCR5 gene type to such an extent.
Dr. Slatkin and his team constructed a mathematical model of the mutation's spread and concluded smallpox was the likely candidate. The highly contagious virus killed up to 40 per cent of its victims in Europe during the Middle Ages and hit the continent's northern countries especially hard.
But scientists now suspect the mutation may be much older than originally thought. German researchers discovered it in the DNA of 2,900-year-old Bronze Age skeletons and in the remains of people who died of bubonic plague in the 14th century. Further genetic analysis also suggests it may be 5,000 to 10,000 years old.
Given these findings, Dr. Slatkin said a number of factors could have contributed to the spread of the protective mutation in Europe. But the smallpox epidemic, he said, "remains a plausible explanation" for its relatively high frequency in Europe.
In fact, Dr. Slatkin estimates that if AIDS continues its deadly spread in Africa, the resistant trait could soar from near zero in the southern part of the continent to as high as 10 per cent in 200 years.
When Sunil Ahuja entered the arcane world of immune-system receptors in the early 1990s, it was, he says, "a sleepy field." But after CCR5's role in HIV was uncovered a decade ago, "there was a stampede."
Yet Dr. Ahuja, now an HIV researcher at the University of Texas Health Science Center at San Antonio, points out that a raft of other traits, both in and around the CCR5 gene, deserve attention.
"People have tended to focus just on this," Dr. Ahuja said, "but what about all of its other partner [mutations]" Dr. Ahuja, collaborating with Lieutenant-Colonel Matthew Dolan of the U.S. Air Force Wilford Hall Medical Center, turned his eye to the genes that produce chemokines.
Since HIV locks on to chemokine receptors as its "kiss of entry" into a cell, he decided to investigate the genetic production of chemokines - molecules the body makes naturally to lock on to that same entry point. A gene called CCL3L1 does exactly that.
When Dr. Ahuja and Col. Dolan analyzed blood samples of more than 4,300 HIV-negative and HIV-positive people of different ancestral backgrounds, they found an astonishing thing: The human genome has mysteriously stockpiled extra copies of this gene.
Some individuals carry as many as 10 to 15 copies of the CCL3L1 gene (generally, people have been thought to inherit two copies of a gene, one from each parent). People of African descent, Dr. Ahuja said, were found to have on average six copies; Hispanics, three and Europeans, two. The study, published in Science in March of 2005, found the fewer copies of this gene people have, the more susceptible they are to being infected after having unprotected sex with someone who is HIV positive.
This is because with extra genes, the body throws so many of its own molecules at the CCR5 entry point, it gums up the lock and makes it tougher for the AIDS virus to break through, Dr. Ahuja explained.
From this, you might assume Europeans are more prone to HIV infection since they have fewer copies of this blocking gene than African populations. But the researchers found that the risk was relative to a person's population - it increased if you had fewer copies than other people in your ethnic group.
African Americans were found to be more susceptible to HIV infection if they had fewer than four copies of the gene. Hispanics were at greater risk if they had fewer than three copies and Europeans if they had less than two copies.
"What we see here is a gene dosage effect," Dr. Ahuja said. "The more genes, the more protection."
Having below the group's average number of genes significantly increased the risk of getting HIV - and the chances of having rapid disease progression. That risk may be even higher if there is a low number of the CCL3L1 gene and the riskier, unmutated form of CCR5.
"The point is that this is going to be a very complex story," Dr. Ahuja said. "There are many questions yet to answer."
Researchers face three major hurdles in finding genes linked to HIV infection. First, doctors don't often come across patients like Mr. Rosenes, who appear to have a natural, if partial resistance to HIV. In B.C., Dr. Harrigan said the trial studying long-term non-progressors has yet to recruit any patients.
Without the big numbers of a large study, it can be tricky to tell when a trait is important or just a personal quirk.
Nor is there any simple way to factor in all of the environmental and behavioural forces that affect a person's risk of contracting HIV.
Even Dr. Pépin admits that his study predicting HIV prevalence in mixed populations is limited by its inability to completely take environmental or behavioural factors into account.
Third, it has been difficult to know exactly where in the genome to look for traits that might confer resistance or susceptibility.
But the newly formed Center for HIV/AIDS Vaccine Immunology (CHAVI), a consortium of universities and academic institutions around the world, has this year launched a massive study it hopes will overcome these issues.
"We have these beautiful machines [for DNA analysis] and the money that the Gates Foundation has given to us, and we have had no people [to study]" said Amalio Telenti, an HIV researcher at the University of Lausanne in Switzerland who is working on the project.
But CHAVI has in fact just recruited 600 Caucasians from Europe and Australia who have all contracted HIV within the past decade. Researchers have access to their personal histories and medical files, and plan to scan half a million genetic mutations in each subject.
Dr. Telenti said the team is using the mutations set out in the Haplotype Map. That map is the first catalogue of the different genetic mutations found in four of the world's major populations - European, Chinese, Japanese and Nigerian.
Once this is complete, the second round of the project will focus on Africans or people of African descent, Dr. Telenti said. He then hopes researchers in other countries will use their approach to scan the genomes of other populations.
But while they are studying groups by ancestral background, Dr. Telenti said he does not expect to find major HIV-response differences between populations.
Rather, he said, it will more likely be the subtle effects of a number of traits.
"No one is looking for a miracle gene, but to help find targets for antiretroviral [agents]" Dr. Telenti said. "We need to understand the basis of susceptibility, and to what extent genes can explain that."
For Mark Wainberg, director of the McGill University AIDS Centre in Montreal, the hunt for genes that affect a person's response to HIV is well worth it, since it may lead to more effective therapies.
"Finding the mutation in CCR5 has already led to efforts to make a drug to block this," he said. "The thinking is, if there are healthy people walking around out there with deleted copies of this gene, then it would be a safe target for a drug."
As well, genes are already known to influence the way people respond to drugs, an issue that is becoming more urgent in the face of growing resistance to current antiretroviral therapies.
But Dr. Wainberg, co-host of this week's International AIDS Conference, also worries that people who believe they carry some form of genetic protection against HIV will become complacent: "It doesn't matter if you have one copy or two copies [of a gene] you should still have safe sex," he said.
Research suggests he has good reason to worry. A 2001 study found a correlation between gay men who carry two copies of the protective CCR5 mutation and an increase in risky behaviour.
Dr. Ahuja saw himself how the public might overestimate the power of genes to protect them from infection. When he once told The New York Times that two copies of the CCR5 protective mutation was like a "genetic condom," his voicemail clogged up with people wanting to know where they could buy it.