Excerpt from the Genome Generation

Elizabeth Finkel
Elizabeth Finkel

 

In her new book, The Genome Generation, journalist Elizabeth Finkel explores what we’ve learned in the ten years since the complete sequencing of the human genome. Her chapter on HIV/AIDS features Dr. Max Essex, Chair of HAI, and his work examining the genetics of the people of southern Africa, where the epidemic has hit hardest.

‘Botswana is a small piece of heaven,’ said the man slowly in his thick Setswana accent. He had come to fix my door at the Gaborone Sun hotel. Arriving 20 minutes earlier into the reeking hot room, I had slid open the balcony door to find a view onto a deserted car park. Then I could not slide the door back. Even though I was in peaceful Gaborone, capital of Botswana, spending the previous two weeks in crime- ridden South Africa had unnerved me. A determined intruder could make it in, even if I was on the first floor. Best to get it fixed. The hotel repairman had come promptly and taken about 20 minutes to fix it. I thanked him, saying I would be able to sleep peacefully as a result. He looked at me for a moment with an injured expression and then retorted, ‘You would have slept peacefully even with a broken door.’ Then he made his proclamation about the heaven that was Botswana.

‘A small piece of heaven’ certainly fits the image of Botswana I had gleaned from reading Alexander McCall Smith’s The No. 1 Ladies’ Detective Agency, part of my background research. Botswana also holds the dubious distinction of being the best place in the world to study HIV. In 1990, HIV was virtually unknown there. The country was rapidly modernizing thanks to the dual blessings of newly discovered diamond mines and a stable, democratic government. Its residents enjoyed the highest life expectancy of anywhere in Africa, 65 years. In a continent ravaged by war, corrupt governments and starvation, Botswana truly was a ‘small piece of heaven’. But through the 1990s, HIV spread like wildfire, especially ravaging women. The average life expectancy crashed to 40 years. Festus Mogae, the Prime Minister, warned, ‘Our population is threatened with extinction. People are dying in chilling numbers.’ In stark contrast to then South African president Thabo Mbeki’s denial of HIV as the cause of AIDS, in 2002 the Botswana government, with support from the Gates Foundation and the pharmaceutical company Merck, rolled out free antiretroviral drugs to the needy population. It was the first country in the world to do so.

For Max Essex, Botswana was the obvious place to look for an answer to the question that has compelled him for decades. While the virus has spread throughout the world, there is nowhere outside of Africa where adult infection rates exceed 4%. In Europe, the US, Australia, China and India, less than 1% of the population carry the virus. And within Africa, southern Africa is by far the worst afflicted. While northern Africans have a prevalence of 0.4%—the same or lower than their European neighbors—and middle African countries average 4.5%; in southern Africa the figure averages 23% for the countries of Botswana, Lesotho, South Africa and Swaziland. In the antenatal clinics of Botswana, a third of women on average are infected but in Francistown, the second largest town, the figure is an apocalyptic 40%.

Some experts have put it down to an unfortunate clustering of high risk factors. There is, for instance, a culture of having multiple concurrent partners, which spreads the virus like a chain reaction. In Botswana men often have a large house for the main wife and smaller ones for their mistresses. Others point to high-risk practices like anal sex and dry sex, or the prevalence of other sexually transmitted diseases that pave the way for HIV. By contrast, northern Africans may be protected by Islamic sexual mores or ritual male circumcision, which can reduce the infection rate by 60%.

Essex has never been convinced by these explanations. ‘It sort of slaps you in the face that rates are a lot higher in Africa and much higher again in southern Africa. You can’t get very far arguing cultural differences or poverty. Papua New Guinea and Cambodia [with a prevalence of 0.9% and 0.5%] are every bit as poor as southern Africa. Thailand has a huge sex industry [and a prevalence of 1.3%]. I think there are only two reasonable explanations. One is the genetics of the virus; the other is the genetics of the people. In southern Africa both are different—I suspect both are important.’

In the icy spring of 2008, I visited Essex in his office at the Harvard School of Public Health, a grey stone building that stretches for an entire block. Essex is a courteous, serious man in his late sixties. After 25 years on the campaign against HIV, clearly his pace and sense of urgency have not slackened. I managed to squeeze in an interview with him before his early morning conference call to Africa.

Essex trained as a vet and is one of the pioneers of HIV research. Together with Robert Gallo and Luc Montagnier he received a Lasker award in 1986, second only to the Nobel Prize in scientific prestige, for his contribution to identifying HIV as the cause of AIDS. Essex has continued to sleuth HIV over two and a half decades and much of the sleuthing has been directed at the mystery of African AIDS. Why did it spread so much more rampantly into the southern most countries? And why did it infect more women than men here, while doing the reverse in America and Europe? To answer those questions and others, in 1996 Essex set up Harvard Botswana, an HIV research institute on the grounds of Princess Marina Hospital.

Perhaps the virus itself was different? In other words, some countries were just unlucky enough to be infected with particularly virulent strains of the virus or strains that preferred women to men. Strains of HIV do indeed differ. This was dramatically illustrated in 1986, when researchers discovered that the populations of West Africa were infected with a much more benign type of virus. Only 1–2% of the population was infected and of those only 1–2% went on to develop AIDS. The virus was so genetically different that it was labeled HIV type 2, or HIV-2. The discovery of this virus made Essex wonder if more subtle genetic differences could explain the different characters of HIV. To a tantalizing extent they did. Within the main virus type, HIV-1, there are different ‘subtypes.’ Subtype B is found in those countries where the epidemic predominates in the gay and drug-using population, and also in the white population of South Africa. Subtype C is found where the epidemic is largely heterosexual, like southern Africa and India. Subtype E is closely related to C and has fuelled the heterosexual epidemic in Thailand.

Laboratory tests by Essex and colleagues shed some light on why the different strains behave differently. Those associated with heterosexual spread, C and E, are good at entering and growing in the cells that line the vagina and foreskin—so-called Langerhans cells (this explains why male circumcision protects against HIV infection). By contrast, subtype B doesn’t do that well in Langerhans cells, which probably explains its very low rate of heterosexual transmission. Studies suggest it’s as low as one in 1,000 exposures of heterosexual intercourse. To enter the body, subtype B probably relies on ruptures to the tissue lining, more common with anal intercourse.

Notwithstanding his own compelling discoveries, Essex doesn’t believe viral subtypes are the whole answer. For one thing, it is hard to understand why subtypes of HIV seem to stay confined in one population when the virus has clearly demonstrated an impressive ability to traipse around the world. HIV-1 seems to have originated in equatorial Africa in the late 19th century when it jumped from chimp to human populations. From there it spread to Haiti, then to the US and back to Africa and the rest of the world.

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When it comes to human genetic variation, nowhere is it greater than across Africa.

This is where the family of man began some 200,000 years ago. The diverse races of Africa represent thick gnarled branches growing out in different directions from the trunk of the family tree. They have had hundreds of thousands of years to diversify. By contrast, the people who populate the rest of the world are all recent offshoots of one branch. They show far less genetic diversity.

So it is not hard to imagine that the genes of Africans might be very different from those of Europeans or Asians when it comes to susceptibility to HIV. Small-scale studies from Harvard Botswana and others have already shown that to be true. For instance, the CCR5 Δ32 gene variant that Steve O’Brien found to reside in about 10% of Europeans is entirely absent from the African population. Africans also miss out on the HLA C protective variant and another one called ZNRD1. And it turns out that a gene variation that protects them from malaria—DARC—may predispose them to HIV infection.

Given these inklings of difference, Essex told me, ‘I think it would be derelict not to examine the genetics of the people.’ His notion that genes hold part of the answer to AIDS in Africa has already started to provide some dividends for people in Botswana, as I discovered on my visit to Harvard Botswana in February of 2008.

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Genome Generation Book CoverWester is a genial, softly spoken man. He and his wife came to Gaborone in 2001 to do AIDS research and helped set up Masa or ‘new dawn’—the program to deliver HAART. There was no guarantee that the AIDS drugs would produce exactly the same effects in southern Africans, nor the same side effects. Wester found a case in point, a type of drug known as a nucleoside reverse transcriptase inhibitor (NRTI). The drug puts a spanner in the works of a crucial bit of the virus machinery, the reverse transcriptase that rewrites the virus’s RNA genome as DNA. If the virus can’t be rewritten as DNA, it can’t replicate. But in some people the spanner also creates havoc in their mitochondria. Mitochondria are power plants that live inside our cells and generate energy from sugars. Curiously they carry their own DNA, probably because they evolved from bacteria. The enzyme that copies their DNA is also susceptible to the NRTI drug. The drug can damage the mitochondria’s DNA and when it does, power generation fails and nasty by-products like lactic acid build up—the same stuff that makes your muscles ache after a workout because your mitochondria can’t keep up. Ultimately it leads to lactic acidosis, a condition that acidifies the blood and causes death within days.Dr Bill Wester met me in the bustling front grounds of Princess Marina Hospital and we made the short stroll around the back to Harvard Botswana. Seeing its granite façade rising above the low cream brick buildings of the hospital, the metaphor of an ivory tower was inescapable.

In studies on Western populations, this side effect is seen with a particular class of NRTIs, known as D drugs, in 0.1–0.4% of people. But in the population of 3,000 Botswana, people that Wester has been studying, 1–1.2% are showing the side effects, up to 12 times the rate. And whereas in the West the symptoms appear in men and women equally, in Botswana women are overwhelmingly the victims. The first symptom is a deceptive one: women start putting on weight, usually a sign that people are responding well to drug therapy. But these weight-gainers are the ones who suddenly develop lactic acidosis. If not taken off their medication promptly they proceed irreversibly to death. Thanks to Wester’s findings, cheaper D drugs are being phased out in Botswana. ‘The good news is our research paper changed public policy.’

The different responses to drugs are just one more compelling reason to peer into the genomes of Africans. While many studies have looked at how the genes of Europeans predispose them to HIV, the question hasn’t been addressed in the population most afflicted by HIV. At Harvard Botswana, Essex is collaborating with Steve O’Brien to do the first systematic study of HIV modifying genes on a southern African population. O’Brien, compelled as ever by the secrets lurking in genomes, told me, ‘Not everyone agrees with Max’s hunch. But I’d love to find the genes that predispose to heterosexual transmission.’ The pair will try to identify genes that predispose people, particularly women, to infection; genes that determine how fast people progress towards AIDS; and genes that determine how fast people recover after drug therapy.

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Despite endless prevention campaigns like Botswana’s ABC: ‘Abstain, Be faithful, Condomize’, HIV continues to spread across sub-Saharan Africa, most aggressively in young women. The majority of those now infected are likely to die terrible deaths because, unlike Botswana, they don’t have access to treatment; while those fortunate enough to be treated may end up trading one disease for another. There is no vaccine and no hope of one for at least a decade. And researchers cannot even say why it has spread so rampantly in some places and not others.

In places like sub-Saharan Africa it seems we are losing the battle against HIV. But we may yet win the war. HIV has taught us to look for answers within. Instructed by genes from rare individuals, the immunologists are learning new lessons that will teach them how to take command of the immune army. The rewards of that will be profound, not only for tackling HIV but also malaria and tuberculosis and the plethora of diseases from cancer to arthritis, that at some level result from an immune system gone awry. The next plague virus that appears out of nowhere will find the human race considerably better prepared. For now, HIV needs to keep blipping loudly on the global radar screen. By the time this book is published some 33 million people will have died from AIDS.

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About Martha S Henry

Martha Henry is the Director of Communications for the Harvard T.H. Chan School of Public Health AIDS Initiative.