A Planet of Viruses - Carl Zimmer (2011)



The Young Scourge

Human Immunodeficiency Virus

Every week, the Centers for Disease Control and Prevention publish a thin newsletter called Morbidity and Mortality Weekly Report. The issue that appeared on July 4, 1981, was a typical assortment of the ordinary and the mysterious. Among the mysteries that week was a report from Los Angeles, where doctors had noticed an odd coincidence. Between October 1980 and May 1981, five men were admitted to hospitals around the city with the same rare disease, known as pneumocystis pneumonia.

Pneumocystis pneumonia is caused by a common fungus called Pneumocystis jiroveci. The spores of P. jiroveci are so abundant that most people inhale it at some point during their childhood. Their immune system quickly kills off the fungus and produces antibodies that ward off any future infection. But in people with weak immune systems, P. jiroveci runs rampant. The lungs fill with fluid and become badly scarred. Its victims struggle to breathe enough oxygen to stay alive. The five Los Angeles patients did not fit the typical profile of a pneumocystis pneumonia victim. They were young men who had been in perfect health before they came down with pneumonia. Commenting on the report, the editors of Morbidity and Mortality Weekly Report speculated that the puzzling symptoms of the five men “suggest the possibility of a cellular-immune dysfunction.”

Little did they know that they were publishing the first observations of what would become the greatest epidemic in modern history. The five Los Angeles men did indeed have a cellular-immune dysfunction, one that would turn out to be caused by a virus known today as human immunodeficiency virus (HIV). The virus, researchers would later discover, had been secretly infecting victims for fifty years. During the 1980s it finally exploded, and since then it has infected sixty million people. It has killed nearly half of them.

HIV’s death toll is all the more terrifying because it’s actually not all that easy to catch. You can’t get HIV if an infected person sneezes near you or shakes your hand. HIV has to be spread through certain bodily fluids, such as blood and semen. Unprotected sex can transmit the virus. Contaminated blood supplies can infect people through transfusions. Infected mothers can pass HIV to their unborn children. Many people who take heroin and other drugs have acquired HIV if they’ve shared needles with infected users.

Once HIV gets into a person’s body, it boldly attacks the immune system itself. It grabs onto certain kinds of immune cells known as CD4 T cells and fuses their membranes like a pair of colliding soap bubbles. Like other retroviruses, it inserts its genetic material into the cell’s own genome. Its genes and proteins manipulate then take over the cell, causing it to make new copies of HIV, which escape and can infect other cells.

At first, the population of HIV in a person’s body explodes rapidly. Once the immune system recognizes infected cells it starts to kill them, driving the virus’s population down. To the infected person, the battle feels like a mild flu. The immune system manages to exterminate most of the HIV, but a small fraction of the viruses manages to survive by lying low. The CD4 T cells in which they hid continued grow and divide. From time to time, an infected CD4 T cell wakes up and fires a blast of viruses that infect new cells. The immune system attacks these new waves, but over time it becomes exhausted and collapses.

It may take only a year for an immune system to fail, or more than twenty. But no matter how long it takes, the outcome is the same: people can no longer defend themselves against diseases that would never be able to harm a person with a healthy immune system. In the early 1980s, a wave of HIV-infected people began to come to hospitals with strange diseases like pneumocystis pneumonia.

Doctors discovered the effects of HIV before they discovered the virus, dubbing it acquired immunodeficiency syndrome, or AIDS. In 1983, two years after the first AIDS patients came to light, French scientists isolated HIV from a patient with AIDS for the first time. More research firmly established HIV as the cause of AIDS. Meanwhile, doctors were discovering more cases of AIDS, both in the United States and abroad. Other great scourges, such as malaria and tuberculosis, are ancient enemies, which had been killing people for thousands of years. Yet HIV went from utter obscurity in 1980 to a global scourge in a matter of a few years. Here was an epidemiological mystery.

To solve it, scientists began to sequence the genes of HIV they isolated from different patients. They examined HIV not just from the United States but from other countries around the world where it was beginning to spread as well. They drew evolutionary trees, with each strain of HIV a branch sprouting from a common ancestor. Researchers discovered that there was not one kind of HIV, but two. The vast majority of cases of HIV were caused by a strain that was dubbed HIV-1, and the rest were caused by a distinct form of the virus, called HIV-2. The two types of HIV could be distinguished in many ways, including the symptoms they caused: HIV-2 was much milder than HIV-1.

HIV, scientists found, belongs to a large group of slow-growing retroviruses, known as lentiviruses. Lentiviruses infect many mammals, including cats, horses, cows, and monkeys. In 1991, Preston Marx of New York University and his colleagues discovered that HIV-2 was closely related to lentiviruses that infect an African species of monkey called sooty mangabeys. They concluded that HIV-2 descended from a mangabey lentivirus. In West Africa, where HIV-2 is most common, some people keep the monkeys as pets; others eat them. Infected mangabeys may have introduced their lentivirus into humans with a bite.

It took scientists longer to pin down the origins of HIV-1, the strain that causes the vast majority of AIDS cases. That’s because the closest relatives of HIV-1 lived in primates that are much harder to study: chimpanzees. Relatively few chimpanzees live in captivity, and trying to get blood samples from chimpanzees in the wild can be a staggeringly hard job. They’re elusive, strong, and not fond of people with needles. Scientists had to develop new ways to test them for HIV, such as searching for the viruses in their feces. Slowly, scientists amassed a collection of HIV-1–like lentiviruses from chimpanzees. Comparing the viruses to each other, they discovered that some strains of HIV-1 are more closely related to certain chimpanzee viruses that they are to other HIV-1 strains. The branchings of the viral tree suggest that HIV-1 actually evolved from chimpanzee viruses several times.

But when did this transition happen? Some scientists tried to get an answer to that question by looking back at patients who had died mysteriously before the discovery of HIV. In 1988, for example, researchers discovered that a Norwegian sailor named Arvid Noe, who died in 1976, had HIV in his tissues. Reaching back further into HIV’s history was nearly impossible, because many of its earliest victims lived in poor countries and died without any careful medical tests that would identify unusual diseases like pneumocystis pneumonia.

It turned out that the viruses replicating in living people offered some powerful clues to the origins of HIV. Through the 1990s, scientists at Los Alamos National Laboratory amassed a database of genetic sequences of HIV taken from thousands of patients. They could then use supercomputers to compare these viruses and figure out which mutations the viruses had acquired since they diverged from a common ancestor. By adding up these mutations, the researchers found that HIV gradually acquires mutations at a roughly regular rate. In other words, the mutations piled up like sand in an hourglass. By measuring how high the sand had piled up, they could estimate how much time had passed. They estimated that the common ancestor of HIV-1 existed in 1933.

That estimate has been confirmed by the remarkable discovery of HIV preserved in tissues stored away in hospitals in Kinshasa, the capital of the Democratic Republic of the Congo in central Africa. In 1998, David Ho and his colleagues at Rockefeller University reported that they had isolated HIV from a blood sample taken from a patient in Kinshasa in 1959. In 2008, Michael Worobey and his colleagues at the University of Arizona discovered HIV in a second tissue sample from another pathology collection in Kinshasa, dating back to 1960. These two samples allowed researchers to confirm that HIV emerged in the early 1900s.

The molecular clock created by the Los Alamos researchers was accurate enough to predict the age of the Kinshasa viruses based on their genetic sequence alone. But the two viruses also provide a surprising glimpse at the diversity of HIV in Kinshasa around 1960. Worobey and his colleagues found that the old viruses were not closely related to each other. Instead, they were each closely related to a different branch of HIV-1 found in patients today. Studying the distant kinship of these two viruses, Worobey and his colleagues concluded that all of the major branches of HIV-1 found in the world today already existed in 1960. What’s more, they were all probably circulating around Kinshasa.

All this evidence is now pointing to how HIV-1 got its start. HIV-1-like viruses had been circulating among populations of chimpanzees throughout Africa. Hunters sometimes killed chimpanzees for meat, and from time to time they became infected by the viruses. But these hunters, living in relative isolation, were a dead end for the viruses. In the early 1900s the opportunities for these viruses changed as colonial settlements in central Africa began to expand to cities of ten thousand people or more. Commerce along the rivers allowed pathogens to reach the cities from remote forests. The chimpanzees carrying viruses most closely related to HIV-1 live today in the jungles of southeast Cameroon. It may be no coincidence that the rivers of that region flow south and eventually reach Kinshasa.

In the growing city of Kinshasa (then known as Leopoldville), HIV-1 could multiply. Instead of a few dead ends, it found a population that could sustain it and inside of which it could evolve into new forms better adapted to humans. By 1960, HIV-1 had bloomed into a wide genetic diversity, although it probably only infected a few thousand people.

Worobey and his colleagues have started to map the subsequent spread of HIV-1 out from Kinshasa to the rest of the world. The most common strain of HIV in the United States, for example, is known as HIV-1 subtype B. The oldest lineages of HIV-1 subtype B are found in Haiti, and Worobey estimates they branched off from African strains in the 1960s. That happens to be a time when many Haitians who had been working in the Congo returned to their homeland after the country became independent from Belgium. They may have unwittingly brought HIV back to the New World with them. Haitian immigrants or American tourists may have then brought HIV to the United States. The oldest lineages of HIV-1 subtype B in the United States, Worobey and his colleagues found, date back to about 1970. That’s about four decades since the virus became established in humans, and about one decade before five men in Los Angeles became sick with a strange form of pneumonia.

By the time scientists recognized HIV in 1983, in other words, the virus had already begun to turn into a global catastrophe. As a result, HIV has had a huge head start on scientists who hope to halt its spread. It would not be until the early 1990s that some strategies began to show real promise for slowing the epidemic. Changing people’s behaviors has proven effective. Uganda launched a major campaign against HIV that featured condom use and other public health measures. As a result, the country reduced its HIV rate from about 15 percent in the early 1990s to about 5 percent in 2001. Unfortunately funding for these programs began to ebb after a few years, and the infection rate in Uganda has begun to rise again.

Other researchers have investigated medications that can slow the rise of HIV in infected people, so that their immune systems can remain strong enough to block the onset of AIDS. Millions of people now take a cocktail of drugs that interfere with the ability of HIV to infect immune cells and use them to replicate. In affluent countries like the United States, these drug therapies have allowed some people to enjoy a relatively healthy life. But the cost of these drugs has meant that most people with HIV—living in the poorest countries—cannot afford a treatment that might give them extra years or even decades of life. That’s beginning to change rapidly, as the United States and nongovernmental organizations are now starting to provide these drugs to the most afflicted countries and as treatment programs are starting to be scaled up dramatically.

Yet these drugs, even if they can prolong lives, are not the perfect cure. They have side effects that can become harmful after years of therapy, and they foster the evolution of resistant viruses, which then requires shifting patients to new drugs. In theory, the best solution to HIV would be a vaccine—either one that could prevent people from becoming infected with the virus or one that could stimulate the immune system of infected people to attack it effectively. Vaccines would be far less expensive than treating HIV infection with drug cocktails and could help slow down the transmission cycle. But the quest for an HIV vaccine has been a disappointing struggle so far. In 2008, for example, a highly anticipated trial of a vaccine developed by Merck had to be abandoned because the vaccine appeared to be making people more likely to acquire HIV, not less.

There’s good reason to worry about any HIV vaccine, even one that shows promise in small trials. That’s because HIV is evolving in overdrive. HIV belongs to a group of viruses—including influenza—that are very sloppy in their replication. They create many mutants in very little time. These mutants provide the raw material for natural selection to act on, producing viruses that are better and better adapted. Within a single host, natural selection can improve the ability of viruses to escape detection of the immune system.

In 2008, Philip Goulder, a medical researcher at Oxford, led an international team of scientists who found evidence for the ongoing evolution of HIV. They studied the immune systems of 2,800 people from all over the world, examining proteins known as human leukocyte antigens, which infected cells use to transport fragments of viruses to their surface. The fragments can then be recognized by immune cells, which destroys the infected cell. Different people carry different variations in the genes for human leukocyte antigens. Goulder and his colleagues found that most of the HIV in each country carried mutations to the most effective human leukocyte antigens in that country’s population. Their findings tell us that HIV is rapidly adapting to the variations in human immune systems around the world. That is sobering news to those who are trying to build HIV vaccines. If a vaccine ever succeeds in boosting an effective immune response in people, HIV might well evolve a way to escape.

It’s possible that vaccine developers could keep HIV from escaping by continually rolling out new vaccines that would stay one step ahead of the virus. Another intriguing possibility is to look back over its history. A team of American scientists compared a wide range of HIV-1 subtype B strains and reconstructed one of the proteins made by their common ancestor. They then used that ancestral protein to make a vaccine. The researchers found that monkeys injected with the vaccine were able to produce an immune response to a much wider range of HIV strains than more conventional vaccines. The future of fighting HIV, perhaps, may lie in its past.