HIV insights from impaired retroviral-defense gene

From Dr. Harmit Malik's perspective, the pressure of disease-causing bacteria and viruses on the body's defenses is akin to the onslaught of computer-system hacking. If there were no "bad guys" in the information-technology world, network-security folks would be expendable. But the existence of new and ever-changing computer viruses keeps the security system active and ready for the next challenge. Without such pressure, we'd be lulled into a false sense of security.

Paradoxically, human immunity works much the same way, Malik and his colleagues have found. While we tend to think that disease-causing pathogens are never good, we actually need such stress from viral invaders to keep our defense systems active.

That's one of the research findings of Malik, of the Basic Sciences Division, and Drs. Sara Sawyer and Michael Emerman. They found a surprisingly large number of people may have impaired function of a recently discovered arm of the body's defense against invading retroviruses like HIV. Their research results, published in the Jan. 10 issue of the journal Current Biology, illustrate how human evolutionary history can shape our susceptibility to present-day and future viral infections.

The researchers, including Dr. Joshua Akey, a former Center postdoctoral fellow now at the University of Washington, and Lily Wu, a research technician in Emerman's lab, studied TRIM5α, a retroviral-defense gene in humans. According to Emerman, an HIV researcher in the Human Biology and Basic Sciences Divisions, TRIM5α represents a newly understood kind of immunity that is separate and distinct from the immune system as we know it. "The typical adaptive or innate immune response to an acute viral infection is to recognize the infection by specialized cells, which then triggers subsequent antiviral responses," he said.

"TRIM5α is intrinsic — it's present in most cells and is always active. It doesn't lead to other responses, but is itself responsible for both recognition and inhibition of viruses. It probably evolved with viral infections on a longer evolutionary time scale than the other two types of immune responses."

The TRIM5α gene encodes one of the key components of this intrinsic immunity. The gene was discovered because the version of it possessed by rhesus monkeys allows them to resist HIV infection, whereas the human version does not. Instead, the human gene predates viruses like HIV by many millions of years and was likely affected by now-extinct retroviruses.

Previous studies suggested that relatively few evolutionary changes in the TRIM5α protein were responsible for this difference in battling retroviral infection. This prompted the researchers to screen human populations for slightly altered versions of TRIM5α that might be able to resist HIV infection. They theorized that there were differences in degrees of susceptibility among humans.

The scientists sequenced the genomes of 37 geographically diverse, indigenous humans from Africa, the Middle East, Southeast Asia, Europe and Central and South America. Looking at indigenous people from the New and Old Worlds avoided the confounding factors of migration and interbreeding.

Evolutionary perspective is critical

Unexpectedly, the researchers found a single mutation in TRIM5α that impairs its ability to defend against retroviruses. This mutation — called H43Y — occurs at a very high frequency in some ethnic groups. It was found in 43 percent of the Central-and South-American samples, compared to only 4 percent of the Old World samples. "That frequency is really high for something that may make us worse off in the face of a retrovirus," said Sawyer, a postdoctoral fellow in Malik's lab.

"We concluded that past periods in human history corresponding to relatively low levels of retroviral infections may have allowed impaired versions of retroviral defense genes — such as the hobbled version of TRIM5α — to arise and thrive," said Malik, an evolutionary biologist who specializes in the study of genetic conflict. "Consequently, the abundance of this impaired gene may have deleterious effects on the ability of present-day humans to ward off infections by both old and new retroviruses."

Malik said the scientific world is starting to appreciate that an evolutionary perspective is almost as critical as a biochemical perspective in understanding disease. It holds huge promise for improving human well-being. HIV is an example of a virus that leaped from animals — chimpanzees, in this case — to humans. Previous to that, the virus was adapted from tree-dwelling monkeys to chimpanzees. With the passage of time, the virus ceased to harm monkeys, in part to allow its own survival. Studying the differences between our species may help pin down the genetic aspects of many such diseases.

The paper is the third in a planned series based on collaboration between the two labs. The joint research began two and a half years ago following a scientific retreat where Emerman described new findings about intrinsic-defense systems. Malik was looking for examples of "arms races" between viruses and hosts. "This work stretched both labs in new directions," Sawyer said.

Trim 5α and HIV infection

The scientists stress that the impaired TRIM5α gene has no effect on current HIV-infection levels because HIV entered the human population in just the last century. "There hasn't been time for the human-gene pool to adapt to the HIV invasion," Malik said.

"Up until 2 million years ago, all humans had a fixed version of this gene because that was the version that was presumably beneficial against some pathogenic virus that was currently threatening the human population," Malik said. "But the people who crossed the Bering Strait and founded the Americas 12,000 to 30,000 years ago faced fewer retroviral challenges. We need constant pathogenic pressure to maintain the defense system."

Lessons from the past

Malik said the New World humans made a tradeoff between defense and autoimmunity. "On one hand, you want a defense gene against retroviruses, but on the other hand, if you don't have any retroviral pathogens around, you might be better off without this defense gene because it could cause something like an autoimmune effect," he said. "It makes complete sense from an evolutionary viewpoint."

Sawyer, Emerman and Malik plan two more prospective studies to identify novel defense systems that exist. "Based on what we now know, we can look for similar evolutionary signatures in other genes," Sawyer said. "Most proteins evolve way below the speed limit; these defense genes are changing at a rate way above the speed limit to keep up with viruses. We're talking about the top 1 percent most rapidly changing genes in the human genome."

Given the migratory nature of modern humans, Malik sees a place for his study of the past. "Every time an isolated ethnic population encounters a new pathogen, it has a devastating effect, like when Native Americans first encountered smallpox," he said. "There are retroviruses that are not common in the New World but are getting reintroduced because of human migration. That's where these people might be particularly susceptible. We think our study may be very informative for that kind of research."

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