Fred Hutch's Dr. Michael Emerman studies the viral, chimp and human evolutionary steps that ultimately allowed HIV to come into the world.

It’s important to understand the protection these genes provide — and why it failed one fateful time — because chimps are our closest relatives and because SIVcpz is very similar to HIV. Once chimps were infected, it was a short hop, evolutionarily speaking, to HIV in humans.

Identifying the chimp genes that protect those animals from contracting other HIV-like viruses will help us understand humans’ strengths and weaknesses against HIV — and which natural monkey viruses may have the potential to spawn new human epidemics, Emerman said.

Of viruses old and new

Chimps naturally prey on a variety of monkeys, and there are several other kinds of monkey viruses (such as simian foamy virus) which easily pass from prey to predator. So there must be something special about SIV — or, more specifically, about chimps’ immune response to SIV — that makes that virus less likely to jump from monkey to ape.

At least 40 species of African monkeys are infected with their own, specialized strains of SIV — and have been for upwards of 10 million years, Emerman said.

SIVcpz and HIV are much newer. The chimp virus arose somewhere between 1,000 and 20,000 years ago. HIV is only about 100 years old — a mere bud on the viral family tree compared to its predecessors.

Viruses’ age tells us something about how pathogenic, or disease-causing, they are. Monkeys and their SIVs have had millions of years of co-existence and live in relative harmony.

SIVs "have been in the monkeys long enough that the hosts have now adapted to tolerate those viruses,” Emerman said. “They don’t cause disease like (HIV does) in humans.”

HIV’s very young age may explain why it’s so virulent in humans: We’re in the rocky phase of our evolutionary relationship with the virus. However, chimps also get sick from their version of SIV, so even another several thousand years’ time won’t fix our relationship problems.

Attack and counterattack

To better understand why chimps were infected only once with SIV, the researchers concentrated on a pair of genes — one viral, one chimp. Emerman and Etienne teamed up with the University of Pennsylvania’s Dr. Beatrice Hahn, the virologist responsible for originally uncovering HIV’s chimpanzee origins. In a previous study, the team found that mutations in one SIV gene, known as vif, were the key that allowed the virus to slip through chimps’ immune defenses.

In their current study, the group looked at the chimpanzee immune defense genes known as the APOBEC3 gene family, the genes that vif evolved to target. Proteins encoded by APOBEC3 genes are able to protect human (or chimpanzee) cells from some viruses, but viruses such as HIV and SIV use the Vif protein to counterattack, causing the host’s cells to destroy their own APOBEC3 proteins and rendering them more susceptible to infection.

Vif from HIV, of course, is able to overcome our own defenses. And SIVcpz Vif can bypass chimpanzee blockades. The researchers engineered HIV to contain a variety of vif genes and then looked at the virus’ ability to infect human or chimpanzee cells containing different chimp APOBEC3 proteins.

They found that the chimp APOBEC3 family could block infection from HIV containing vifs from 10 different monkey species, including those the chimp feeds on in the wild, but not vif from SIVcpz — the virus that naturally infects chimpanzees. One of the chimp proteins, APOBEC3G, had the strongest antiviral powers, but some of the other APOBEC3 proteins also blocked infection.

Those findings suggest that this family of potent antiviral genes is likely the reason that SIV has not made the leap from monkey to chimp more than once, the researchers wrote.

Having several different APOBEC3 genes in this large antiviral family “contributes to a better protection of the host, as the incoming virus would need to adapt and counteract diverse opponents,” Etienne said.

Understanding the interplay between vif and APOBEC3 “helps us better understand which viruses may be more prone to cross the species barrier to humans,” Etienne said. With the knowledge uncovered by this study, researchers could test vif genes from more African monkeys to understand whether any of those SIVs may be close to broaching our immune defenses. And knowing more about our natural defenses to HIV and other viruses could help researchers design better antiviral drugs to help our bodies combat them, she said.