A New Possibility for How HIV Made the Leap to Humans

Kei Sato, PhD

Scientists have a new theory of how the simian immunodeficiency virus (SIVcpz) might have made the evolutionary leap from chimpanzees to humans.

An international team led by researchers at the University of Kyoto, Japan, report that a variant of the HIV accessory protein Vpu has the ability to inhibit tetherin, a protein that serves as a natural defense mechanism and slows viral replication. In their paper, the team posits that this variation is the key function that allowed SIV to infect a new host—humans.

Study author Kei Sato, PhD, associate professor at the University of Tokyo’s Institute of Medical Science, told MD Magazine that tetherin is an intriguing piece of the HIV story.

“The interaction between human tetherin and lentiviral Vpu is strange,” Sato said. He noted that of the four subtypes of HIV type 1, only one subtype, M, is pandemic. That type has a unique link to tetherin.

“Interestingly, only group M HIV-1 Vpu is able to antagonize human tetherin, while the others cannot,” Sato said.

However, further back in the virus’ evolutionary chain, the Vpu associated with SIVcpz has no such tetherin-antagonizing capability.

Thus, Sato and his colleagues surmised that the defeat of tetherin had to be critical in order for SIV to leap into humans, and for the resulting HIV virus to efficiently transmit from human to human.

To test the hypothesis, the researchers used an immunodeficient mouse model with a reconstituted human immune system, made from human blood-forming stem cells. The team then used genetic reverse-engineering to pit several variants of HIV against different mutations of Vpu, in hopes of determining which Vpu function allowed the virus to infect humans. They confirmed that Vpu can defeat tetherin by inhibiting immune signaling pathways in the cell, thereby decreasing tetherin.

They further found that SIV itself was unable to infect the human blood cells in the experiments, except when SIV was given properties similar to HIV Vpu. Only then could the virus replicate in the human cells.

Sato said this insight could have implications not just for HIV, but for any number of animal-to-human viruses, including Ebola or Zika viruses.

“I think revealing host-virus interaction at the molecular level (i.e., the battle of tetherin and Vpu, in our case) will lead to not only understanding how viruses leaped from animals to humans but also providing a novel insight to prevent viral transmission from animals to humans,” he said.

He noted that, “the antiviral effect of human tetherin is not so strong compared to the other restriction factors. But still, the viruses without functional Vpu do not efficiently expand in vivo (humanized mouse model).”

Earlier, Sato’s team published a study showing that tetherin can play a role in “herd immunity” against HIV-1 in humans. Further investigation is needed to clarify exactly how tetherin is able to control the infection and spread of HIV-1.

Sato’s paper, “Human-Specific Adaptations in Vpu Conferring Anti-tetherin Activity Are Critical for Efficient Early HIV-1 Replication In Vivo,” was published earlier this year in Cell Host & Microbe.