By Laura Seeholzer
Have you ever wondered what mysteries primate poop could unlock? No? Me neither. But luckily, Dr. Beatrice Hahn did. Dr. Hahn was deeply curious about the origin and evolution of HIV (human immunodeficiency virus) so, naturally, her path lead to poop.
Don’t see the connection? Well, during Dr. Hahn’s recent visit to The Rockefeller University, she walked us down the poop path toward some astounding conclusions.
When HIV was identified in 1983, researchers almost immediately suspected that the virus came from non-human primates. This suspicion was heightened when a team of researchers found AIDS (acquired immunodeficiency syndrome), the fatal final stage of HIV, in a captive colony of macaque monkeys.
Over the last two decades, Dr. Hahn’s team has shown that HIV originated in a sub-species of chimpanzee. But how did they solve this mystery?
HIV in Humans
HIV is diagnosed in humans by looking for antibodies against the virus in the blood and saliva. When infectious agents like viruses or bacteria enter our body, our immune system generates antibodies that help destroy the invaders. Importantly, each of the thousands of antibodies we make generally recognizes one type of foreign substance. For instance, I got chicken pox when I was three, so if you searched in my blood, you would find antibodies against this virus. Conversely, I thought I had malaria on my 21st birthday, but a blood test revealed that my body was not producing antibodies against it- I was just really sick for some other reason.
SIV in monkeys
Simian immunodeficiency virus (SIV is the monkey equivalent of HIV) is also diagnosed by finding antibodies against the virus. The natural place to look for these antibodies would be the blood. But, fortunately or unfortunately, there are very strict regulations on working with wild monkey populations and Dr. Hahn’s collaborators did not get permission to collect blood. So how did they collect antibodies?
Ingeniously, Dr. Hahn and her colleagues devised a way to find SIV antibodies in feces! Over the past decade, teams of animal trackers across Africa have mailed Dr. Hahn’s lab fecal samples taken from primate populations.
Determining evolutionary relationships
Once Dr. Hahn’s team found SIV antibodies in the poop of many species of monkey, how did she determine which SIV was the ancestor of HIV?
Scientists can determine evolutionary relationships by evaluating the similarity of genetic sequences between species. For instance, when trying to determine our closest evolutionary relative, scientists compared human genetic sequences (our DNA) to ape and monkey sequences. Chimpanzees were found to be humans’ closest evolutionary relatives because their genetic sequences were more similar to ours than to other monkeys. This also means that chimpanzees and humans share a common ancestor.
Dr. Hahn used the same logic to determine the evolutionary relationship of the viruses, except instead of directly comparing genetic sequence, she compared the sequence of antibodies made by the host against the virus.
SIV has jumped the species barrier to infect humans in only a handful of cases, but Dr. Hahn’s group found that all HIV came from central African chimps. HIV’s cross-species jump has occurred independently at least four times. One of those jumps was the source of the pandemic M group HIV-1, which is responsible for 90% of the 33 million cases of HIV/AIDS.
While studying these cross-species jumps, Dr. Hahn found it curious that although there were two closely related types of SIV in chimps (one that infects chimps in central Africa and one that infects chimps in eastern Africa), the HIV originating from the central African SIV has been much more devastating to humans.
Why hasn’t SIV from eastern African chimps infected humans?
Dr. Hahn laid out three possibilities.
1. People were not exposed to SIV from these chimps
Very unlikely. Researchers think that humans became infected with SIV (which then evolved into HIV) by hunting and eating chimps. Both central and eastern chimps are killed for their meat.
2. Infection has occurred, but just hasn’t been detected
Unlikely, but still possible.
3. This type of SIV needs to undergo more mutations in order to survive in a human
Most likely. In order to survive and replicate (and cause all the nasty HIV/AIDS symptoms), the virus needs to interact with many host proteins. One barrier to SIV jumping species is that the primate version of a protein can look very different from the human version. If the primate virus cannot recognize the human protein, it cannot interact with it. Therefore, in order for primate virus to start infecting humans, it has to mutate (change its genetic code) to recognize human proteins.
In support of the third possibility, Dr. Hahn’s group found one striking example of a viral protein that needs to mutate to infect human hosts. Interestingly, this viral protein needs to undergo fewer mutations in the central African SIV than the eastern African SIV to become infectious to humans. They hypothesize that the need for fewer mutations made it easier for the central African virus to jump species and become infectious compared to the east African virus.
Why is this protein special?
Background: HIV and SIV replicate inside a specific type of immune cell (CD4+). To infect more cells, the virus needs to leave the cell it is in. Imagine an infected CD4+ cell as a ship that is being plundered by pirates (HIV). The pirates, after plundering the ship, want to leave and go plunder other ships. Before leaving this ship, they need to cut the ropes that are tethering them.*
Tetherin, a membrane protein discovered by Rockefeller’s Paul Bieniasz, binds to the HIV virus as it passes from the inside of the cell to the outside, preventing it from leaving. If the tetherin rope is not cut, the HIV pirates cannot leave to go plunder other ships. In order to cut these ropes, they need a very special knife. There are two types of proteins that are effective knives: vpu and nef.
The rope vs the knife: To cut ropes from a chimp ship (CD4+ cell), the chimp pirate uses a nef knife. However, chimp nef knives cannot cut human tetherin ropes. Biologically speaking, this is because the chunk of tetherin protein that nef recognizes has been deleted in humans. The virus that wants to jump ship (from chimps to humans) needs a new knife to infect humans. The protein knife can only change as a result of random mutation (genetic changes that happen to the virus by accident as it replicates).
The outcome: Unfortunately for millions of people, one of those random mutations (in another protein, called vpu) created a new protein knife for the virus. In humans, HIV pirates use vpu to cut the tetherin ropes and go plunder other CD4+ ships. Each time SIV jumped species to become HIV, a slightly different mutation turned vpu into a good tetherin knife. The vpu of the pandemic HIV is the most effective cutter of them all. Dr. Hahn speculates that this is why this specific type is so infectious.
Interestingly, vpu in SIV from eastern chimps needs to mutate more times to adapt to human tetherin. In other words, the knife needs to change more in order to cut the tetherin ropes. This could be one reason why only central chimp SIV has successfully jumped the species barrier.
By removing SIV antibodies from African monkey poop and comparing their sequence to HIV antibodies from humans, Dr. Hahn’s group showed that the pandemic HIV arose from chimpanzees from central Africa. Dr. Hahn has gone on to discover many other interesting facts about humans and monkeys. For instance, using similar techniques, she has found that western gorillas are the reservoir of Plasmodium falciparum, the most deadly form of malaria. But that is a story for a different post.
*Disclaimer: I use the word “cut” for illustrative purposes. It is unknown how vpu and nef disrupt the function of tetherin.
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