Pangolins, Pan troglodytes, and Pandemics

Crossing the Pan troglodyte Bridge It took over 30,000 years.1,2 Immunodeficiency viruses have been infecting primates for tens of thousands of years. Simian immunodeficiency virus, or SIV, has been infecting nonhuman primates for millennia, including chimpanzees, gorillas, and sooty mangabeys.3 Yet human beings were likely immune to SIV epidemics for much of that time.4,5 Thanks to a favorable genetic mutation – the deletion of 5 amino acids in a protein called tetherin – SIV cannot successfully release virus particles from infected cells inside the human body.6 Around the start of the 20th century, something changed. SIV infections are still common among monkeys and often asymptomatic.7 They can also be found in chimpanzees, which live in close proximity to many species of monkeys and often prey on them. While the details are still unclear, chimpanzees likely picked up cross-species forms of SIV over time, and possibly simultaneous infections from different species of monkeys.8 By chance, these SIV viruses combined to create a new strain of SIV known as SIVcpz.9-12 This new chimeric strain of SIV in chimpanzees developed a feature that its predecessors lacked. It had an accessory protein, known as Vpu. This accessory protein just so happened to be the perfect countermeasure to tetherin, the very protein that had been protecting us from infections all this time. With this new mutation, immunodeficiency viruses finally had a way in.13,14 The virus that we know today as HIV, or human immunodeficiency virus, is closely related to SIV. Different types and subtypes of HIV can be traced to different strains of recombinant SIV. The HIV-1 group M subtype, which has been responsible for most of the HIV infections across the world, is likely the evolutionary descendant of the recombinant SIV strain found in chimpanzees.15 Other HIV variants appear to be more closely related to SIV subtypes found in gorillas or sooty mangabeys.16 The crossover between chimpanzees and humans most likely occurred around a hundred years ago.17 Bloodborne transmission remains the most likely route of cross-species spillover. Routine hunting and butchering practices may have led to humans with open wounds touching virus-laden blood from their primate prey.17 However, viral transmission in and of itself was not sufficient to cause disease, let alone cause a global pandemic. Left untreated, HIV leads to acquired immunodeficiency syndrome, or AIDS, which weakens the immune system and leads to a variety of secondary infections as a result. Treatments and preventative measures have come a long way in the past few decades, transforming HIV infections from a guaranteed death sentence into a manageable chronic condition, but access to treatment remains deeply unequal, and the global burden of HIV/AIDS is still unacceptably high. The HIV/AIDS pandemic now ranks among the deadliest in human history.18,19 Yet, it remains unclear why HIV leads to such a devastating outcome for human beings in the form of AIDS, especially when its predecessor, SIV, can often be asymptomatic for monkeys.20,21 The relative novelty of HIV at only 100 years old, as compared to the age of SIV – closer to 32,000 years old – almost certainly makes it harder for us to coexist with our species-specific version of the immunodeficiency virus.23 Still, more research is needed to understand not only how viruses spill over from other animals into humans, but also why, when, and how they start to pose a real risk to human health.22 The different types and subtypes of HIV, as well as the different evolutionary pathways they took, all suggest that immunodeficiency viruses were given lots of opportunities to cross over from nonhuman primates into the human population, and that they were successful more than once. Humans constantly interact with their environment and with each other. Lucky for us, most of these interactions do not result in deadly infections, but each interaction presents an opportunity for such an event to occur. While a hundred monkeys on a hundred typewriters have yet to give us Hamlet, it turns out that if you give more than 40 different species of monkeys about 32 000 years to circulate a variety of immunodeficiency viruses, at some point the viruses do end up with enough mutations to infect other primates, including human beings. Exonerating the Pangolins In 1984, the American Journal of Medicine identified a Canadian HIV/AIDS patient as “Patient O,” which stood for “out-of-California.” At the time, several case clusters had been identified, including one in California. “Patient O” appeared to be the link among this California cluster. Somewhere along the way, the “O” was either misread or otherwise changed to a zero. The term patient zero has since come to signify the first person infected with a new virus, and in more sinister interpretations, the person responsible for the outbreak.23,24 The scapegoated patient zero of the HIV/AIDS pandemic recalls the plight of Mary Mallon, an Irish immigrant who immigrated to America in the late 1800s. She worked as a cook for wealthy families around New York City until a typhoid outbreak in one of the homes she worked at caught the attention of the local landlord, who was concerned about his property values. Mary turned out to be an asymptomatic typhoid carrier. She was branded as the culprit behind the outbreak and imprisoned.25,26 We now know that a lot of asymptomatic carriers were probably spreading typhoid around New York City at the turn of the 20th century, and that the HIV/AIDS pandemic began well before 1984. The HIV-1 group M subtype likely began spreading in west central Africa around 1920. Kinshasa, the capital of the Democratic Republic of Congo, was probably one of the earliest epicenters. In addition to the biological factors that led to the viability of this strain in humans, social factors – such as colonization, urbanization, and new forms of transportation – may have also contributed to this new virus exploding into a worldwide pandemic.27-29 Moreover, we have also gained awareness of just how complex the origin of any given pandemic can really be. In the early decades of the HIV/AIDS pandemic, there was a theory put forth that oral polio vaccines were responsible for introducing HIV. A wealth of new evidence has since discredited this hypothesis.30 It turns out the origin story of HIV is far older and more complicated, and the long, multifaceted history of this virus suggests that the solution to preventing future such pandemics is long-term investment across a multitude of fronts. The more recent COVID-19 pandemic has parallels to the origin story of HIV/AIDS as well. In the case of COVID-19, wet markets in Wuhan became a focal point when trying to identify the source of the pandemic. Pangolins emerged early on as possible culprits, though we have since learned that there is more to the story. The SARS-CoV-2 virus moves relatively easily between different mammals, including bats, cats, and raccoon dogs. A single human-animal encounter at one market may not be entirely at fault.31-33 While understanding transmission chains is important for preventing future pandemics, it is also important to remember that a staggering number of factors must line up in order for a virus to become both biologically viable in human beings, as well as highly transmissible and consequential to us. No one person, one event, or one location can shoulder all the blame. Preventing the Next Pandemic Simplicity is appealing. What caused this catastrophe? An errant wet market in China. A fatally flawed vaccine trial. One rogue, careless individual. These discrete events are things we can identify and easily prevent: shut down the market, pull the vaccine, imprison Mary Mallon. A single point of failure means a single solution might be possible. But biology is rarely so convenient or so tidy. New pathogens emerge from a complex system of interactions between humans and their environment. Our evolutionary heritage as social creatures means that any pathogen that can spread from person to person will have ample opportunity to do so, and the tightly interconnected world we have built means that just about any pathogen can gain global access soon enough. That we experience widespread pandemics among our species is not surprising. What is far more surprising is how effective we have become at detecting and stopping them. Public health interventions have successfully slowed the spread of many pandemics, including HIV/AIDS, and scientific research, along with incredible breakthroughs in medicine, have made widespread prevention and effective treatments possible. Pandemics remain a constant risk for human beings, and not every variable involved is in our control. But several are, including our willingness to invest in preventing them. What we learn today can help us stop an outbreak tomorrow. Perhaps it can even help us bring an end to the current HIV/AIDS outbreak, as we unravel a biological legacy that started over 30,000 years ago.1pt?>

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