The ongoing COVID-19 pandemic is caused by SARS-CoV2, a member of a larger family of coronaviruses with various natural hosts, ranging from birds to mammals. As with most viruses, coronavirus infections tend to be host-restricted; meaning that they can only infect their natural host species. However, SARS-CoV2 is thought to be a bat coronavirus that switched hosts and adapted to infect humans.
So, how is it that a virus that evolved to infect bats can adapt to infect humans? And what makes human cells a permissive or restrictive to infection by a given virus? This antiviral protection relies on host-encoded antiviral proteins, called restriction factors, which can target, and sometimes destroy, viral proteins to stop viral replication.
Many of the human restriction factors have orthologs in other mammalian and bird species, suggesting that these first-line defense mechanisms have evolved in a shared common ancestor long ago. Yet, due to their continual evolution, these restriction factors have very different antiviral specificities. For example, whereas the rhesus macaque version of the restriction factor TRIM5α is highly effective at curbing the HIV-1 virus, the causative agent of the ongoing HIV/AIDS pandemic, human TRIM5α is mostly ineffective against HIV-1. This rapid functional divergence is thought to result from an evolutionary arms race between viruses and their respective hosts. This is the focus of joint research in the Malik lab (Basic Sciences Division), which studies evolutionary arms races, and the Emerman lab (Basic Sciences & Human Biology Divisions), which studies how primate restriction factors interact with HIV and related retroviruses.
HIV is thought to have evolved in old world primates before it could infect chimpanzees and subsequently jump to humans. Viruses like HIV-1 evolve rapidly, which helps them evade the effects of newly encountered restriction factors as they jump between species. Indeed, the ability of viruses to infect different primate hosts can be attributed to the fact that primates do not evolve as fast as viruses. With primates at a disadvantage in this arms race, how can their immune systems possibly keep pace with viral evolution? Researchers from the Malik and Emerman labs sought to answer this question in a recent study led by Dr. Jeannette Tenthorey, an HHMI Hanna Gray postdoctoral Fellow in the Malik and Emerman labs.
“Although we have a pretty good handle on how viruses evolve to escape restriction factors, both from in vitro evolution experiments and deep mutational scanning studies like those from Jesse Bloom’s group, we’ve had much less understanding of the other side of the evolutionary arms race.” Said Tenthorey who is interested in the evolutionary strategies that allow hosts to “keep up” with pathogens in these arms races, despite the inherent disadvantage of lower mutation rates. She focused on the restriction factor TRIM5α, which restricts HIV and other retroviruses such as the related simian immunodeficiency viruses or SIVs. Noting that TRIM5α of rhesus macaques can restrict several retroviruses including HIV-1 while human TRIM5α cannot, Tenthorey and colleagues set out to investigate the mutational constraints acting on TRIM5α in simian primate species. They published their findings in a recent issue of Elife.
Protein evolution is a slow and incremental process. However, not every mutation makes the protein better. Indeed, most mutations are thought to worsen protein function rather than improve it. Protein domains that carry out essential functions are less forgiving to even small changes. Tenthorey wished to investigate if this was also true of restriction factors like TRIM5α, which are among the most rapidly evolving proteins, yet single changes in which could dramatically alter antiviral potency. Tenthorey and colleagues used deep mutational scanning to introduce all possible amino acid substations to the human TRIM5α domain that binds viruses. They found that most random mutations did not disrupt TRIM5α ability to restrict retroviruses. Contrary to their expectation, they found that most single amino acid substitutions led to a gain of antiviral activity. In fact, many possible single mutations would make human TRIM5α better at blocking HIV-1 (alas, these mutations either don’t exist or are very rare in the human species).
“This study is the first to ask how rapidly evolving restriction factors not just DO, but how they CAN, evolve to combat viruses.” Tenthorey said, underscoring the significance of their work. “Surprisingly, we found that restriction factors like TRIM5α have a lot of mutational flexibility. Specifically, TRIM5α can sample many amino acid variants to improve activity against novel viruses without losing activity against viruses it’s already effective against. This should really come in handy in its evolutionary arms races with viruses.”
Gains in potency against one virus can sometimes be offset by a concomitant loss of function against other viruses. Such functional tradeoffs might partially explain the evolutionary constraints acting on primate TRIM5α sequences. Therefore, the researchers asked whether mutations in human TRIM5α that resulted in a gain of antiviral restriction against HIV led to decreased reduced restriction against other retroviruses. They found that changes that improved HIV restriction by TRIM5α also improved the antiviral restriction against the other retroviruses tested. Most dramatically, most single mutations were not disruptive to antiviral function. Thus, rather than sitting on steep fitness peaks (like the black diamond ski slopes), restriction factors like TRIM5 appear to be sitting in broad fitness plateaus, where it is not easy to ‘fall off’ the fitness high.
In the future, the authors wish to determine “whether this mutational flexibility in fact does constrain viral escape from TRIM5α’s restriction.” Said Tenthorey who also wishes to determine what viral variants can escape wildtype TRIM5α, and whether hosts that express multiple TRIM5α variants can prevent viral escape because no single solution works against both variants. “We would also like to know whether this permissive evolutionary landscape is true of other restriction factors, suggesting a broadly effective strategy for hosts to keep up with the (viral) Jones’.” She added.
The study demonstrates that TRIM5α exhibits a broad mutational resilience with a remarkable adaptive landscape. Restriction factors such as TRIM5α are fighting an uphill battle against fast evolving viruses. This mutational resilience of TRIM5α can help even the playing field in this tit-for-tat arms race against viruses. With gene therapy technologies on the horizon, one can envisage a future where human cells are edited to contain “super” TRIM5α that is better able to restrict and control HIV infection.
Tenthorey JL, Young C, Sodeinde A, Emerman M, Malik HS. (2020). Mutational resilience of antiviral restriction favors primate TRIM5α in host-virus evolutionary arms races. Elife. doi: 10.7554/eLife.59988
This work was supported by a Hanna H Gray fellowship, an EXROP award, and an Investigator award from Howard Hughes Medical Institute, in addition to grants from the Mathers Foundation and the National Institutes of Health.
UW/Fred Hutch Cancer Consortium member Harmit Malik and Michael Emerman contributed to his work.