With Friday’s last-minute decision to move to an all-virtual format, the opening session of the 2020 Conference on Retroviruses and Opportunistic Infections (CROI) was certainly an unusual one. “We are in uncharted waters,” conference co-chair Sharon Hillier, Richard Sweet Professor of Reproductive Infectious Disease at the University of Pittsburgh School of Medicine, told the audience via livestream.

Attendees largely made the best of it, posting reports of watching the Bernard Fields and N’Galy Mann lectures with their dog, with a drink, or simultaneously with their children’s middle school baseball game.

Even if CROI had not moved to a virtual format, 2020 Bernard Fields award winner Michael Emerman would not have been able to deliver his award lecture in person. Emerman is a member of the human biology and basic sciences divisions at the Fred Hutchinson Cancer Research Center, which is located in hard-hit Seattle and activated mandatory work-from-home policies and travel bans for its employees last week.

In his lecture, Emerman gave an overview of his work, which is focused on the evolutionary arms race between HIV and its predecessor simian immunodeficiency virus (SIV) and host antiviral proteins, also called restriction factors.

In particular, he and his colleagues study the co-evolution of the restriction factor apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G (APOBEC3G) and HIV’s viral infectivity factor (VIF).

APOBEC3G is a host restriction factor that is packaged into virions during viral replication. There, it encourages hypermutation of the viral genome, leading to viruses that are ineffective at infecting further cells. VIF inhibits APOBEC3G, unless APOBEC3G mutates in such a way to no longer be sensitive to VIF, unless VIF mutates in such a way to restore its ability to inhibit APOBEC3G, unless… well, you get the picture.

Arms race or tango?

Understanding the molecular details of the arms race between VIF and APOBEC3G can be used to date the origin of primate lentiviruses. While it was once assumed that SIV and other lentiviruses had been infecting primates for only a few thousand years, that timeline has steadily been pushed back. In lemur genomes, there is evidence of lentiviral infection several million years ago.

Michael Emerman and Harmit Malik. Credit: Robert Hood, Fred Hutch News Service

That, in turn, could point to strategies for making HIV infection less deadly. Viruses and their hosts are in an arms race. But for evolutionarily ancient infections, they are also in a dance of sorts, where the virus and the host immune system live in relatively benign coexistence. Understanding such pathogen tolerance could point to ways to replicate it for HIV.

The interaction between VIF and APOBEC3G can also be used to understand how HIV-1 managed to jump species. APOBEC3G differs between primate species in small but significant ways, and in order to be able to jump species, VIF had to undergo changes that enabled it to inhibit human APOBEC3G.

Pharmacologically targeting those changes, in turn, could be another way to fight the virus. HIV-1, for example, evolved from an SIV that infected red capped mangabeys, via an intermediate SIV that gained the ability to infect chimpanzees.

In the jump from mangabeys (an old world monkey species) to chimpanzees, VIF lost the protein Vpx, leading to structural changes that enabled VIF to inhibit chimpanzee and human APOBEC proteins. Vpx also inhibits another restriction factor, the Human Silencing Hub (HUSH). In 2019, Emerman’s group published work describing the structural changes wrought by Vpx loss and their consequences for VIF binding. In his lecture at CROI, he speculated that the inability to inhibit HUSH brought about by the loss of Vpx could be exploited in kick and kill strategies to bring HIV out of latency, which could help eliminate the viral reservoir that has thwarted cure attempts to date.

As 4-million-year old lentiviral ghosts in lemur genomes show, “host antiviral proteins have defeated previous lentiviral infections of primates,” Emerman said. “But the innate immune system of modern humans is not optimized to defeat HIV-1,” implying, among other things, that “augmentation of the host innate immune system is a key component for curing retroviral infections.”

That could be done by methods that include inducing higher expression of restriction factors, optimizing restriction factor activity via small molecules, or, as Emerman and his team have recently demonstrated in conjunction with the laboratory of Harmit Malik, another member of the basic sciences division at Fred Hutch, by engineering restriction factors toward greater effectiveness. The researchers used the restriction factor MxA, a broad-spectrum restriction factor that inhibits animal viruses, including H5N1 avian influenza virus and a group of viruses named Thogotovirus. They showed that by switching out specific amino acids, they were able to engineer “super-restriction factors” that were 10 times as effective as naturally occuring MxA at inhibiting Thogotovirus.

In an evolutionary tradeoff, most of those engineered proteins paid for better Thogotovirus restriction with reduced ability to inhibit H5N1. But a few of the proteins were able to potently restrict H5N1 even with improved activity against Thogotovirus.

HIV infects only humans, and so its restriction factors, too, have some unique characteristics. But, Malik said in a prepared statement when the work was published in 2019, “I'm really hopeful that … this strategy is going be something that would be applicable to any antiviral or any anti-pathogen gene.”

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