Tracing the structural changes that helped HIV-1 become a human pathogen

From the Emerman lab, Human Biology Division, and Jennifer Binning and John Gross at UCSF

The human immunodeficiency virus (HIV)-1 we are currently struggling to contain is the result of a long chain of viral cross-species transmission events in African non-human primates. Many species of African non-human primates are naturally infected with species-specific strains of simian immunodeficiency virus (SIV). SIVcpz from chimpanzees is the immediate precursor of HIV-1; SIVcpz jumped to humans on several occasions giving rise to the global HIV-1 pandemic. Importantly, SIVcpz itself has its origins in host switching and it is derived from a recombination of two Old World monkey (OWM) strains, including SIVrcm from red-capped mangabey monkeys. The birth of SIVcpz involved the substantial modification of an SIVrcm gene called vif, which has an essential role in counteracting the antiviral effects of a family of host proteins known as APOBEC3 (A3) proteins. A3 proteins are a major barrier for SIV cross-species transmission. The resulting SIVcpz Vif had the capacity to antagonize two chimpanzee A3 proteins, A3G and A3D, a critical adaptation to facilitate the SIV host switch from OWM to a host more closely related to humans.

To better understand the evolutionary requirements for cross-species transmission of SIV into hominids (chimpanzees and humans), the Emerman lab (Human Biology Division), in collaboration with Jennifer Binning and John Gross at UCSF, structurally and functionally characterized SIVrcm Vif to reveal the adaptations that occurred during the SIV cross-species transmission that led to SIVcpz. The group recently published their findings in Cell Host & Microbe. “While we know that pandemic HIV-1 originated from a cross-species transmission of SIV from chimpanzees, the specific events that led to adaptation of SIV from Old World monkeys to hominids like chimpanzees is less clear,” explained Dr. Nicholas Chesarino –a postdoctoral fellow in the Emerman lab and a co-author of the study.

Silhouette of red-capped mangabey with corresponding SIV next to Vif crystal structure on ribbon format arrow points to the right onto a second Vif crystal structure. The right side of the image corresponds to hominid SIV vif.
Changes in Old-World monkey SIV Vif loop5 conferred hominid primate A3G antagonism. Image provided by Dr. Nicholas Chesarino.

To determine how Vif adaptations that arose during cross-species transmission from OWM to hominid primates allowed antagonism of A3 proteins, collaborators at UCSF solved the crystal structure of SIVrcm in complex with co-factors that support ubiquitination and subsequent targeting of A3 for proteasomal degradation. The authors then compared the structures of SIVrcm Vif and HIV-1 Vif and found that the overall protein fold is the same, and that the hydrophobic patch critical for A3G antagonism in HIV-1 is conserved in SIVrcm. This led the authors to hypothesize that HIV-1 Vif, SIVcpz Vif, and SIVrcm Vif use a common hydrophobic patch to engage A3G. To test this hypothesis, the group individually mutated residues in the hydrophobic patch in SIVrcm Vif. All the resulting proteins lost the ability to antagonize chimpanzee A3G (cpzA3G), which suggested that, similar to hominid primate Vifs, SIVrcm Vif uses the same hydrophobic region to bind A3G.

However, the potency of SIVrcm Vif antagonism against cpzA3G is lower than that of SIVcpz Vif against cpzA3G. This result motivated the authors to identify subsequent adaptations needed for efficient antagonism of cpzA3G. Guided by the structure, they focused on regions in proximity to the hydrophobic patch. They identified the loop5 as a good candidate for cpzA3G adaptation because of its close proximity to the hydrophobic patch and flexible conformation that allows for less evolutionary restriction. The researchers then swapped the loop5 region from SIVcpz Vif to SIVrcm Vif. This change was sufficient to confer SIVrcm Vif full potency to antagonize cpzA3G. The authors then built single-point mutants in the SIVrcm background and identified a single amino acid change in SIVrcm Vif that was sufficient to confer specificity for cpzA3G. Importantly, this single change in SIVrcm Vif was also sufficient to fully antagonize human A3G. Dr. Chesarino added that “Once adapted to chimpanzee APOBEC3G, no further changes in Vif were needed to antagonize human APOBEC3G, allowing the virus to overcome a significant barrier that normally hinders cross-species transmission of lentiviruses.”

This research was supported by NIH/NIAID funding for the HIV Accessory & Regulatory Complexes (HARC) Center, an NIH/NIAID postdoctoral fellowship, and a University of Washington STD/AIDS Research Training Fellowshi

Jennifer M. Binning, Nicholas M. Chesarino, Michael Emerman, John D. Gross, Structural Basis for a Species-Specific Determinant of an SIV Vif Protein toward Hominid APOBEC3G Antagonism, Cell Host & Microbe.

Fred Hutch/UW cancer consortium member Dr. Michael Emerman contributed to this work.


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