Alex Compton, Ph.D.
Work in the Antiviral Immunity and Resistance Section, led by Alex Compton, Ph.D., is guided by integrative approaches combining experimental virology, cell biology, and evolutionary biology to reveal dynamic host-virus interactions important for public health. A focus is placed on mechanisms of protection mediated by the cell-intrinsic innate immune response, as well as the strategies employed by HIV and emerging viruses to evade or overcome these immune barriers.
Evolution-Guided Strategies to Improve Antiviral Immunity
The age of primate lentiviruses. While the origins of HIV infection in humans have been traced to cross-species transmission events from similar lentiviruses naturally circulating in chimpanzees and other African monkeys, many questions persist regarding the nature of these lentiviruses. For example, while lentivirus infection in humans is known to be quite recent, the extent to which nonhuman primates have coexisted with their respective lentiviruses has been the subject of a long debate. Moreover, many questions have been raised regarding the pathogenicity of simian lentiviruses, since an apparent lack of disease observed in “natural” lentivirus infections in wild monkeys contrasts greatly with debilitating AIDS in humans. By focusing on a host-virus interaction over evolutionary time, we found that the gene encoding a cell-intrinsic innate immune effector known as APOBEC3G contains a “footprint” of past lentivirus infections [Compton et al., Cell Host Microbe, 2012]. At precisely the same site of the protein recognized by a lentivirus-encoded antagonist protein known as Vif, diversifying positive selection has resulted in a high rate of mutation, made visible by comparing the gene sequence across different primate species. I showed that specific mutations appearing independently in APOBEC3G of different primate species prevented antagonism by simian immunodeficiency virus (SIV) Vif proteins, suggesting that these mutations were selected to confer resistance. By dating the appearance of these mutations, we calculate that a Vif-carrying lentivirus must have been present in simian ancestors 6-12 million years ago [Compton and Emerman, PLoS Pathog., 2013]. Moreover, the recurrent mutation of the APOBEC3G gene revealed that it must take part in a host-pathogen interaction of exceptional importance to the survival of certain species.
Pathogenesis of lentiviruses, in the past and present. Our finding that ancient primate lentiviruses left an adaptive “footprint” in the genomes of primates strongly suggests that the viruses responsible incurred a “cost” to infected hosts. In addition, some “footprints” are more recent than others. Heterozygosity in the APOBEC3G genes of modern primate species demonstrates that some adaptive mutations at the interface with lentiviral Vif are not “fixed” within species, suggestive of a relatively recent selection pressure. These findings suggested that modern SIVs, not just those of the past, may also inflict harm to the hosts they infect. This discovery also provided insight into the protective role that genetic heterozygosity may play against lentivirus infections. By studying viral sequences obtained from experimentally infected monkeys, we found that the counter-evolution of the viral Vif (adaptation to the mutations in APOBEC3G of the host) was constrained if the individual was heterozygous at the interface recognized by Vif [Compton et al., Philos. Trans. R. Soc. Lond. B Biol. Sci., 2013]. Thus, these experiments revealed that the evolution of antiviral genes can have functional consequences regarding susceptibility to lentivirus infections.
Virus restriction mechanisms within infected cells (late-stage virus inhibition strategies). Certain lessons gleaned from a single host-pathogen interaction can have a bearing on other antiviral genes across the genome. We discovered that the interferon-induced transmembrane (IFITM) proteins, in addition to their role in preventing virus infection in uninfected cells, also provide a protective function to cells that have already infected [Compton et al., Cell Host Microbe, 2014]. This dual mechanism of protection, acting at both early and late stages of the virus life cycle, was previously unrecognized among antiviral restriction factors. IFITM proteins incorporate into the viral lipid bilayer and reduce the infectivity of virions produced in their presence. As our findings with HIV-1 may also be applicable to diverse enveloped viruses, these findings add to the potential importance of a restriction factor family known for its breadth and potency.
Rationale for prolific antiviral gene duplication in animal genomes. Our studies of antiviral gene evolution have revealed key evolutionary strategies that animals have employed to survive pathogenic virus infections. Most recently, we revealed that IFITM3 is undergoing recurrent gene duplication in primates. IFITM3 homologs exhibit divergent antiviral specificities, suggesting that the duplication and divergence of IFITM genes occur in response to selective pressure from multiple virus infections [Compton et al., EMBO Rep., 2016]. By demonstrating that different mutations result in a functional trade-off (enhanced activity against one virus comes with reduced activity against another), we provide a rationale for the occurrence of gene duplication among antiviral genes. By increasing the copy number of antiviral genes in the genome, the host can provide balanced antiviral coverage to the cell without incurring a trade-off cost. This finding, along with the previous discovery that heterozygosity confers an advantage to host species, could inform therapeutic efforts aiming to boost the antiviral coverage of human cells through genome modification.
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View Dr. Compton's ORCID Bibliography.
Selected Key Publications
Natural mutations in IFITM3 modulate post-translational regulation and toggle antiviral specificity.EMBO Rep. 17(11): 1657-71, 2016. [ Journal Article ]
- Cell Host Microbe. 16(6): 736-47, 2014. [ Journal Article ]
- Philos Trans R Soc Lond B Biol Sci. 368(1626): 20120496, 2013. [ Journal Article ]
Convergence and divergence in the evolution of the APOBEC3G-Vif interaction reveal ancient origins of simian immunodeficiency viruses.PLoS Pathog. 9(1): e1003135, 2013. [ Journal Article ]
The host restriction factor APOBEC3G and retroviral Vif protein coevolve due to ongoing genetic conflict.Cell Host Microbe. 11(1): 91-8, 2012. [ Journal Article ]
Dr. Alex Compton received his Ph.D. in Molecular and Cellular Biology from the University of Washington in 2012. As a doctoral student in the laboratory of Dr. Michael Emerman (Fred Hutchinson Cancer Research Center), he investigated the HIV-1 Vif protein and its target APOBEC3G, revealing lentivirus-driven evolution of host proteins on a million-year time scale. Dr. Compton was the recipient of a Pasteur Foundation Postdoctoral Fellowship and an ANRS (French National Agency on AIDS Research) Grant during his postdoctoral training with Dr. Olivier Schwartz at the Pasteur Institute in Paris, where he made key discoveries on the mechanisms by which the interferon-induced transmembrane (IFITM) proteins restrict HIV-1 infection. These studies provide important insight into the complex ways in which mammalian cells have evolved to counteract viral infections. Because the APOBEC and IFITM proteins restrict the replication of a number of viruses in addition to HIV, this work has broad implications for the understanding of host-pathogen interactions. In 2017, Dr. Compton joined the HIV Dynamics and Replication Program as Head of the Antiviral Immunity and Resistance Section to develop a research program focused on mechanisms of protection mediated by the cell-intrinsic innate immune response, as well as the strategies employed by HIV and emerging viruses to evade or overcome these immune barriers.
|Charles Coomer M.Sc.||Predoctoral Fellow (Graduate Student)|
|Tirhas Dempsey||Student (Special Volunteer)|
|Saliha Majdoul Ph.D.||Postdoctoral Fellow (Visiting)|
|Kazi Rahman Ph.D.||Postdoctoral Fellow (Visiting)|
|Guoli (Scarlett) Shi Ph.D.||Postdoctoral Fellow (Visiting)|