A Brief History of TRIM5α

In spite of the fact that the first isolates of HIV-1 became available more than 20 years ago, there isstill no robust animal model for HIV-1 replication and pathogenesis. This is largely due to the existenceof multiple genetic barriers to HIV-1 replication in most nonhuman primates, including a severe blocktargeting the early, post-entry phase of the viral replication cycle. It is now known that a protein calledTRIM5α mediates this early restriction in nonhuman primate cells. Tissue culture experiments, togetherwith genetic association studies involving multiple HIV/AIDS cohorts, indicate that the humanorthologue of TRIM5α does not have a significant impact on HIV-1 replication. However, most humanalleles encode a functional protein that can restrict at least one retrovirus unrelated to HIV-1 (Ntropicmurine leukemia virus), although one deleterious mutation (H43Y) is present at high frequencyin human populations. Phylogenetic analyses of the TRIM5 locus reveal that prehistoric retroviralepidemics, not unlike the current HIV/AIDS pandemic, played a significant role in the evolutionaryhistory of humans and their primate relatives. The discovery of TRIM5α’s antiretroviral activity sparkedthe imaginations of many laboratories, and considerable effort has now been channeled into characterizingthe protein and determining its possible mechanism(s) of action. It is hoped that researchon TRIM5α will contribute to the establishment of new and improved models for HIV replication andAIDS pathogenesis, point the way towards novel therapeutic targets to stem the tide of the humanAIDS epidemic, provide an experimental window onto the early, post-entry stages of the retroviralreplication cycle, and even inspire the search for other cellular factors that modulate retroviral infection.