Abstract
Viral–host interactomes map the complex architecture of an evolved arms race during host cell invasion. mRNA and protein interactomes reveal elaborate targeting schemes, yet evidence is lacking for genetic coupling that results in the co-regulation of promoters. Here we compare viral and human promoter sequences and expression to test whether genetic coupling exists and investigate its phenotypic consequences. We show that viral–host co-evolution is imprinted within promoter gene sequences before transcript or protein interactions. Co-regulation of human immunodeficiency virus (HIV) and human C-X-C chemokine receptor-4 (CXCR4) facilitates migration of infected cells. Upon infection, HIV can actively replicate or remain dormant. Migrating infected cells reactivate from dormancy more than non-migrating cells and exhibit differential migration–reactivation responses to drugs. Cells producing virus pose a risk for reinitiating infection within niches inaccessible to drugs, and tuning viral control of migration and reactivation improves strategies to eliminate latent HIV. Viral–host genetic coupling establishes a mechanism for synchronizing transcription and guiding potential therapies.
Highlights
Viral–host interactomes map the complex architecture of an evolved arms race during host cell invasion. mRNA and protein interactomes reveal elaborate targeting schemes, yet evidence is lacking for genetic coupling that results in the co-regulation of promoters
Implementing a comprehensive search for similarity between viral and human promoter sequences, we discover the existence of genetic coupling and co-regulation of highly similar promoters of human immunodeficiency virus (HIV), cytomegalovirus (CMV) and corresponding human genes, whereby co-expression of the HIV long terminal repeat (LTR) promoter and human C-X-C motif chemokine receptor-4 (CXCR4) facilitates migration and reactivation of dormant or latently infected cells
Similar to the LTR, the distance of nuclear factor kappa B (NFKB) and the most upstream specificity protein 1 (SP1) site in the CXCR4 and factor 3 (F3) promoters is within a reported range required for cooperativity by both transcription factors in promoter activation[21]
Summary
Viral–host interactomes map the complex architecture of an evolved arms race during host cell invasion. mRNA and protein interactomes reveal elaborate targeting schemes, yet evidence is lacking for genetic coupling that results in the co-regulation of promoters. Reports have shown methodologies for quantifying the real-time activity of transposable elements in single bacterial cells[13], identified the rewiring of transcriptional circuitry in pluripotent stem cells by transposable elements[14] and revealed widespread similarity of enhancers of innate immune response genes in a number of viruses[15] These studies highlight that investigating endogenous retroviral elements may provide a deeper understanding of viral–host regulatory relationships and have broad therapeutic potential by identifying novel drug targets of viral–host regulation and their interlaced phenotypes. Implementing a comprehensive search for similarity between viral and human promoter sequences, we discover the existence of genetic coupling and co-regulation of highly similar promoters of human immunodeficiency virus (HIV), cytomegalovirus (CMV) and corresponding human genes, whereby co-expression of the HIV long terminal repeat (LTR) promoter and human C-X-C motif chemokine receptor-4 (CXCR4) facilitates migration and reactivation of dormant or latently infected cells We show that both migration and reactivation can be differentially controlled using drug treatments. These findings further complicate leading strategies for eliminating latent reservoirs of HIV16, as current approaches risk reactivating latent virus in migrating cells that can reach target-rich cell niches[17]
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