Immune Protein GBP7 Turns Traitor, Helping Herpes Simplex Virus Translate Its Way to Infection

Guanylate-binding proteins, a family of seven enzymes collectively known as GBPs, have long been cast as foot soldiers of the antiviral immune response. Produced in abundance when interferon alarms sound, these large guanosine triphosphatases are best known for their roles in attacking intracellular pathogens, from bacteria to protozoan parasites. A new study published in PLOS Pathogens now complicates that picture considerably. Working on the least characterized member of the family, GBP7, a research team led by Jinshen Wang, Liangbing Man and Shuwen Liu reports that this interferon-induced GTPase does not fight herpes simplex virus 1 at all. Instead, it actively promotes the virus, acting as a molecular accomplice that accelerates the very protein synthesis machinery HSV-1 depends on to replicate.

The discovery emerged from a systematic examination of how the GBP family behaves during HSV-1 infection. When the researchers depleted GBP7 from infected cells, viral replication dropped markedly, an outcome opposite to what would be expected from a conventional antiviral factor. The effect was not subtle. Knockdown of GBP7 produced significant antiviral consequences, and the team traced this activity to the enzyme’s catalytic core: when its GTPase function was disabled, the proviral effect vanished. In other words, it is not merely the presence of GBP7 but its enzymatic activity that matters, a detail that would later prove central to both the mechanism and the therapeutic strategy that grew out of the work.

To determine whether the phenomenon extended beyond the culture dish, the investigators turned to mice engineered to lack the GBP7 gene. When these GBP7-deficient animals were infected with HSV-1, they fared substantially better than their wild-type counterparts. Survival rates climbed, and the clinical symptoms of infection were milder across the course of the disease. The in vivo data confirmed that the proviral role observed in cells translates into a meaningful determinant of disease severity in a living host. For a gene induced by interferon, the canonical signal of antiviral mobilization, to instead enhance viral fitness in vivo represents an unexpected twist in the biology of this protein family.

The search for a mechanism led the team to the translational apparatus of the host cell itself. Using immunoprecipitation followed by mass spectrometry, a technique that captures a bait protein along with everything physically bound to it and identifies the passengers, the researchers found that GBP7 associates with eukaryotic translation elongation factor 1 alpha 1, or eEF1A1. This factor is one of the most abundant and essential components of the protein synthesis machinery, responsible for delivering aminoacylated transfer RNAs to the ribosome during each elongation cycle. Binding between GBP7 and eEF1A1 was subsequently validated with direct affinity assays, establishing that the interaction is physical and specific rather than an artifact of the screening method.

What makes the partnership consequential is its effect on the enzymology of translation. eEF1A1 is itself a GTPase: each cycle of tRNA delivery requires the factor to bind GTP, and the energy of GTP hydrolysis drives the conformational changes that allow the factor to release the tRNA into the ribosomal acceptor site and dissociate for another round. The study found that GBP7 uses its own GTPase activity to assist eEF1A1 in this hydrolysis step, effectively speeding up the elongation factor’s catalytic cycle. With eEF1A1 working faster, the overall rate of protein translation in the cell rises. For a virus like HSV-1, which commandeers the host translational machinery to mass-produce its own proteins, a turbocharged elongation factor is a direct growth advantage.

The consequences for the virus follow logically from the biochemistry. With GBP7 present and active, eEF1A1 accelerates protein synthesis, viral proteins accumulate more rapidly, and viral replication proceeds at a higher rate, deepening the infection. When GBP7 is removed, or when its GTPase activity is lost, the boost disappears and the virus replicates more poorly. This mechanistic chain, from GTPase-assisted GTP hydrolysis to enhanced elongation to increased viral output, provides a coherent explanation for every observation in the study, from the cell culture knockdown experiments to the improved survival of GBP7-deficient mice. It also reframes GBP7 as part of a growing appreciation that interferon-stimulated genes can cut both ways, sometimes serving pathogens that have learned to exploit the host’s defensive mobilization.

Identifying a host factor that a virus exploits naturally raises the question of whether that dependency can be turned against the pathogen. Because the proviral effect requires GBP7’s catalytic activity, the enzyme’s GTP-binding and hydrolysis site presents an obvious drug target. The team pursued this avenue through high-throughput virtual screening, computationally docking large libraries of candidate molecules against the protein in search of compounds predicted to occupy and disable its active site. Among the hits that emerged was S-adenosylhomocysteine, or SAH, a well-known metabolite that is produced naturally in cellular methylation reactions as the byproduct of S-adenosylmethionine-dependent methyltransferase activity.

Experimental testing confirmed the computational prediction. SAH bound and inhibited GBP7, and in cells infected with HSV-1 the compound displayed potent antiviral activity, suppressing replication in a manner consistent with the loss of GBP7’s proviral function. Notably, the authors report that SAH showed broad-spectrum potential, suggesting that the GBP7-eEF1A1 axis may be exploited by viruses beyond herpes simplex virus 1. If that holds up in further studies, a strategy aimed at dampening this host pathway could offer a template for antivirals that are harder for viruses to escape, since the target is a host protein rather than a viral one. Host-targeted antivirals generally impose a higher genetic barrier to resistance, because the pathogen cannot simply mutate the drugged protein.

The findings also carry implications for how the GBP family is understood. GBPs have been studied most intensively in the context of immunity to intracellular bacteria and parasites, where several members direct autophagy, inflammasome activation and direct antimicrobial attack. GBP7 had remained comparatively obscure, and the new work assigns it a defined and surprising role: an interferon-induced GTPase that potentiates translation elongation through a direct physical partnership with eEF1A1. That a family member deployed during antiviral signaling would instead facilitate a viral infection underscores how incomplete the functional annotation of interferon-stimulated genes remains, and it raises the possibility that other GBPs or related GTPases may harbor similarly counterintuitive activities in different infection contexts.

For the field of antiviral research, the study offers both a mechanism and a starting point. The GBP7-eEF1A1 axis is now a defined node at which viral replication can be throttled, and SAH provides a chemical lead whose activity against HSV-1 can be optimized and whose spectrum can be mapped. At the same time, many questions remain open, including precisely how GBP7’s GTPase cycle is coupled to eEF1A1’s hydrolysis step, whether the interaction is regulated during the interferon response, and how inhibiting the axis in patients might affect normal cellular protein synthesis, given eEF1A1’s essential housekeeping role. What the work establishes firmly is that the boundary between host defense and viral exploitation is thinner than the textbook account of the GBPs suggests, and that a protein summoned to the front lines of the immune response can end up serving the enemy’s supply chain.

Subject of Research: The role of the GTPase GBP7 and the translation factor eEF1A1 in herpes simplex virus 1 replication and host-targeted antiviral therapy

Article Title: GTPase GBP7 promotes HSV-1 infection by interacting with and activating eEF1A1 to accelerate the protein translation process

Article References: Wang, J., Man, L., Rong, B., Lu, K., Cheng, L., He, J., Li, H., Su, H., Lin, X., Li, R., Zou, M., Yang, C., & Liu, S. (2026). GTPase GBP7 promotes HSV-1 infection by interacting with and activating eEF1A1 to accelerate the protein translation process. PLOS Pathogens, 22(10), e1014652. https://doi.org/10.1371/journal.ppat.1014652

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014652

Keywords: GBP7, guanylate-binding proteins, HSV-1, herpes simplex virus, eEF1A1, protein translation, GTPase, interferon, host-targeted antivirals, S-adenosylhomocysteine, viral replication, PLOS Pathogens