Engineered Herpes Simplex Virus Induces Genetic Chain Reaction During Co-infection
核心洞察
Researchers have engineered HSV-1 (搜索) to carry a DNA editing strategy to neurons, targeting the virus during latency and potentially preventing or curing disease.
In a mouse model of acute HSV-1 (搜索) encephalitis, gene drive was evident in up to 80% of viruses in certain areas of the nervous system, demonstrating in vivo co-infection.
The team is now focused on optimizing the engineered virus to balance its safety and efficacy in inactivating the wild-type virus, aiming to reduce viral shedding and disease.
Researchers at Fred Hutchinson Cancer Center have engineered a herpes simplex virus (搜索) (HSV) that can trigger a genetic chain reaction, effectively rewriting the genes of the virus during co-infection. This innovative approach, detailed in a recent publication, holds promise for new therapeutic strategies against HSV-1 (搜索) and HSV-2 (搜索).
The research team, led by Dr. Jerome and Dr. Walter, developed a CRISPR (搜索)-based gene drive method that leverages natural viral DNA recombination to insert a gene for a red fluorescent protein into the viral DNA. This allows the team to visually track gene drive in action, as the targeted HSV naturally glows yellow, and a shift to orange indicates successful gene drive.
In Vivo Co-infection and Gene Drive
To investigate the extent of co-infection in living organisms, the team used two mouse models: one for acute HSV-1 (搜索) encephalitis and another for reactivated latent infection. In the acute infection model, they found that up to 80% of viruses in some areas of the nervous system showed evidence of gene drive. In the latency model, they observed several instances of recombination with non-engineered viruses, confirming that both co-infection and gene drive can occur during latent HSV infections.
"We showed that you often have two viruses that infect the same cell," Walter said. "This is where the paper brings in a lot of interesting basic biology, because it shows that [co-infection is] actually happening at a high frequency, which nobody had really shown in that way before."
Balancing Safety and Efficacy
The team is now focused on translating these findings into a therapeutic strategy. "We're trying to see if we can use the technique as a way to prevent or cure disease," Walter explained. The key challenge lies in finding the right balance: the engineered virus must be safe on its own but also capable of effectively recombining with and inactivating the wild-type virus.
"You need an engineered virus that by itself does not cause disease, but needs to be able to meet and recombine with the wild-type virus to inactivate it," Walter said. "So we need to find the balance between having an engineered virus that in itself doesn't cause disease, but gets where it needs to go."
To refine their approach, the researchers are using a preclinical model that more closely mimics human HSV infection. They are also investigating the factors that influence the efficiency of gene drive during latent HSV infection. The insights gained from HSV-1 (搜索) models will be applied to HSV-2 (搜索) research as well.
The ultimate goal is to reduce viral shedding and disease. "The goal is to reduce the level of viral shedding and disease, but if we only reduce the level of symptomatic disease, it's already a big win," Walter said.
Jerome emphasized that the insights from Walter's work are complementary to other gene therapy approaches being studied in his lab, accelerating the overall research effort. "It's really sped up the overall work and that's really the goal here: To provide something new to help people who are living with the virus," Jerome said.