Herpes Simplex Virus 1 (HSV-1) Infection in Alzheimer's Disease Overview - Signaling Pathway, Pathological Features and Therapy

1 Major signaling pathways for HSV-1-induced AD

1.1 NLRP3 Inflammasome Pathway

HSV-1 activates the NLRP3 inflammasome pathway through a multi-tiered molecular cascade to drive the pathological progression of AD. This pathway is initiated by the specific binding of the C-terminal domain of the viral envelope glycoprotein gB to Toll-like receptors (TLR2/4) on the surface of host microglia, triggering NF-κB signaling to upregulate transcriptional expression of NLRP3 and pro-IL-1β. Following viral endocytosis, the capsid protein VP16 compromises lysosomal membrane integrity, leading to cytosolic leakage of cathepsin B (CatB), which cleaves the NACHT domain of NLRP3 to relieve its autoinhibited state. Concurrently, mitochondrial stress induced by viral replication causes a burst of reactive oxygen species (ROS), and oxidatively damaged mitochondrial DNA directly binds to the leucine-rich repeat (LRR) domain of NLRP3. These events synergistically promote prion-like oligomerization of ASC and autoproteolytic activation of pro-caspase-1. Activated caspase-1 cleaves gasdermin D to form transmembrane pores, facilitating the release of mature IL-1β and IL-18. IL-1β upregulates transcription of β-secretase (BACE1) via the neuronal JNK/c-Jun signaling pathway, enhancing aberrant cleavage of amyloid precursor protein (APP) and elevating Aβ42 production rates. Meanwhile, IL-18 inhibits the function of the lysosomal V-ATPase complex in microglia through STAT3 phosphorylation at Tyr705, reducing Aβ degradation efficiency. This process establishes a positive feedback loop, whereby Aβ fibrils, through hydrophobic interactions with the LRR domain of NLRP3, further stabilize the inflammasome complex, resulting in a self-perpetuating cycle of neuroinflammation and exacerbated amyloid deposition.

1.2 GSK-3 Pathway

HSV-1 also exacerbates AD pathogenesis by activating the GSK-3 pathway, a serine/threonine kinase integral to diverse cellular processes. Following neuronal infection, the viral capsid protein VP16 induces dysregulated intracellular Ca²⁺ signaling, triggering GSK-3β activation. Activated GSK-3β phosphorylates APP, enhancing its affinity for β-secretase (BACE1) and shifting APP processing toward the amyloidogenic pathway. This results in elevated extracellular Aβ production and accumulation of neurotoxic APP C-terminal fragments. Concurrently, GSK-3 activation drives tau hyperphosphorylation and aberrant nuclear aggregation, which disrupts chromatin remodeling and suppresses DNA repair gene expression. Furthermore, HSV-1 inhibits autophagosome-lysosome fusion, impairing Aβ clearance and sustaining intracellular Aβ aggregates in infected primary hippocampal neurons. Notably, Aβ exhibits dual roles in viral pathogenesis: while Aβ oligomers entrap HSV-1 particles to limit viral spread, viral glycoprotein B reciprocally accelerates Aβ fibrillization, establishing a self-reinforcing cycle of viral persistence and amyloid deposition.

2 Pathological Features of AD Induced by HSV-1

The pathological features of AD induced by HSV-1 infection are similar to those of classical AD, including:

• Aβ plaques: HSV-1 infection leads to the increased production and accumulation of Aβ plaques in the brain. These plaques are extracellular deposits that disrupt neuronal function.
• Neurofibrillary tangles (NFTs): HSV-1 infection promotes the hyperphosphorylation of tau proteins, which accumulate within neurons to form NFTs. NFTs disrupt the neuronal cytoskeleton and impair axonal transport.
• Neuroinflammation: HSV-1 infection triggers a strong inflammatory response in the brain, characterized by the activation of microglia and the release of pro-inflammatory cytokines.
• Neuronal loss and synaptic dysfunction: The combined effects of Aβ accumulation, tau hyperphosphorylation, and neuroinflammation lead to neuronal damage, synaptic dysfunction, and ultimately, neuronal loss.

3 Anti-HSV-1 Therapies for AD

Given the potential role of HSV-1 in the pathogenesis of AD, researchers are actively exploring various therapeutic strategies centered on anti-herpetic drugs.

3.1 Exploration of Existing Antiviral Drugs

• Acyclovir (ACV): Studies have shown that ACV can reduce HSV-1-driven tau protein phosphorylation and Aβ formation in vitro. Acyclovir, a guanine analog, interferes with herpesvirus replication by inhibiting viral DNA polymerase. Its effectiveness in reducing tau phosphorylation and Aβ formation in cell cultures suggests it may directly impact key pathological processes involved in AD. However, the clinical efficacy of acyclovir in AD patients has been limited, potentially due to factors such as poor penetration of the blood-brain barrier and administration at later stages of AD.
• Valacyclovir: Ongoing clinical trials are evaluating the efficacy of valacyclovir, a prodrug of ACV with improved bioavailability, in improving cognition and function in HSV seropositive AD patients. Valacyclovir is rapidly converted to acyclovir in the body, but its higher bioavailability allows for more efficient absorption and distribution, including to the brain. These ongoing trials are crucial in determining whether this enhanced delivery of acyclovir can translate into significant clinical benefits for AD patients.
• Other Antiviral Drugs: Other antiviral agents, such as penciclovir and foscarnet, have also shown promise in reducing the accumulation of Aβ and phosphorylated tau in infected cell cultures. Penciclovir, akin to acyclovir, functions as a guanine analogue to impede viral DNA replication. Conversely, foscarnet, a pyrophosphate mimetic, directly targets and inhibits viral DNA polymerase activity. These drugs may offer additional therapeutic options for AD patients, particularly if they prove effective at crossing the blood-brain barrier.

3.2 Novel Approach

Researchers are also exploring innovative strategies such as targeting HSV-1 neuroinvasiveness and using CRISPR-Cas9 systems to target the HSV-1 genome in infected cells. These approaches represent promising but still experimental avenues for future therapeutic interventions. Targeting neuroinvasiveness aims to prevent the virus from entering the brain, while CRISPR-Cas9 holds the potential to eliminate the virus from latently infected cells. While these methods hold great potential, they are in the early stages of development, and significant safety and efficacy issues need to be addressed.

In summary, therapeutic strategies targeting HSV-1 offer a potential direction for intervention in AD. While the clinical effectiveness of existing antiviral drugs has been limited, the exploration of novel agents and innovative approaches continues to advance, offering hope for more effective treatments for AD patients in the future.

The Role of Herpes Simplex Virus 1 (HSV-1) in Alzheimers Disease A Pioneering Frontier for Therapeutic Innovation