Herpes simplex virus 1 (HSV-1) is a neurotropic pathogen best known for establishing latency in sensory ganglia. Beyond neuronal infection, HSV-1 profoundly reshapes host cell physiology, including lipid handling pathways that govern membrane biogenesis, immune signaling, and antigen presentation. A key experimental observation highlighted in journal-discussion contexts is that HSV-1 can alter lipid metabolism and drive lipid droplet accumulation within dendritic cells (DCs), particularly in functionally impaired mouse DC populations. Understanding this phenomenon requires integrating virology, immunometabolism, and DC differentiation.
Dendritic cells are professional antigen-presenting cells that orchestrate adaptive immunity. Their ability to capture antigens, process proteins, and present peptide–MHC complexes depends on coordinated membrane trafficking and metabolic programs. DC function is tightly linked to lipid composition in organelles and signaling competence at the plasma membrane and endoplasmic reticulum. Lipid droplets (LDs) are cytosolic storage organelles containing neutral lipids stabilized by proteins such as perilipins. Far from being inert fat depots, LDs participate in antiviral and inflammatory responses by modulating lipid-derived mediators, buffering lipotoxic species, and serving as platforms for host–virus interactions.
HSV-1 entry and replication demand substantial lipid remodeling. Viral replication complexes rely on modified host membranes and lipid availability to generate double-membrane vesicles and envelope components. Consequently, HSV-1 can activate host lipogenesis, increase uptake of fatty acids, and reprogram cholesterol and triglyceride pathways. Mechanistically, infection may influence transcription factors and metabolic sensors that regulate genes involved in lipid synthesis and oxidation, such as SREBP-family regulators and pathways downstream of mTOR and AMPK. While these routes can initially support immune homeostasis, sustained metabolic rewiring may promote an LD-rich state.
In dendritic cells, altered lipid metabolism can impair antigen presentation and costimulatory signaling. DCs rely on controlled lipid flux to maintain endosomal maturation and effective processing of antigens. Excess LD formation is often associated with dysfunctional endolysosomal trafficking, heightened endoplasmic reticulum stress, and altered redox balance. In addition, lipid signaling can tune cytokine production; saturated lipid species and cholesterol-rich microdomains can bias inflammatory programs, while dysregulated fatty acid oxidation can blunt the metabolic flexibility required for effective DC maturation.
Functionally impaired DCs show reduced capacity to induce T-cell responses. In mouse models, HSV-1–exposed DCs may display diminished expression of activation markers, reduced antigen presentation efficiency, and skewed cytokine profiles. Lipid droplet accumulation can serve as both a marker and contributor to this impairment. LD-associated lipids can influence membrane curvature and trafficking, potentially limiting formation of antigen-loading platforms and disrupting receptor recycling. Moreover, LD expansion can foster pro-oxidant conditions if lipid synthesis outpaces neutralization capacity, leading to mitochondrial dysfunction and compromised energy supply.
The virus may directly exploit LD biology. Many herpesviruses associate with lipid-rich compartments during assembly and egress. LDs can provide reservoirs of neutral lipids that are mobilized via lipases to supply viral membrane synthesis. HSV-1 may also modulate LD-associated enzymes or signaling cascades to optimize viral replication. Thus, the observed LD accumulation could reflect a dual process: viral acquisition of lipid resources and host immune failure caused by metabolic stress and signaling derailment.
From an immunometabolic perspective, lipid droplet accumulation intersects with innate immune recognition. DCs detect viral components through pattern-recognition receptors such as cGAS–STING and RIG-I–like receptor pathways. Lipid-mediated changes can modulate these signaling axes by altering membrane composition, affecting trafficking of cytosolic DNA or RNA sensing complexes, and changing the availability of lipid-derived second messengers. Dysregulated metabolism may therefore reduce type I interferon induction and impair downstream antiviral programs, allowing persistent or exacerbated impairment of DC function.
Therapeutically, targeting lipid metabolism represents an emerging strategy to influence antiviral immunity. Potential approaches include modulating cholesterol trafficking, inhibiting lipogenesis, or regulating LD biogenesis and lipolysis. However, given the central role of lipids in normal immune cell physiology, interventions must balance antiviral benefit with toxicity and preservation of DC maturation. Future work should delineate whether LD accumulation is causative of DC dysfunction or a consequence of viral replication, and should identify specific metabolic nodes responsible for impaired antigen presentation.
In sum, HSV-1 can reprogram host lipid metabolism and promote lipid droplet accumulation in dendritic cells, especially when those cells become functionally impaired. This immunometabolic shift likely affects membrane dynamics, endosomal antigen processing, cytokine signaling, and innate immune activation, thereby weakening the ability of DCs to prime effective T-cell responses. Source: FOCIS_FCE (FOCIS Journal Club announcement regarding HSV-1, lipid metabolism, and lipid droplet accumulation in impaired mouse dendritic cells).
FOCIS_FCE: 🚨 One week to go! Join us on July 29 for the next FOCIS Journal Club: HSV-1 alters lipid metabolism and induces lipid droplet accumulation in functionally impaired mouse dendritic cells Registration is FREE! | Recording only available to FOCIS members.. #breaking
— @Focis_FCE May 1, 2026
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