Resolving HSV-1 latency in non-neuronal cells: methodological rigor, host-immune evasion, and immunological implications for chronic disease

Herpes simplex virus type 1 (HSV-1) is a widespread pathogen known for its ability to establish lifelong latent infections. Historically, the scientific consensus has held that HSV-1 latency is strictly restricted to sensory neurons within the trigeminal and dorsal root ganglia. However, recent high-throughput studies have challenged this paradigm. Researchers using advanced single-cell RNA sequencing (scRNA-seq) have claimed to detect latent HSV-1 transcripts, such as the latency-associated transcript (LAT), within non-neuronal ganglionic cells and various immune populations. These findings suggest that non-neuronal cells might serve as alternative reservoirs for viral persistence, potentially redefining our understanding of host antiviral immune responses, particularly how HSV-1 exploits host immune receptors to evade detection and establish long-term residence in these populations. Conversely, independent bioinformaticians and virologists have strongly contested these assertions. They suggest that the apparent viral signals in non-neuronal populations result from experimental artifacts rather than genuine latent infection, sparking an intense debate regarding the true boundaries of HSV-1 tissue tropism.This Research Topic aims to establish rigorous validation standards for HSV-1 latency in non-neuronal cells and establish a clearer, consensus-driven view of viral persistence and its immunological consequences. The primary challenge lies in connecting the interpretation of high-dimensional single-cell genomic data to functional immune biology. Critics argue that claimed non-neuronal latency is an artifact of ambient RNA contamination, index hopping, barcode swapping, or cell-cell doublets in scRNA-seq datasets, but other signals may reflect genuine, receptor-mediated host-virus interactions worth characterizing mechanistically. To move the field forward, this collection brings together virologists, immunologists, and computational biologists to critically evaluate these claims and their implications for host-virus interactions, immune evasion, and neurodegenerative disease pathogenesis. We seek to address how methodological differences impact biological conclusions and define rigorous validation standards for viral transcript detection. By integrating reanalyses of existing datasets with new experimental models—such as high-resolution in situ hybridization, flow cytometry, receptor-binding assays, and highly purified cell-sorting techniques—this topic will help determine whether non-neuronal cells truly support latency or if these observations are purely methodological artifacts.We welcome original research, reviews, mini-reviews, and perspective articles addressing:o Rigorous bioinformatic and experimental validation of viral latency in immune and glial populations, addressing technical artifacts (such as ambient RNA or doublets) in immunovirological datao In vitro and in vivo models of HSV-1 interaction with non-neuronal cells, focusing on how these interactions shape local innate and adaptive immune responses, including receptor-mediated entry and immune-evasion mechanismso The immunological consequences of non-neuronal viral persistence in the context of neurodegenerative and chronic inflammatory diseases, including evidence linking persistent viral infection to immune-genetic risk factors in conditions such as Alzheimer’s disease and multiple sclerosis Topic editors: Simone Agostini, Tadahiro Suenaga Source: https://www.frontiersin.org/research-topics/83992/resolving-hsv-1-latency-in-non-neuronal-cells-methodological-rigor-host-immune-evasion-and-immunological-implications-for-chronic-disease