The producer cell type of HSV-1 alters the proteomic contents and infectious capacity of virions.

The cell that a virus replicates in, that is, the producer cell, can alter the macromolecular composition and infectious capacity of the virions that are produced. Herpes simplex virus type 1 (HSV-1) primarily infects keratinocytes of the epidermis or oral mucosa prior to establishing latency in neurons of the peripheral nervous system, where the virus can persist for the lifetime of the host. Many cell lines that are used to amplify HSV-1 are derived from species and tissue types that are less physiologically relevant to HSV-1 disease. To understand whether the producer cell type influences HSV-1 infection, we tested the infectivity of HSV-1 derived from immortalized African green monkey kidney cells (Vero), immortalized human keratinocytes (HaCaT), and primary human foreskin fibroblasts (HFF-1). We observed that the producer cell type alters the capacity of HSV-1 to produce viral transcripts, proteins, and infectious virions from infected cells and susceptibility to inhibition of replication by interferon treatment. HaCaT-derived HSV-1 consistently exhibited enhanced replication over HFF-1 or Vero-derived virus. To determine whether the producer cell type changes the protein composition of virions, we performed an untargeted LC/MS-MS analysis of virions purified from each cell line. Comparison of virion-associated proteins revealed quantitative differences in composition of both cellular and viral proteins, including ICP0, pUL24, and pUL42. These results highlight the influence that the producer cell type has on HSV-1 infection outcomes and suggest that cell-type-specific factors can alter HSV-1 and impact viral replication. IMPORTANCE: Approximately 67% of the human population harbors herpes simplex virus type 1 (HSV-1) infection. To study HSV-1, laboratories utilize several different cell lines to propagate HSV-1 for downstream experiments. The type of cell used to produce a virus, that is, the producer cell type, can alter the macromolecular composition, immunogenicity, and infectivity of the virions that are produced across several virus families. We found that the producer cell type of HSV-1 alters virion infectivity and virion protein composition. Therefore, the producer cell type may have implications in the spread of HSV-1 and subsequent disease outcomes in humans. Our results also raise concerns about how the use of different cell types to propagate HSV-1 may alter the outcome, interpretation, and reproducibility of experimental results.