Immune characteristics correlating with HSV-1 immune control and effect of squaric acid dibutyl ester on immune characteristics of subjects with frequent herpes labialis episodes

Immun Inflamm Dis. 2019 Mar;7(1):22-40. doi: 10.1002/iid3.241. Epub 2019 Feb 12.


Introduction: Differences in immune characteristics, including immune gene expression by peripheral blood mononuclear cells (PBMCs), correlating with herpes labialis and good or poor immune control of herpes simplex virus type 1 (HSV-1), and how these characteristics change after dosing with squaric acid dibutyl ester (SADBE), were investigated.

Methods: PBMCs were collected from persons positive for IgG against HSV-1 and having frequent, infrequent, or no herpes labialis outbreaks. The PBMCs were tested for proliferation against HSV-1 and a fungal antigen (Candida) and immune gene expression in the presence of HSV-1 and Candida. On day 1 after blood collection the subjects with frequent outbreaks were dosed topically on the arm once with SADBE, and their PBMCs were collected and tested 8 weeks later.

Results: Those with good immune control of their HSV-1 infection (fewer outbreaks) differ from those with poorer immune control in these ways: (1) Greater PBMC proliferation in vitro to HSV-1, HSV-1-infected cell extracts, and Candida considered together (P < 0.01). (2) Higher expression of IFNG and five other immune-related genes (P < 0.05 for each) and lower expression of IL5 and two other immune-related genes (P < 0.05 for each) in PBMCs in vitro stimulated with HSV-1 virus. The subjects with frequent outbreaks were treated once with SADBE, and 56 days later the PBMCs of these subjects differed from PBMCs from the same subjects taken on day 1 before treatment in exactly the same ways listed above as differences between those with good and poor immune control of HSV-1, and at the same levels of significance.

Conclusions: Higher IFNG and lower IL5 expression by PBMCs in the presence of HSV-1 correlate with fewer herpes labialis outbreaks, and a single topical dose of SADBE to the arm of subjects with frequent herpes labialis episodes improves immune response to HSV-1.

Keywords: herpes labialis; herpes simplex; herpesvirus 1; interferon gamma; interleukin-5; squaric acid; squaric acid dibutyl ester.

MeSH terms

  • Adolescent
  • Adult
  • Antiviral Agents / therapeutic use*
  • Candida / immunology*
  • Cyclobutanes / therapeutic use*
  • Female
  • Gene Expression Regulation
  • Herpes Labialis / immunology*
  • Herpes Simplex / immunology*
  • Herpesvirus 1, Human / physiology*
  • Humans
  • Interferon-gamma / metabolism
  • Interleukin-5 / metabolism
  • Leukocytes, Mononuclear / physiology*
  • Male
  • Middle Aged
  • Recurrence
  • Young Adult


  • Antiviral Agents
  • Cyclobutanes
  • Interleukin-5
  • squaric acid dibutyl ester
  • Interferon-gamma