Effect of the N-butanoyl glutathione (GSH) derivative and acyclovir on HSV-1 replication and Th1 cytokine expression in human macrophages

Med Microbiol Immunol. 2014 Aug;203(4):283-9. doi: 10.1007/s00430-014-0335-4. Epub 2014 Mar 29.


Macrophages are an important defense against in vivo herpes simplex virus (HSV) infection by early cytokine secretion; however, they can be infected by HSV-1 and they may be compromised in their ability to produce cytokines. In this paper, we studied the expression of two Th1 cytokines, interleukin (IL)-12 and IL-27, upon HSV-1 infection of human macrophages, and how it is regulated by treatment with two antiviral drugs exerting their anti-HSV-1 activity through different mechanisms of action. We found that infection does not alter intra-macrophage thiol content, while it induces mRNA expression of IL-12 p35 and IL-12 p40 as well as of IL-27 p28 and IL-27 EBI3, as revealed by RT-PCR. The increased expression of mRNA is accompanied by increased production of IL-12 p40 and IL-27 p28 protein, as detected in the culture supernatants by ELISA. The two antiviral drugs tested were acyclovir (ACV), commonly used to treat herpes virus infections, and an N-butanoyl glutathione (GSH) derivative, GSH-C4. While ACV inhibits viral DNA polymerase, GSH-C4 inhibits virus replication by interfering with protein folding and maturation of viral particles. Indeed, GSH-C4, altering the intracellular redox state, may modulate the Th1/Th2 balance favoring Th1-type response. Our data show that both drugs inhibit HSV-1 replication in macrophages, without significantly affecting cytokine mRNA levels. Nonetheless, lower levels of IL-12 p40 and IL-27 p28 proteins were found in the supernatants of macrophages treated with either GSH-C4 or ACV, likely as an indirect consequence of inhibited HSV-1 replication.

MeSH terms

  • Acyclovir / pharmacology*
  • Adult
  • Antiviral Agents / pharmacology*
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Profiling
  • Glutathione / analogs & derivatives*
  • Glutathione / pharmacology
  • Herpesvirus 1, Human / drug effects
  • Herpesvirus 1, Human / immunology
  • Herpesvirus 1, Human / physiology*
  • Humans
  • Interleukin-12 / analysis
  • Interleukin-12 / genetics
  • Interleukin-12 / metabolism*
  • Interleukins / analysis
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Macrophages / immunology*
  • Macrophages / virology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Th1 Cells / immunology
  • Virus Replication / drug effects


  • Antiviral Agents
  • IL27 protein, human
  • Interleukins
  • glutathione-C4
  • Interleukin-12
  • Glutathione
  • Acyclovir