17-beta estradiol promotion of herpes simplex virus type 1 reactivation is estrogen receptor dependent.
Correlations between estrogen and herpes simplex virus (HSV) reactivation from latency have been suggested by numerous clinical reports, but causal associations are not well delineated. In a murine HSV-1 corneal infection model, we establish 17-beta estradiol (17-betaE) treatment of latently infected ovariectomized mice induces viral reactivation, as demonstrated by increased viral load and increased immediate-early viral gene expression in the latently infected trigeminal ganglia (TG). Interestingly, the increased HSV reactivation occurred in the absence of inhibition of viral specific CD8(+) T-cell effector function. 17-betaE administration increased HSV reactivation in CD45(+) cell-depleted TG explant cultures, providing further support that leukocyte-independent effects on latently infected neurons were responsible for the increased reactivation. The drug-induced increases in HSV copy number were not recapitulated upon in vivo treatment of latently infected estrogen receptor alpha-deficient mice, evidence that HSV reactivation promoted by 17-betaE was estrogen receptor dependent. These findings provide additional framework for the emerging conceptualization of HSV latency as a dynamic process maintained by complex interactions among multiple cooperative and competing host, viral, and environmental forces. Additional research is needed to confirm whether pregnancy or hormonal contraceptives containing 17-betaE also promote HSV reactivation from latency in an estrogen receptor-dependent manner.
Vicetti Miguel
Rodolfo D
RD
Graduate Program in Immunology, Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. [corrected].
Sheridan
Brian S
BS
Harvey
Stephen A K
SA
Schreiner
Robert S
RS
Hendricks
Robert L
RL
Cherpes
Thomas L
TL
D000818:Animals; D003316:Corneal Diseases / Q000821:virology; D004958:Estradiol; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000502:physiology*; D015828:Eye Infections, Viral; D005260:Female; D017781:Genes, Immediate-Early; D018259:Herpesvirus 1, Human / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011960:Receptors, Estrogen; D019562:Viral Load; D014775:Virus Activation; D017735:Virus Latency
D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D004958:Estradiol