Nuclear factor erythroid 2-related factor 2 (Nrf2), the cellular master regulator of the antioxidant response, dissociates from its inhibitor Keap1 when activated by stress signals and participates in the pathogenesis of viral infections and tumorigenesis. In latently infected ganglia, HSVs express a long noncoding RNA, a latency-associated transcript (LAT), which plays a key role in maintaining latently infected neurons, but not viral proteins. Here we report that activating transcription factor 3 (ATF3) is induced by stress both in infected cells in culture and in ganglia harboring latent virus. Here we show that the Lyta promoter region was heavily methylated in latently infected cells. Here we show that LANA interacts with Aurora kinase B (AK-B) and induces phosphorylation of survivin at residue T34. No shedding of viruses occurred before flight, but 9 of the 17 (designated “virus shedders”) shed at least one or more viruses during and after flight. A leading role in the repression of viral genes is carried out by histone deacetylase (HDAC)/corepressor element-1 silencing transcription factor (CoREST)/lysinespecific demethylase1(LSD1)/RE1-silencing transcription factor (REST) repressor complex (HCLR).
These results suggest a relationship among a demethylation status in the Lyta promoter, the reactivation of KSHV, and the development of KSHV-associated diseases. We also observed promiscuous activation of several reporter constructs by Rta, suggesting that Rta activation of gene expression may involve a general non-DNA binding mechanism. In virus shedders, plasma IL-4 (a Th2 cytokine) was elevated 21-fold at R+0, whereas IFNγ (a Th1 cytokine) was elevated only 2-fold indicating a Th2 shift. The inflammatory cytokine IL-6 was elevated 33-fold at R+0. In non-shedding astronauts at R+0, only IL-4 and IP-10 levels were elevated over baseline values. Elevated cytokines began returning to normal by R+3, and by R+120 all except IL-4 had returned to baseline values. These data show an association between elevated plasma cytokines and increased viral reactivation in astronauts.