Targeting Viral Epigenetics for the Control of Human Adenovirus Replication

Abstract

Human adenovirus (HAdV) causes minor illness in healthy individuals, but can cause severe disease in at-risk individuals, such as pediatric, geriatric, and especially immunocompromised individuals. This is problematic, as no approved therapeutic exists for treating HAdV infection, worsening the burden these individuals face. During infection, HAdV exploits epigenetic regulation of the host cell by modulating chromatin dynamics, promoting expression of cellular genes productive to infection. Epigenetic regulation of viral DNA is also important, as HAdV DNA is chromatinized during infection. As such, we hypothesized that treatment with compounds capable of regulating viral epigenetics during infection would be an effective strategy in combating HAdV infection. Though treatment with curcumin and CBL0137 have diverse effects within the cell, these compounds are each capable of affecting epigenetic processes, by modulating the expression of epigenetic machinery as well as inhibiting histone chaperones. Thus, we aimed to evaluate the effect of curcumin and CBL0137 treatment, as well as siRNA-mediated depletion of the histone chaperone facilitates chromatin transactions (FACT) complex on HAdV infection. Treatment with curcumin inhibited expression of the viral early 1A (E1A) proteins as well as the late capsid protein hexon. E1A is the first region expressed during infection, and the E1A proteins are vital for modulating cellular gene expression and transactivating other viral genes, and the lack of E1A proteins following curcumin treatment subsequently impacted viral DNA replication and progeny formation. CBL0137 treatment also prevented E1A protein production, which was attributed to CBL0137-induced degradation of the catalytic subunit of RNA polymerase II. However, we noted that other early viral genes contribute to the stabilization of RNA polymerase II during CBL0137 treatment. Finally, the role of the FACT complex in HAdV infection was explored. Depletion of the FACT complex reduced E1A production by lowering the amount of E1A transcripts within the cell. The FACT complex was also observed co-localizing with viral replication centers, with the FACT complex associating with the viral DNA-binding protein, a key protein in viral replication centers. Taken together, these results indicate targeting E1A production by interfering with viral chromatin is a viable strategy in treating HAdV infection.