HDAC Inhibitor Stops HPV in its Tracks
It may come as a surprise for a virus to be name-dropped during a stand-up comedy show, but in Ali Wong’s Netflix special “Baby Cobra” she exclaims, “Everybody has HPV, OK? Everybody has it… If you don’t have it yet, you go and get it.”
And, she’s right. According to the CDC about 80% of people will contract a human papillomavirus (HPV) infection in their lifetime . It is one of the most common sexually transmitted infections. While many kinds of HPV infections cause no symptoms and will go away on their own, some strains of the virus can cause cancer. In fact, 99% of cervical cancers are caused by HPV . In 2006 the first vaccine against the high-risk, cancer-causing strains of HPV became available, and since then the CDC has found that infections by these strains have dropped by 71% in women . Importantly, though, the vaccine only prevents new infections. It does not work against infections that are already present.
In an effort to identify treatments for established HPV infections, a new study by Banerjee et al demonstrates that the histone deacetylase (HDAC) inhibitor, Vorinostat, can halt the amplification of HPV-18, a high-risk strain of the virus.
Chromatin remodelers like histone acetyl transferases (HATs) and HDACs are integral to HPV infection because they regulate the transcription of viral proteins such as E6 and E7, which are necessary for HPV to replicate . Like many viruses, HPV hijacks its host cell’s DNA replication machinery so that it can replicate its own DNA and make more copies of itself.
To ask how the HDAC inhibitor Vorinostat affects HPV infection, the researchers studied the infection in organotypic raft cultures of primary human keratinocytes (PHK). Organotypic raft cultures serve as a model for human skin that can be studied in the laboratory. To create the raft cultures, scientists allow human skin cells to attach to a synthetic base and then differentiate as they would in actual human skin . Using these raft cultures, Banerjee et al determined that a treatment of 5µM Vorinostat is an optimal concentration at which viral DNA is lost and cellular DNA replication is reduced by 94%, indicating that the virus is no longer present and replicating its DNA.
To confirm that Vorinostat was indeed inhibiting HDACs, the authors assessed histone acetylation and the expression of HDACs in infected cells upon treatment with Vorinostat. They found that histone H4 remained acetylated and that HDACs 3, 4, 5, and 6, which increased expression during HPV infection, decreased expression under treatment with Vorinostat.
They next asked which proteins known to be involved in HPV progression and replication are affected by 5µM Vorinostat. They found that when infected rafts were treated with 5µM Vorinostat, expression of many components of the apoptosis – cell death – pathway were upregulated. Additionally and most importantly, they found that only the cells infected with HPV began to undergo apoptosis. Uninfected cells were completely unaffected, lending support for Vorinostat as a good therapeutic because of its specificity to HPV infected cells.
Digging deeper to uncover which apoptosis pathway was induced by Vorinostat, the researchers found that the E2F-1 pathway and not the p53 pathway was activated, consistent with prior work using other HDAC inhibitors on HPV infection .
In summary, Banerjee et al show that the HDAC inhibitor Vorinostat downregulates the expression of a number of HDACs that are important for DNA replication in HPV infected cells, and that it selectively induces DNA damage and the apoptosis pathway to kill HPV-infected cells and not uninfected cells, making Vorinostat an excellent candidate for a therapeutic against established HPV infections. While the authors show that prolonged use of Vorinostat is toxic to cells, future research into the proper dose and time-frame of administration may help reduce the prevalence of HPV and HPV-caused cancers for future generations.
Original article: Banerjee NS, Moore DW, Broker TR, Chow LT (2018). Vorinostat, a pan-HDAC inhibitor, abrogates productive HPV-18 DNA amplification. Proc Natl Acad Sci U S A, pii: 201801156. DOI: 10.1073/pnas.1801156115.
 Center for Disease Control (2018). Human Papillomavirus: 6 Reasons to Get HPV Vaccine for Your Child. https://www.cdc.gov/hpv/infographics/vacc-six-reasons.html
 World Health Organization (2018). Immunization, Vaccines and Biologicals: Human papillomavirus (HPV). https://www.who.int/immunization/diseases/hpv/en/
 Finzer P, Krueger A, Stöhr M, Brenner D, Soto U, Kuntzen C, Krammer PH, Rösl F (2004). HDAC inhibitors trigger apoptosis in HPV-positive cells by inducing the E2F-p73 pathway. Oncogene, 23(28):4807-17. DOI: 10.1038/sj.onc.1207620.