Herpes simplex research
Research into herpes simplex is ongoing.
Researchers at the University of Florida have made a Hammerhead ribozyme that targets and cleaves the mRNA of essential genes in HSV-1. The hammerhead, which targets the mRNA of the UL20 gene, greatly reduced the level of HSV-1 ocular infection in rabbits, and reduced the viral yield in vivo. The gene-targeting approach uses a specially designed RNA enzyme to inhibit strains of the herpes simplex virus. The enzyme disables a gene responsible for producing a protein involved in the maturation and release of viral particles in an infected cell. The technique appears to be effective in experiments with mice and rabbits, but further research is required before it can be attempted in people infected with herpes.
Another possibility to eradicate the HSV-1 variant is being pursued by a team at Duke University. By figuring out how to switch all copies of the virus in the host from latency to their active stage at the same time, rather than the way the virus copies normally stagger their activity stage, leaving some dormant somewhere at all times, it is thought that immune system could kill the entire infected cell population, since they can no longer hide in the nerve cells. This is a potentially risky approach especially for patients with widespread infections as there is the possibility of significant tissue damage from the immune response. One class of drugs called antagomir could trigger reactivation. These are chemically engineered oligonucleotides or short segments of RNA, that can be made to mirror their target genetic material, namely herpes microRNAs. They could be engineered to attach and thus 'silence' the microRNA, thus rendering the virus incapable to keep latent in their host. Professor Cullen believes a drug could be developed to block the microRNA whose job it is to suppress HSV-1 into latency.
Various vaccine candidates have been developed, the first ones in the 1920s, but none have been successful to date. One vaccine that was under trial was Herpevac, a vaccine against HSV-2. The National Institutes of Health (NIH) in the United States conducted phase III trials of Herpevac. In 2010, it was reported that, after 8 years of study in more than 8000 women in the United States and Canada, there was no sign of positive results against the sexually transmitted disease caused by HSV-2 (and this despite earlier favorable interim reports).
A laboratory at Harvard Medical School has developed dl5-29 (now known as ACAM-529), a replication-defective mutant virus that has proved successful both in preventing HSV-2/HSV-1 infections and in combating the virus in already-infected hosts, in animal models. It has been shown that the replication-defective vaccine induces strong HSV-2-specific antibody and T-cell responses; protects against challenge with a wild-type HSV-2 virus; greatly reduces the severity of recurrent disease; provides cross-protection against HSV-1; and renders the virus unable to revert to a virulent state or to become latent. His vaccine is now being researched and developed by Accambis (acquired by Sanofi Pasteur in September 2008), and is due to be applied as an Investigational New Drug in 2009. However, the status of ACAM-529 became after the acquisition somewhat unclear. According to Jim Tartaglia, a company representative of Sanofi Pasteur, ACAM-529 is still under development and should enter phase I clinical testing in 2012.
A private company called BioVex began Phase I clinical trials for ImmunoVEX, another proposed vaccine, in March 2010. A completely new approach has the "HSV-2 ICP0 live-attenuated HSV-2 vaccine" investigated by Dr. William Halford at the Southern Illinois University (SIU) School of Medicine.
Herpes has been used in research with HeLa cells to determine its ability to assist in the treatment of malignant tumors. A study conducted using suicide gene transfer by a cytotoxic approach examined a way to eradicate malignant tumors. Gene therapy is based on the cytotoxic genes that directly or indirectly kill tumor cells regardless of its gene expression. In this case the study uses the transfer of the Herpes simplex virus type I thymidine kinase (HSVtk) as the cytotoxic gene. Hela cells were used in these studies because they have very little ability to communicate through gap junctions. The Hela cells involved were grown in a monolayer culture and then infected with the HSV virus. The HSV mRNA was chosen because it is known to share characteristics with normal eukaryotic mRNA.
The HSVtk expression results in the phosphorylation of drug nucleoside analogues; in this case the drug ganciclovir, an anitiviral medication used to treat and prevent cytomegaloviruses, converts it into the nucleoside analogue triphosphates. Once granciclovir is phosphorylated through HSV-tk it is then incorporating DNA strands when the cancer cells are multiplying. The nucleotide from the ganciclovir is what inhibits the DNA polymerization and the replication process. This causes the cell to die via apoptosis.
Apoptosis is regulated with the help of miRNAs, which are small non-coding RNAs that negatively regulate gene expression. These miRNAs play a critical role in developing the timing, differentiation and cell death. The miRNAs effect on apoptosis has affected cancer development by the regulation of cell proliferation, as well as cell transformation. Avoidance of apoptosis is critical for the success of malignant tumors, and one way for miRNAs to possibly influence cancer development is to regulate apoptosis. In order to support this claim, Hela cells were used for the experiment discussed.
The cytotoxic drug used, ganciclovir, is capable of destroying via apoptosis transduced cells and non-transduced cells from the cellular gap junction. This technique is known as the "bystander effect,” which has suggested to scientists that the effect of some therapeutic agents may be enhanced by diffusion through gap junctional intercellular communication (GJIC) or cell coupling. GJIC is an important function in the maintaining of tissue homeostasis and it is a critical factor in balance of cells dying and surviving.
When Hela cells were transfected with the HSV-tk gene, and were then put in a culture with nontransfected cells, only the HSV-tk transfected Hela cells were killed by the granciclovir, leaving the nonviral cells unharmed. The Hela cells were transfected with the encoding for the gap junction protenin connexin 43 (Cx43) to provide a channel that permits ions and other molecules to move between neighboring cells. Both Hela cells with the HSV-tk and without the HSV-tk were destroyed. This result has led to the evidence needed to state that the bystander effect in the HSV-tk gene therapy is possibly due to the Cx-mediated GJIC.
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