It wasn’t very long ago that the idea of an HIV cure was scoffed at. The concept of a curative method for dealing with chronic viral infections, as opposed to preventative (such as vaccines) or treatment (such as antivirals), has a history of controversy among the field.
Our immune system can naturally clear certain viruses, such as influenza, resulting in an infection ‘running its course’ without the need for a cure. Others set up shop so that once the host is infected, they are infected for life. These pernicious chronic infections undergo stages of viral latency, which are typically asymptomatic, and replication, which cause clinical disease ranging from acute illness to cancer. Examples of these viruses include HSV, human papilloma virus (HPV), hepatitis B virus (HBV) and HIV.
VIDD Associate Member Dr. Keith Jerome, who is also professor and head of the Virology Division, and director of the Molecular Virology Laboratory in the Department of Lab Medicine at the UW, studies novel ways to treat these viruses.
“What we are trying to do here in VIDD is build a program with emphasis on curative approaches for these [chronic] viral infections,” said Jerome. “I think that’s an evolving effort but it’s clearly an area of growth for the division.”
Just like many antivirals, targeted genomic (or gene) editing exploits the vast differences between humans and viruses. Viral pathogens express certain essential genes required for infection and replication in target host cells; when those genes are damaged, the virus is unable to cause further harm. Most antiviral treatments work by inhibiting a step in the viral life cycle; such as acyclovir, which inhibits HSV DNA replication; or protease inhibitors that prevent effective HIV protein assembly. The problem with these treatments is that they are only effective when the virus is replicating and would need to be taken continually to prevent viral replication and transmission.
Scientists have identified enzymes called endonucleases that mutate DNA at specific sequences. HSV1m5 is an HSV-1 endonuclease the Jerome lab studies that targets a 24 nucleotide ‘genetic barcode’ that mutates the gene encoding HSV-1 DNA polymerase. When the latent virus containing the mutated gene transfers to its replicative state in the human host cell, the non-functional DNA polymerase is expressed and inactive virus is produced (see figure). This concept of targeted gene editing has shown great promise as a method to cure chronic viral infections.
“The technology is so powerful that we are able to do some just fantastic things that were never possible before,” Jerome said. “It’s a very exciting time for cure. And has completely changed how we think about these viruses.”
Two current projects in the lab are in vitro culture models of viral infection: HSV and HBV. They’ve shown that these enzymes can successfully attack the dormant virus and block viral replication. This is really the foundation upon which Jerome is now able to ask: how effective can these be in an infected organism?
“We are going into animal models now, which allow us to work on the next set of challenges,” Jerome said.
defeatHIV is part of an NIH sponsored program known as the Martin Delaney Collaboratory: Towards an HIV-1 Cure that has been put forward by the federal government to think about a cure for HIV. defeatHIV co-PIs Jerome and Dr. Hans-Peter Kiem, who is a member of the Clinical Research Division, have spearheaded the campaign to use genome editing as a curative approach to HIV therapy.
“When we think about those grant cycles, how you have this 5 year period and the clock ticks, we try to make ourselves think about the people who are affected by HIV and that’s really the clock we are trying to outpace.”
Jerome continues, “The path to a cure is going to have a lot of twists and turns. But this concept is not going to go away. We’ve reached a point where the science is ready to do this. We need to seize this opportunity to bring it to reality as soon as possible.”
On behalf of Fred Hutch, defeatHIV, University of Washington Center for AIDS Research (UW CFAR) and the UW Virology Division, Jerome and other Hutch investigators welcomed scientists from around the globe to a forum for the international community to highlight curative approaches for HIV infection: the Conference on Cell and Gene Therapy for HIV Cure 2014, which took place August 26-27, 2014.
In other news, Keith will be promoted to VIDD member effective January 1, 2015. Congratulations!