What Could Be a HIV Vaccine…
Researchers from the University of Nebraska-Lincoln have engineered an on/off replication switch in weakened HIV in the hopes of developing a highly effective and safe vaccine against the virus. The study, published in ACS Synthetic Biology, is the continuation of similar work done by the same team in 2014.
It is estimated that around 35 million people have died because of HIV in the last four decades and while treatment therapies are improving, neither a cure nor a vaccine have proven suitably effective or safe. A vaccine for the virus could use either deactivated or weakened HIV, with weakened viruses being preferable for generating stronger and longer-lasting immunity, but carrying more risk of infection.
Other teams have tried to synthesise vaccines in the past, with one in particular demonstrating the ability to immunise 95% of rhesus monkeys, but the question of safety has repeatedly halted progress. Most of these vaccines rely on removing genes from the virus that enable replication, thereby limiting HIV’s ability to proliferate and preventing an infection. However, the virus displays a very high mutation rate that has made it very difficult to circumvent, allowing the virus to overcome the engineered limitations and return to its usual replication rate.
This new study involves genetically modifying HIV to contain a ‘switch’ which allows the researchers to activate or deactivate replication of the virus. The concept relies on being able to produce sufficient levels of the virus to trigger an immune response, then halting replication completely so that the virus can be wiped out naturally. The team’s ability to reliably halt replication at will means that their technique may be the safest potential vaccine so far.
“Safety is always our biggest concern,” said Wei Niu, Ph.D., co-author of the paper and Associate Professor of Chemical and Biomolecular Engineering. “In this case, [it means] we’re one step closer to generating a vaccine.”
The study investigated a developed form of a previously engineered virus, created by the same team in 2014. In that study, they replaced three nucleotides that coded from a protein essential in virus replication, known as a sense codon, with a ‘nonsense’ codon that could not be transcribed by the viral transfer RNA (tRNA). The change meant that the functional protein could not be produced and so replication was halted. The team then engineered a synthetic, unique tRNA and an accompanying enzyme which could read the nonsense codon and, when supplied with a non-natural amino acid, could synthesise the protein once more and enable replication.
Their work was successful in that they could activate or deactivate replication of the virus as desired, but there were some drawbacks with their system. The biggest problem was that they could only induce a single round of replication before it stopped, meaning that the levels of the virus were insufficient to trigger the immune system.
The new study tried to fix this problem. The team adapted their genetic mutation so that they could embed the switch into the HIV genome. This meant that the change was present in all copies of the virus and when the synthetic amino acid was supplied, the virus could undergo multiple replication cycles while maintaining the mutation.
“The machinery can be carried to the next cycle and the next cycle,” said Zhe Yuan, lead author and Doctoral student in Biological Sciences. “It’s much easier to control feeding or [restriction] of the unnatural amino acid.”
The results were very promising and may be the first steps in developing a functional, safe vaccine for HIV, but there is more work that needs to be done. The team hope to be able to move their research from cell lines in petri dishes to small animal trials over the course of the next year, as well as investigating the effect of adding more nonsense codons to further reduce the likelihood of corrective mutations occurring.
“That’s the big milestone,” said Qingsheng Li, Ph.D., Professor of Biological Sciences and Member of the Nebraska Centre for Virology. “If that works well, we need to go to the pre-clinical animal model before going to a clinical trial. That’s our goal and road map.”