Altering how cells first interact with HIV could be the difference between lifelong infection and being completely cleared of the virus - but once the viral DNA is integrated, it’s hard to do much beyond stifling the emerging viruses. A new study has shown that genetic modification of Tre recombinase has significant antiviral properties at the genomic level and could potentially be used as part of a cure for HIV. Lead author Ilona Hauber from the Heinrich Pette Institute at Leibniz Institute for Experimental Virology published the study in PLoS Pathogens.
HIV mostly infects helper T cells, though macrophage and microglial cells can also come under attack. The virus down regulates the cells’ immunological response, leaving the host person defenseless against other infections and cancers. There are also cells that are infected but do not actively produce the virus, which means it can hide from traditional therapies. This is known as the HIV latent reservoir and was recently discovered to be sixty times larger than previously thought.
Current HIV treatments can suppress the virus to near-undetectable levels, but simply cannot eradicate it completely because they only work on an active viruses. As long as the viral DNA is still integrated in the cell, there is always the threat of it activating and generating new viruses. Traditional treatments are very expensive and can run $2000-5000 per month for one individual. While HIV-positive patients are living longer than ever before, longterm use of the drugs can make the person more susceptible to complications involving metabolic disorders, kidney disease, heart disease, and more.
Taking the next step
Cre recombinase is an enzyme that is responsible for recombining genetic information using the loxP site. It targets specific genetic sequences so it can snip the DNA, allowing foreign sequences to be inserted. In nature, this is used to help P1 bacteriophages infect cells and also does some proofreading against dimers. Scientists have found a way to exploit this practice and use Cre-Lox as an effective means of genetic modification for a seemingly endless amount of applications.
In 2007, the team modified Cre so that it would target the DNA that had been added into the human genome by HIV. This new recombinase enzyme was called Tre. While other treatments target enzymes and stop the virus from spreading, this would actually go into the infected cell’s nucleus and remove the problem once and for all. This could also solve the problem of HIV hiding in the latent reservoir, since it does not require active production of the virus.
In the most recent study, the team put Tre to the test. It was shown not only to remove the viral DNA, but did not pose toxicity risks to the cells themselves. Even when Tre was overexpressed for three straight weeks, the cells didn’t incur any damage. In fact, the treated cells were virtually indistinguishable from the control cells that had not been infected, showing that Tre does not pose a risk to human genetic material; it only targets the viral DNA.
Next, mice were genetically modified so that they would have a more humanized immune system. Tre recombinase was administered to the mice who were infected with HIV-1. After 16 weeks of treatment, there were highly significant results that the virus had actually been eliminated from many of the cells.
Future study will build on these results by targeting more cells, including those in the latent reservoir. Gene therapy does present an increased risk of cancer, though Tre is specific enough to where that might not be a large issue. In addition to other immuno-boosting treatments, this technique may eventually be used to help bring eradication to the virus that has infected 70 million people and has taken over 35 million lives.
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