Preventing a Comeback

The Human Immunodeficiency Virus (HIV) is one of the greatest scourges of mankind, with the World Health Organization estimating that over 37 million people are currently infected. And while there is no cure, nor any approved method of destroying the virus, treatments, therapies, and retroviral cocktails do exist which seek to keep the viral levels of the disease in the bloodstream low.

These treatments often suppress the effects of the virus, and when combined with other drugs put a halt to its further progress. The problem, however, is that HIV remains in the bodies of those infected, lurking in their DNA, and will often come back after a patient goes off their medication. And these medications frequently cause unwanted side effects, are expensive, and potentially cause drug resistance.

But a new study in Nature Biotechnology offers a possible alternative to these medications with a custom-made enzyme. Their enzyme was able to selectively and reliably cut away HIV sequences from various cell types, such as bacteria, human cell lines used in research, and in cells culled from HIV patients.

This alternative relies on the enzyme targeting a sequence of genetic code that borders HIV genomes when they’re lodged in human DNA. While not every HIV strain contains these sequences, it is estimated to occur in 82% of infected individuals.

Evolving a Solution
A scanning electron micrograph of HIV (in green) emerging from a lymphocyte (red).  Source: Wikimedia Commons

The HIV-zapping enzyme—known as Brec1, short for “broad range recombinase 1″—originally snipped out a different genetic sequence. The researchers were able to make the enzyme cut out HIV by mutating the virus. These mutated versions were then screened according to their ability to cut sequences related to that sequence which bordered the HIV sequence. This cycle was repeated, with each generation of mutants gradually shifting their target towards this sequence.

After 145 cycles, the researchers had a mutated form of Brec1 that cut the exact genetic sequence flanking the HIV genome, and that sequence alone. Once Brec1 cuts through this sequence, the whole HIV genome is removed and trashed. The enzyme then patches up the break it created in the DNA—conveniently cleaning up after itself.

While other genetic scissors such as ZFN, TALEN and CRISPR can be used by researchers to cut out specific genetic elements, these can accidentally cut non-target genetic sequences which can have disastrous effects in living humans. More importantly, they don’t patch up their cut, which can lead to triggering a cells’ DNA repair systems and generate more problems.

Brec1 has the benefits of having zero side effects and none of the drawbacks of other genetic scissors. It was also able to cut the HIV sequence reliably out of every cell type researchers tested. While tests have been conducted on “humanized” mice (genetically engineered to possess human immune cells) to mimic its potential reaction in human beings, no actual human trials have been undertaken. If Brec1 is successful in human trials, it could eventually wean HIV patients off drug treatments.

While it may take a long time to get to a working treatment, the research currently offers one of the best hopes for eradicating HIV. “Complete elimination of replication-competent HIV, including latent viral reservoirs, may be the only way to achieve a genuine cure,” the authors say in their paper describing the research.

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