В Германии представили первые результаты испытаний экспериментального препарата Brec1
For the approximately 37 million people worldwide who are infected with HIV (human immunodeficiency virus), the newest cocktails of anti-retroviral drugs have come a long way in beating back the retrovirus and keeping an infection in check. Still, those drugs are no cure. While the treatments snarl the viral assembly line and thwart new infectious particles from invading the body’s cells, HIV itself is still there, hunkered in the DNA of a patient’s genome until there’s an opportunity for a comeback—say, when a patient goes off their medication.
As long as there’s lingering HIV, patients must keep taking the drugs, which cause side-effects, make for high prescription bills, and raise the threat of drug resistance. At least, that's the case for now. In a new study, scientists reveal a possible way to literally hack those lurking viruses out of a person's DNA strands.
With a custom enzyme made through coerced evolution, researchers selectively and reliably sliced HIV sequences from a number of cell types: bacteria, human cell lines used in research, in cells collected from patients with HIV infections, and in “humanized” mice with HIV. Though the strategy is early in development—far from clinical use—the data so far points to an effective and safe way to help drug treatments completely finish off HIV infections. This is a “promising strategy for future clinical applications,” the authors report.
The method relies on an enzyme that researchers forced into targeting a highly conserved, 34-base sequence of genetic code that flanks HIV genomes when they're lodged in human DNA (these implanted sequences are called proviruses). Of course, not every HIV provirus has these 34-base sequences—but most of the ones infecting humans do. The sequence, found in most HIV-1 subtypes, is estimated to occur in 82 percent of individuals infected with HIV.
The HIV-targeting enzyme, dubbed Brec1 (for broad range recombinase 1), originally sought out and snipped a completely different genetic sequence. But the researchers coaxed it into chopping HIV by making mutated versions. Then, researchers screened the mutants for the ability to cut sequences related to the conserved HIV sequence. Then, they repeated the process, gradually shifting the target sequence until it matched HIV.
With each cycle, the researchers would fish for a mutated version of the enzyme that got closer and closer to cutting the specific string of genetic bases in the HIV provirus. After 145 cycles, they had Brec1 that cut the exact provirus sequence and only that exact sequence.
Once Brec1 slashes the flanking HIV sequence, the whole provirus gets extracted and trashed. Then the enzyme patches up the DNA break it's created.
There are other genetic scissors that researchers can use to cut out specific genetic elements, such as proviruses. Most notably, there’s ZFN, TALEN an CRISPR. But those methods can accidentally cut non-target genetic sequences, a dangerous possibility in living humans. And they don't patch up their cut, leaving damage that can trigger cells’ emergency DNA repair systems, creating other cellular mayhem. Brec1 so far seems to avoid both of those problems.
In lab tests, researchers found that Brec1 could cut the HIV sequence out of every cell type they tested. And, the enzyme worked to carve out HIV without any toxic or genetic side effects, the researchers carefully noted.
They also reported success in mice, specifically "humanized” mice. The researchers engineered the animals to carry human immune cells that can be infected with HIV. Given a dose of Brec1—delivered via a genetically hollowed out, harmless virus—HIV infection in the mice declined over time to the point where HIV was no longer detectable, even though uninfected human cells persisted in the animals.
If the result holds up in humans, the enzyme may finally offer a solution to lingering HIV infections in patients on drug treatments. “Complete elimination of replication-competent HIV, including latent viral reservoirs, may be the only way to achieve a genuine cure,” the authors conclude.