Bacteria Are Already Making the Best HIV Treatment in Nature

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The promise is of an HIV meta-drug. Not only would it function as a vaccine, but also has a treatment—effective at all stages of the disease—and even just maybe a cure.

After three decades in the HIV/AIDS research trenches, it sounds like a cruel tease. A long slow slog, littered with many millions of bodies, and there it is: the answer. But this is what researchers at the Salk Institute are currently chasing. By "hacking" the extremely powerful and well-attuned immune responses offered by bacteria against viral infection, it may be possible to wield something like "cellular scissors" against HIV.

The Salk group, led by biochemist Hsin-Kai (Ken) Liao, describes t​heir most recent efforts in the current issue of Nature Communications.

The method depends on a bacterial defense mechanism called CRISPR. Bacteria are, after all, viral targets as well and, in a sense, they've been working on the problem for a lot longer than we have.

CRISPR does its work by functioning as a sort of genetic editor—or a pair of "cellular scissors"—with the capability of snipping the viral genome in just the right places to make it harmless.

"To combat hostile viruses, bacteria and archaea [nonbacterial single-celled microbes] have evolved a unique antiviral defense system composed of clustered regularly interspaced short palindromic repeats (CRISPRs), together with CRISPR-associated genes (Cas)," the paper explains. "The CRISPR/Cas9 system develops an adaptive immune resistance to foreign plasmids and viruses by creating site-specific DNA double-stranded breaks." These breaks are then all it takes.

To be sure, Liano and his group's work is not alone. The use of gene-editing to excise viruses from their cellular hosts is a promising and actively ​explored possibility, with several recent studies finding some success.

Here, the reverse-transcribed products of viral RNA are targeted and disrupted directly and throughout their lifecycle within host cells. The group has so far screened several potential target sites for their effectiveness in offering long-term and lasting protection against continued infection.

The particular sort of virus being targeted here, the lentivirus, is among the most challenging that humans face. With HIV being the prime example, these viruses work by invading healthy host immune cells and setting up shop, integrating themselves into the host's genome itself (the human genome). Once integrated, the virus just sort of blends in and becomes part of a latent infection, foiling any further potential immune response just by being really good at hiding out and by being patient.

This latency, where the virus just hangs out in an immune cell disguise, is part of the whole problem of treating and curing HIV. If the virus is latent, it's invisible to the immune system and, similarly, to treatments. We can beat down the active virus well enough—via highly-active antiretroviral therapy, an ability existing since the mid-'90s that's effectively turned HIV from an immanently deadly infection into a chronic, manageable infection—but we can't get rid of it.

This is why HIV treatment requires rigorous daily maintenance; left to its own devices, the virus will eventually start replicating and attacking, beating the immune system down until HIV infection becomes AIDS, which is where lives start being lost. So, managing the infection means continually, actively beating into if not into submission, than latency.

"Patients normally need to drugs every day or every week for their whole lives, because of the HIV that can be latent," Liao notes in a Salk Institute statement. "This costs money, time and effort."

Bacteria are way ahead, however. With CRISPR, bacteria are able to dictate the required molecular slices and cuts to neutralize lentiviruses at their base-level dormant state. This is achieved using what's known as guide RNAs, which are just instructions for where those cuts should go to be the most effective. Liao and his group were able to hack this part of the CRISPR system, redirecting those cuts to be most effective against HIV, inactivating the virus as it lies in wait.

The effect is of "editing out" HIV from the human genome. A lentivirus without a place to wait and hide is, thus, quite suddenly just a normal, vulnerable virus.

None of this is that easy, of course. HIV is also characterized by its adaptability. This allows the virus to evade potential defenses by outrunning them, in a sense. This aspect remains an open question. "The HIV virus can mutate very quickly," says Liao. "If we target multiple regions at the same time, we reduce the chance that the virus can develop resistance."