If you are a fan of Marvel Comics, Harry Potter or Disney, you may be familiar with the shape-shifting capabilities of Mystique, the Hogwarts Polyjuice Potion or the caterpillar in Alice in Wonderland. However, are you aware that HIV can shape-shift beyond all recognition too? A Johns Hopkins-led study reveals a potential therapeutic strategy to eradicate these mutant HIV-infected cells.

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Scientists have found a method to train the immune system to detect, attack and destroy mutant HIV once coaxed out of its latent state.

Luring dormant HIV out of hiding and obliterating its last cure-defying holdouts has become the holy grail of HIV eradication, but several recent attempts to do so have proven futile. A new study published in the journal Nature reveals why the efforts have failed and offers a strategy that could form a blueprint for a therapeutic vaccine to eradicate the lingering virus from the body.

HIV eradication endeavors have been hindered by the virus’ ability to mutate in such a way that it becomes unidentifiable and resistant to destruction from the immune system, even when lured out of hiding. The scientific team behind the study has found a way to train the immune system to recognize, attack and subdue mutant HIV once coaxed out of dormancy.

In a description of their “proof of principle” research, the team says they tamed mutant HIV by training a class of immune sentinel cells known as killer T cells to spot and eliminate HIV-infected cells capable of evading immune surveillance and impervious to immune system extermination.

While sounding like something out of a sci-fi movie, the team’s strategy manages to address one of HIV’s most challenging behaviors. HIV has an ability to hijack a class of immune cells known as memory CD4+ T cells. After infection the virus goes into hiding and becomes dormant, undetectable to the immune system and unreachable by antiviral drugs.

Finding the key to coaxing the virus out of dormancy and permanently finishing it off has been the focus of numerous research hours. However, new findings from the study show that the latent virus is not merely out of reach; it is also genetically transformed to evade recognition by the immune system, even after latency reversal.

“Our results suggest that luring HIV out of hiding is winning only half the battle,” says senior investigator Dr. Robert Siliciano, professor of medicine, molecular biology and genetics at the Johns Hopkins University School of Medicine in Baltimore, MD.

We found that these pools of dormant virus carry mutations that render HIV invisible to the very immune cells capable of disarming it, so even when the virus comes out of hiding, it continues to evade immune detection.”

A technique known as deep sequencing was used to narrow down HIV’s genetic features to a single infected cell. Scientists examined blood samples from 25 HIV-infected patients; 10 of which had begun therapy early – within 3 months of infection. The remaining patients began treatment after the 3-month stage, when HIV infection is considered to be at a chronic stage.

All viruses and bacteria carry key protein identifiers. Intact, these identifiers are spotted by the immune system as “foreign,” triggering an immune attack. However, soon after infection, HIV quickly alters these “marker” regions, making them unrecognizable to the immune system.

The researchers report that they discovered that patients who began antiviral therapy within a few weeks or months of infection:

  1. Harbored largely non-altered HIV
  2. Appeared to have halted the mutation process, freezing the virus in its original state.

Those who began treatment later:

  1. Had viral reservoirs composed almost entirely of HIV carrying the so-called escape mutations – occurring when key sections of the viral protein shape-shift
  2. Had more than 98% of the virus in latent reservoirs that were broadly altered.

Siliciano and colleagues report that every HIV-infected cell preserves a small portion of the original viral protein intact – a feature that could be exploited and used as a solution to the problem of the immune system “recognition” issue.

“We hypothesized that if these killer T cells were somehow nudged to spot the tiny segments of unaltered virus, they would kill the entire HIV-infected cell,” says Kai Deng, PhD, lead author of the study and a postdoctoral research fellow at Johns Hopkins.

To put the hypothesis into action, scientists isolated killer T cells from patients and mixed them either with mutant forms of HIV or with a cocktail that contained both mutated and non-mutated lab-made masses of HIV protein.

Each group of killer T cells was exposed to cells infected with HIV obtained from patients carrying the escape mutations.

The killer T cells primed with the cocktail of mutated and non-mutated HIV destroyed 61% of the HIV-infected cells. By contrast, killer T cells primed with only mutant HIV destroyed only 23% of HIV-infected cells. Siliciano comments:

It’s as if the immune system had lost its ability to spot and destroy the virus, but priming killer T cells that recognize a different, non-mutated portion of HIV’s protein reawakened that natural killer instinct.”

The next stage of the research tested whether primed killer T cells could perform outside of the lab dish.

Humanized mice received bone marrow from an HIV-infected patient, giving rise to a humanized immune system.

All mice developed full-blown HIV infections. Mice injected with patient-derived killer T cells primed solely by mutated viral proteins succumbed to infection. Dissimilarly, mice primed with the mix of mutant and non-mutant HIV were able to control the infection and experience a thousand-fold drop in the amount of circulating virus, with some suppressing HIV below detectable levels.

“Our results show that any curative strategy designed to eradicate HIV infection would need to include the use of killer T cells primed to recognize non-mutant forms of HIV,” Deng concludes.

Medical News Today recently reported on a new study that explains why experimental HIV vaccines tend to backfire.