Novel Immunologic Approaches to Fighting HIV

Scientists "train" immune cells to be effective killers

in the lab
U.S. Military HIV Research Program (MHRP)

In recent years, researchers have placed a greater focus on various immunologic approaches to neutralizing HIV, wherein the body's own immune system is spurred into active defense against the invading virus. In most individuals, the body's ability to defend itself wanes over time as its so-called "killer" cells, known as CD8+ T-cells, gradually lose their ability to recognize the rapidly mutating virus.

To complicate matters, HIV has the ability to quickly establish itself in what is called latent reservoirs—essentially cellular hiding places—where it can continue to persist for years and even decades even in the face of successful antiretroviral therapy (ART).

In order to eradicate HIV from the body, scientists would have to not only release the dormant HIV from these sanctuaries but to kill them with either some fully neutralizing agent or by triggering a heightened immune response (or both). Even as investigators are exploring new and promising ways to potentially kick HIV out into the open, to date we have not yet discovered the means by which to kill the virus once it is released.  

Scientists at Johns Hopkins University School of Medicine, led by senior investigator Robert Siciliano, M.D., Ph.D., have not only revealed why this phenomenon occurs but have proposed a strategy which may open the door to creating a vaccine able to fully eliminate the lingering viral particles.

Model for "Training" Killer T-Cells

In their research, Siciliano and his team have reported that newly released HIV is often so mutated as to be completely unrecognizable to CD8+ T-cells. They believe that by "training" these defensive cells to better spot and kill the very infected cells providing them haven—known as memory CD4+ T-cells—they may be able to purge the body of HIV or, at the very least, control the virus without the use of medications.

The investigators started by taking blood samples from 25 HIV-positive patients, 10 of whom started ART within three months of infection and the remainder of whom started therapy later during the chronic stage of infection when the initial signs and symptoms of the disease first appear.

Not surprisingly, those who started ART early had largely unaltered HIV while those who started later had so-called "escape" mutations which allowed the viral protein to mask itself from detection.  However, what Siciliano and his researchers were able to find was that both unaltered and altered HIV retained a small portion of their original viral protein. By priming CD8+ T-cells to recognize this protein "marker," the scientists believe that the cell may be better able to target and destroy the virus.

In in vitro lab studies, the investigators first obtained killer T-cells from their patients and exposed them to either mutant HIV or a combination of viral protein chunks taken from both mutated and non-mutated HIV. The sample was then later exposed to HIV-infected CD4+ T-cells taken from patients known to have the escape mutation.  After analyzing the results, Siciliano and his team found that the killer T-cells exposed to both mutated and non-mutated HIV were able to kill 63% of the infected cells while those exposed to mutant HIV were only able to kill 23%.

The researchers then explored the model in humanized mice (i.e., mice bioengineered to have a human immune response) that had each been exposed to HIV.  When the mice developed later-stage, symptomatic disease and were injected with either one or the other "trained" killer T-cells samples, the results were the same. All of those that had received killer T-cells primed with only mutated HIV died. Those that had received T-cells primed with mutated and non-mutated HIV experienced a profound, thousand-fold drop in viral load, with some suppressed to fully undetectable levels.

The Johns Hopkins research provides a compelling proof-of-concept that may eventually pave the way an entirely new model of HIV eradication or control.

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