How Close Are We to a Functional Cure for HIV?

Key Discoveries Pave the Way to Long-Term Remission

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International AIDS Vaccine Initiative (IAVI)

A functional cure is an evidence-based hypothesis by which HIV may be kept in check without the use of chronic medications. As opposed to a sterilizing vaccine, in which HIV would be fully eradicated from the body, a functional cure serves more along the lines of a remission wherein the virus is unable to cause illness even if traces of the virus still remain.

There has been much enthusiasm and almost as much controversy surrounding the prospect of a functional cure. Françoise Barré-Sinoussi, the co-discover of HIV, stated in 2013 that she fully believes that such a cure may be found "within the space of the next 30 years." By contrast, Robert Gallo (also credited with discovering HIV) considers the concept flawed and believes that parts of the theory are "not likely to work."

How a Functional Cure Might Work

One of the biggest facing challenges facing researchers has been the cells and tissues of the body (called latent reservoirs) where HIV can persist even the face of complete viral suppression. Hidden within these cellular reservoirs is the genetic code of HIV, which the immune system is unable to detect.

Since the virus is not actively replicating—but is rather carried along passively as the host cell replicates—it is largely unaffected by antiretroviral drugs (since antiretrovirals work by interrupting a stage in the virus' life cycle, and not the host's).

There are several models being explored to address this:

  • Purge the latent reservoirs. Some scientists have shown that, by stimulating the reservoirs, HIV can be reactivated and released from their hidden sanctuaries. Doing so allows ART and other neutralizing agents to fully eradicate the newly purged virus, a strategy known as "kick-kill." Several drugs have the ability to clear these vital reservoirs but to date, only partially. Newer drug combinations are hoped to improve upon these results.
  • Stimulate the body to produce "killer" antibodies. There are types of immune proteins, called antibodies, that are produced by the body in response to infection. Some of these have the ability to neutralize HIV. The problem is that HIV mutates so quickly that there is never a large enough variety of "killer" antibodies to neutralize all of the strains. In recent years, however, scientist have discovered that certain, rare individuals have specialized broadly neutralizing antibodies (BnAbs) that can kill a wide spectrum of HIV mutations. Scientists are exploring ways to stimulate these naturally occurring agents, the strategy of which may help fulfill the "kick-kill" promise

    Evidence in Support of a Functional Cure

    While research into a functional cure has been on the table for some years, three specific events provided the foundational proof-of-concept.

    Chief among them is the one patient believed to be "cured" of HIV in 2009. Timothy Brown (the Berlin Patient) was an HIV-positive American living in Berlin who was given an experimental bone marrow transplant to treat his acute leukemia. Doctors selected a stem cell donor with two copies of a genetic mutation called the CCR5-delta-32, known to resist HIV in a rare population of people.

    Routine tests performed soon after the transplant revealed that the HIV antibodies in Brown's blood had decreased to such levels as to suggest the complete eradication of the virus. Subsequent biopsies confirmed no evidence of HIV in any Brown's tissue, supporting claims that the man was, indeed, cured. While the risk of death is considered too high to explore bone marrow transplants as a curative option, the case at least provided the evidence that a cure is, in fact, possible.

    Meanwhile, other scientists have been investigating experimental agents that have the ability to purge HIV from their latent reservoirs. One of the earliest studies, conducted at the University of North Carolina in 2009 demonstrated that a class of drugs called histone deacetylase (HDAC) inhibitors could reactivate latent HIV at drug levels considered safe and tolerable.

    While subsequent studies have suggested that the use of a single HDAC agent may only provide partial reactivation, there is some evidence to suggest that combination HDAC therapy or newer classes of anti-cancer drugs (called ingenol compounds) might fully flush latent HIV from their hidden reservoirs.

    The Path Forward

    As promising as all of the research may seem, they raise just as many questions as they do answers. Chief among them:

    • Will purge HIV from its reservoirs be enough to ensure that the virus does not re-establish reservoirs in the same (or other) cells?
    • How important might broadly neutralizing antibodies be to a functional cure given that the stimulation of a single antibody of this sort is theoretic at best?
    • How certain can we be that viral rebound won't occur as had happened with the Mississippi baby case and other failed attempts?

    While we appear to be the right track, it's important to view the research with guarded optimism. Even as scientists continue to unlock the mysteries surrounding HIV, none of these advances even vaguely suggest that the rules regarding the prevention and treatment of HIV have changed.

    If anything, given the evidence that early detection and intervention are key to a cure, the imperative to remain vigilant is, perhaps, more important than ever.

    View Article Sources
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    • Archim, N.; Espeseth, A.; Margolis, D.; et al. "Expression of Latent HIV Induced by the Potent HDAC Inhibitor Suberoylanilide Hydroxamic Acid." AID Research of Human Retroviruses. February 2009; 25(2):207-212.
    • Sáez-Cirión, A.; Bacchus, C.; Hocqueloux, L.; et al. "Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study." PLoS Pathology. March 14, 2013; 0(3):e1003211.
    • Jiang, G.; Mendes, E.; Kaiser, P.; et al. "Synergistic Reactivation of Latent HIV Expression by Ingenol-3-Angelate, PEP005, Targeted NF-kB Signaling in Combination with JQ1 Induced p-TEFb Activation." PLoS Pathogens. July 30 2015; DOI: 10.1371/journal.ppat.1005066.