How Close Are We to a Functional Cure for HIV?

Key Discoveries Pave the Way to Potential Therapeutic Solutions

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Photograph © International AIDS Vaccine Initiative (IAVI)

A functional cure is an evidence-based hypothesis by which HIV may be kept in check to undetectable levels without the use of chronic medications. Rather than a sterilizing cure, in which HIV would be fully eradicated from the body, a functional cure serves more along the lines of a remission—whereby the manifestations of the disease are removed, even though traces of the infective agent 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 viral reservoirs. Some have theorized that, by stimulating the reservoirs in such a way that it "reactivates" the virus, the HIV will be effectively exposed to the immune system. The latent reservoirs that had unwittingly shielded the virus will quickly die out and, under the pressure of antiretroviral therapy (ART), the viral activity may be able to be suppressed to such a level that ART will no longer be needed.
  • Intensify ART at the time of infection. While latent reservoirs are largely unaffected by ART, that shouldn't suggest that it has no effect. (Mathematical models have shown the patients on ART would eventually be able to deplete these reservoirs, but only within the space of 60-80 years.) Some studies suggests that initiating ART at the time of infection may reduce HIV's ability to establish these reservoirs in the first place.
  • Stimulate the body to produce "killer" antibodies. A subset of white blood cells called antibodies are programmed by the immune system to neutralize infective agents like HIV. the problems is that HIV mutates so quickly that it numerous subtypes that most "killer" antibodies cannot neutralize. Research into the development of therapeutic vaccines has focused on the production of so-called broadly neutralizing antibodies, known kill a wide spectrum of HIV subtype. Scientists are exploring ways to stimulate these naturally occurring agents, the strategy of which ultimately eradicate viruses released from the hidden reservoirs.

    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 (a.k.a. the Berlin Patient) was an HIV-positive American living in Berlin who was given a 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.

    Where Do We Go From Here?

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

    • Will purging HIV from its reservoirs be enough to ensure that the virus does not re-establish reservoirs in the same (or other) cells?
    • How big a role might early ART play in a functional cure, if any?
    • 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 in the Mississippi baby case and in other children proclaimed functionally cured?

    While we appear to be the right track (and are certainly closer to a solution than we've ever been), it's important that we 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.


    Connor, S. "A cure for HIV is now a realistic possibility." The Independent. May 19, 2013.

    Andriote, J. "The Prospects for a 'Sterlizing' Cure." The Altantic. November 29, 2012.

    Hütter, G.; Nowak, D.; Mossner, M.; et al. "Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation." New England Journal of Medicine. February 12, 2009; 360:692-698.

    Archin, 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.

    The Fold/Washington Post. "Was that toddler really cured of HIV?" Broadcast March 15, 2013.

    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.

    John Hopkins University. "Drugs Fail to Reawaken Dormant HIV Infection." Baltimore, Maryland; press release issued March 24, 2014.

    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.

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