A functional cure is an evidence-based hypothesis by which HIV may be kept in check to undetectable levelswithout the use of chronic medications. Rather than asterilizing 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, fully believes that it is likely possible "within the space of the next 30 years." Meanwhile, 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 "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 therapy (since antiretrovirals work by interrupting a stage in the virus' replication cycle).
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 die out quickly 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 it was mentioned that 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.) Evidence now suggests that initiating ART at the time of infection may reduce HIV's ability to establish these reservoirs in the first place. It is further theorized that, by keeping the viral population low from the start, HIV's ability to mutate would be greatly diminished, while immune function could preserved to such a degree that a person may eventually be able to control the virus without ART.
Additionally, research into the development of therapeutic vaccines has focused on the production of broadly neutralizing antibodies, known to neutralize a wide spectrum of HIV. Scientists are exploring ways to stimulate these naturally occurring agents, the strategy of which may be applied to a functional cure.
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:
- **The Berlin Patient. Timothy Ray Brown, an HIV-positive American living in Berlin, was given a bone marrow transplant in 2009 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 his blood had decreased to such a level as to suggest the complete eradication of the virus from his system. Subsequent biopsies confirmed no evidence of HIV in any of Brown's tissues, making him the first person officially cured of HIV. While the risk of death is considered too high to explore bone marrow transplants as a curative option, "The Berlin Patient" at least provided the evidence that a cure was possible.
- **HDAC Inhibitor Research. A number of different agents have been explored to elicit the "purging" of latent HIV reservoirs, but it was in 2009 that researchers from the University of North Carolina first suggested that a class of drugs called histone deacetylase (HDAC) inhibitors could reactivate HIV in latent cells. Long used as mood stabilizers, HDAC inhibitors have shown greater utility in recent years in the treatment of T-cell lymphoma (a type of non-Hodgkin lymphoma). Subsequent research has shown that other types of HDAC inhibitors—most predominantly panobinostat—may be able to induce the same effect with lower dosing and minimal toxicities.
[**UPDATE** - March 23, 2014 - In a report published in the journal Nature Medicine, researchers at John Hopkins University tested a variety of HDAC drugs on white blood cells extracted from HIV-positive patients. While earlier research had shown positive results, those studies relied solely on white blood cells infected in the test tube. Using patient-derived cells, this new study had hoped to provide a "real-life" confirmation of the activation strategy. It didn't. In fact, none of the tested agents worked. In order to be considered successful, the HDAC inhibitors would need to have elicited a 100-fold increase in viral RNA production. At best, the drugs spurred a one- to 10-fold increase, falling well short of the desired target.While the setback is regarded as considerable, the researchers are aiming to examine whether a combination of HDAC inhibitors might be more effective in spurring HIV reactivation.] - The Case of the Mississippi Toddler and the Visconti Cohort. Two separate cases in 2013 hinted at the potential of early ART in controlling HIV. The first involved a Mississippi child who was provided ART at the time of birth, the treatment of which continued for 18 months until the mother decided to stop. Qualitative viral load test had earlier confirmed that the baby was, in fact, HIV-positive. When the child was relinked to care after a five month gap, all HIV tests were negative—leading researchers to proclaim the toddler "functionally cured" (although some, including Anthony Fauci of the National Institutes of Health, have questioned the interpretation of the findings).
[**UPDATE** - July 14, 2014 - The National Institute of Allergies and Infectious Diseases (NIAID) reported that viral rebound had occurred in the Mississippi baby... Read more]
The second case involved 14 French patients who were provided ART within 10 weeks of infection, all of whom stopped treatment for various reasons after achieving viral suppression. Researchers from the French National Agency for Research on AIDS and Viral Hepatitis later discovered that the patients (who were part of the 70-participant Visconti Cohort Study) were able to control the virus to fully suppressed levels, some for as long as ten years. To some, this suggested that early intervention may have somehow stopped HIV from establishing reservoirs, although other factors (such as severe primary infection with high viral loads) were also noted.
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 part might early ART play in a functional cure? Is it the major driver, or are there other genetic and/or biological factors that play a more important role?
- How certain can we be that viral rebound won't occur in the people who we've identified as being "functionally cured?"
- How important might broadly neutralizing antibodies be to a functional cure, and how far away are we from a viable approach given the setbacks we've seen in vaccine research?
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.
Sources:
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.
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