How Close Are We to a Functional Cure for HIV?

Key discoveries pave the way to long-term remission

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

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There has been much enthusiasm and almost as much controversy surrounding the prospect of a functional cure. Françoise Barré-Sinoussi, Nobel Prize laureate and co-discoverer of HIV, stated in 2014 that she was “personally convinced we can reach permanent remission—a functional cure.”

Others like Bruce Walker, noted HIV researcher and Director of the Ragon Institute at Harvard University, remains cautious, suggesting that a functional cure as currently envisioned is "unlikely" and that vast gaps in our understanding about HIV need to be filled before a true, scalable solution can be found.

How a Functional Cure Might Work

One of the biggest facing challenges facing researchers is that HIV not only circulates in the blood and quickly embeds itself into cells and tissues throughout the body (called latent reservoirs) where it is shielded from detection by the immune system and can persist even in the face of complete viral suppression.

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's life cycle—not the host cell's).

In order for a functional cure to be achieved, not one but multiple barriers have to be overcome to put the virus into remission. In recent years, scientists have dubbed this the "kick-kill" (or "shock-and-kill") strategy, for which two primary aims need to be achieved.

Reverse Viral Latency

The first goal of the strategy is to release the latent "proviral" form of HIV from the hidden reservoirs, bringing the virus out into the open. To date, scientists have had some success with this using a variety of drugs that have latency-reversing properties. These include histone deacetylase (HDAC) inhibitors commonly used as mood stabilizers or to treat epilepsy and cancers like T-cell lymphoma.

Although many of these drugs have shown promise, the results thus far have fallen short with no evidence that they alone can fully clear the viral reservoirs.

Among the challenges, scientists are still not even sure how extensive latent reservoirs are and why certain cells and tissues are more affected than others.

Moreover, there is evidence that the latent viruses can change the longer that a person has HIV, creating a wide diversity of HIV variants. This suggests to some that latent reservoirs become less self-contained over time, facilitating cross-infection back and forth between the blood and the latent reservoirs.

All of these things present challenges in reversing viral latency. Increasing the doses of latency-reversing drugs may help but, as with all drugs, doing so poses a risk of toxicity. Research is ongoing.

Viral Clearance or Control

If and when scientists are able to purge the viral reservoirs, the next step would be to either clear the viruses before they can reestablish reservoirs (a sterilizing cure) or control the viruses so that both latent HIV and circulating HIV are below levels where they can cause immune injury (a functional cure).

Antiretroviral therapy on its own will unlikely help given that it can't stop the reestablishment of reservoirs. To this end, most scientists agree that multiple agents will be needed.

Among some of the approaches currently under investigation:

  • Broadly neutralizing antibodies: Also known as BnAbs, these are immune proteins that are able to kill the majority of HIV variants. These antibodies have been identified in a subset of people, called elite controllers, in whom HIV does not progress after infection. To some, BnAbs offer the best promise of a functional cure given that current vaccine models are nowhere near able to neutralize that multitude of HIV variants circulating worldwide.
  • Vaccines: While vaccines alone may not be able to effect a cure for HIV, some under investigation may be able to provide sustained immunity to the virus—one that may not be sterilizing but enough to achieve asymptomatic (symptom-free) infection. Several experimental T-cell vaccines used with the HDAC inhibitor romidepsin have shown promise, although not yet to a point where the promise of remission can be achieved.
  • Nef Inhibitors: When HIV infects a cell, it utilizes a protein called negative factor (Nef) to override a protein on the cell's surface that "tells" the immune system when it is infected. By doing so, HIV is able to infect and spread more efficiently. Scientists have now found that certain agents, like a class of antibiotics known as pleicomacrolides, can disable Nef and may help the body better control HIV on its own.

Novel approaches like these will be needed before a true functional cure can be found.

Evidence in Support of a Functional Cure

While research into a functional cure has been on the table for some years, there were two events that provided the foundational proof-of-concept.

The first was Timothy Brown (a.k.a. the "Berlin Patient"), who was the first of only a small handful of people "cured" of HIV. An HIV-positive American living in Berlin, Brown was given an experimental bone marrow transplant in 2009 to treat acute myeloid 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 elite controllers.

The resulting cure provided evidence that HIV could, in fact, be fully eradicated from the body. Even so, the procedure was too costly and dangerous to be considered a viable option.

A year later, in 2010, scientists were able to isolate two BnAbs called VRC01 and VRC02 from several elite controllers that were able to neutralize over 90% of HIV variants in lab studies.

The findings offered scientists hope that the same antibody defense that naturally occurs in elite controllers—who account for one of every 500 people with HIV—may one day be replicated in non-elite-controllers.

Insights from these and similar cases have provided scientists with the template by which functional cure research is largely based.

A Word From Verywell

As promising as the research may seem, they raise just as many questions as they do answers. Even as scientists continue to unlock the mysteries surrounding HIV, none of the advances even vaguely suggest that we are close to a cure for HIV, or that the rules governing the prevention and treatment of HIV have changed.

If anything, the imperative to remain vigilant—and to seek testing and treatment when needed—remains as important today as it has ever been.

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