What Is a Functional Cure for HIV?

Challenges, Goals, and Barriers to Achieving Drug-Free Viral Control

When most people talk about a cure for HIV, they generally imagine a drug or vaccine that would remove all traces of the virus from the body (referred to as a sterilizing cure). However, as scientists better understand how HIV infiltrates tissues and cells, a sterilizing cure is not only considered more difficult to achieve but, to some, is highly unlikely—at least for the foreseeable future.

In response, much of the current research has been focused on a functional cure for HIV. Instead of eradicating the virus, a functional cure would aim to suppress viral activity to levels where it cannot cause the body any harm and do so without the ongoing use of drugs.

Close up of HIV virus in bloodstream
Ian Cuming / Getty Images

At its heart, a functional cure aims to replicate the mechanisms that prevent elite controllers—people with HIV who experience no disease progression—from developing symptomatic disease.

Most scientists believe that a functional cure will require a multi-pronged approach to not only extract the virus from tissues and cells where it is embedded but also to spur the immune system to better fight and control the infection.

A functional cure would not eradicate the virus but rather enable the body to stop HIV from proliferating without the need for further treatment.

Goals and Challenges

There is no consensus on how a functional cure might work, and there are enormous gaps in science to be filled before one can be fully realized. With that said, there are several approaches that scientists are actively pursuing as well as key challenges they have yet to overcome.

Immunologic Control

Elite controllers, also known as long-term non-progressor, account for less than 1% of people living with HIV. They have built-in immune mechanisms that manage to keep the virus under control without antiretroviral drugs. Some, in fact, have lived with the virus for more than 30 years with no signs of disease progression.

There are many mechanisms that contribute to this effect, but one that is of special interest involves a unique body of proteins called broadly neutralizing antibodies (bNaBs). This is a rare type of antibody that can neutralize the multitude of HIV variants that exist within a single viral population.

Among the antibodies under investigation are VRC01, VRC02, and VRC03, which were identified in several elite controllers back in the early-2010s and have proven to neutralize over 90% of HIV variants on their own.

While scientists are exploring ways to stimulate the immune system to produce these and other bNaBs, results thus far have fallen short. In non-elite progressors, any attempt to stimulate an individual bNaB is typically met with a contradictory response in which the immune system will "reboot" the antibody production to restore homeostasis (an established state of equilibrium).

Until this barrier is overcome, scientists will be hard-pressed to mimic the natural defenses afforded to elite controllers.

Viral Reservoirs

While some scientists believe that a functional cure can be achieved solely by suppressing circulating viruses, others remain doubtful. This is because HIV quickly embeds itself into cells and tissues throughout the body called viral reservoirs soon after infection. There, it remains in a latent state, hidden from the immune detection.

If a person on antiretroviral therapy suddenly stops treatment, these reservoirs can suddenly activate and release new viruses into circulation, causing a viral rebound.

Because the virus is hidden within cells and tissues as a provirus, replicating silently in tandem with the host, bNaBs cannot actively target them for neutralization. It is only when they are released from these reservoirs that bNaBs (or some other agent) can act.

Many scientists contend that some form of "kick-kill" (a.k.a. "shock-kill") strategy is needed to render a functional cure. This is a strategy in which latency-reversing drugs are used to purge the reservoirs, after which another agent (or agents) provides viral control and prevents the establishment of new reservoirs.

Scientists know that the reservoirs can be cleared based on the Berlin Patient case, in which an American living in Germany experienced completely viral clearance after undergoing an experimental stem cell transplant. Even so, the procedure is considered too risky to be a viable option.

Several agents have shown promise in activating viral reservoirs, including histone deacetylase (HDAC) inhibitors used to treat certain cancers. Although the response to date has been minimal, different combinations of drugs are hoped to approve upon these early results.

Immune Exhaustion

Another mechanism that scientists need to overcome is immune exhaustion. This is a phenomenon that contributes to HIV progression, wherein the immune system increasingly becomes "blind" to the virus.

Chronic immune activation, in which the immune system is left a constant state of alert, is believed the cause of this problem. When it occurs, the immune system—recognizing that chronic activation is abnormal—will counter with a protein called programmed death-1 (PD-1). This is the protein that the body uses to downregulate the immune response and prevent overactivation.

Even if bNaBs or other agents have the potential to neutralize circulating HIV, they may be less able to do so unless immune exhaustion is reversed.

There are several agents that have shown potential in reversing immune exhaustion. These include chimeric antigen receptor (CAR) T-cell therapy currently used to stimulate the immune system to better fight certain cancers.

Is a Functional Cure the Answer?

As ideal as it may seem to have a natural defense to HIV, there are challenges that even elite controllers face. Even if the virus is naturally suppressed by the immune system, it is still there actively generating low-level inflammation.

Studies have shown that, over time, this can trigger the early onset of heart diseases, including atherosclerosis and hypertrophic cardiomyopathy (thickening of the heart muscle).

Other studies have shown that elite controllers have just as many hospitalizations as their non-elite controller counterparts and are more likely to experience heart diseases than people on fully suppressive antiretroviral therapy.

As a result, many researchers endorse the use of antiretroviral therapy in elite controllers—not to prevent HIV-related diseases but rather non-HIV-related ones.

Given that non-HIV-related diseases—namely cardiovascular disease, cancers, and liver disease—are today the leading causes of death in people with HIV, it questions whether mimicking elite control should be the ultimate goal.

Until scientists are better able to answer these and other questions, the best thing to do is stay the course and adhere to antiretroviral drugs that have not only increased life expectancy to near-normal levels but have reduced the incidence of severe HIV-related and non-HIV-related illnesses by 61%.

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