Are We Near a Cure for HIV? Challenges and Progress

Despite more than 35 years of research, scientists have yet to find a cure for the human immunodeficiency virus (HIV): the virus that causes acquired immunodeficiency syndrome (AIDS).

Antiretroviral therapy (ART) has been a major breakthrough that does help suppress the virus, but it's not a cure. And while there have been a few well-publicized cases in which HIV was said to have been cured—including that of Timothy Brown, aka the Berlin Patient—there has yet to be an approach that can consistently and safely eradicate HIV on an individual basis, much less a global scale. Even so, progress is being made.

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Challenges

There are several reasons why finding a cure for HIV/AIDS has been such a long road of challenge after challenge. HIV is such a complex, multifaceted, ever-changing virus that it makes it difficult to keep up with.

Some of the current general challenges facing HIV research include:

Reaching populations most at risk of HIV infection and transmission
Ensuring that research takes place with participants' fully-informed consent, meaning that they fully understand both the risks and benefits of the trial
Developing safe and effective HIV vaccine candidates to test via clinical trials with both human- and nonhuman primates
Gaining a better understanding of immune response mechanisms in humans
Taking HIV comorbidities into account in research, so any potential cure would benefit as many people as possible
Increasing focus on the study of remission observed in rare patients who have stopped their treatment
Defining exactly what is meant by a "cure" for HIV
Decreasing the stigma that still surrounds HIV, with the aim of minimizing its impact on participation in HIV research
Gaining a better understanding of how to effectively treat HIV coinfections and manage treatment failures

Transmission Reduction

While it's not a "cure," per se, the "treatment as prevention" (TasP) strategy—involving taking daily HIV medication—has been highly effective in reducing transmission for those who are already HIV-positive.

Moreover, in 2020, it was announced that the life expectancy for those with HIV in the United States was the same as those who had never been infected with the virus—though they enjoyed far fewer years of good health.

Ideally, the next step will be the development of a safe and effective HIV vaccine, but there are some challenges currently standing in the way of progress being made with the research.

Genetic Variability

One of the most significant obstacles to creating a widely effective HIV vaccine is the genetic diversity and variability of the virus itself.

The Challenge of the Replication Cycle

Instead of being able to focus on a single strain of HIV, researchers have to account for the fact that it replicates so quickly, which can cause mutations and new strains. The replication cycle of HIV takes a little more than 24 hours.

And while the replication process is fast, it's not the most accurate—producing many mutated copies each time, which then combine to form new strains as the virus is transmitted between different people.

For example, in HIV-1 (a single strain of HIV), there are 13 distinct subtypes and sub-subtypes that are linked geographically, with 15% to 20% variation within subtypes and variations of up to 35% between subtypes.

Not only is this a challenge in creating a vaccine, but also because some of the mutated strains are resistant to ART, meaning that some people have more aggressive mutations of the virus.

Latent Reservoirs

In addition to the constantly evolving and mutating strains of HIV, another challenge in developing a vaccine is something called latent reservoirs. These are established during the earliest stage of HIV infection, and can effectively "hide" the virus from immune detection, as well as the effects of ART.

This means that if the treatment is ever stopped, a latently-infected cell can be reactivated, causing the cell to begin to produce HIV again.

While ART can suppress HIV levels, it can't eliminate latent HIV reservoirs—meaning that ART cannot cure HIV infection.

Immune Exhaustion

There is also the challenge of the immune exhaustion that comes with a long-term HIV infection. This is the gradual loss of the immune system's ability to recognize the virus and launch an appropriate response.

Any type of HIV vaccine, AIDS cure, or other treatment must be created taking immune exhaustion into consideration, finding ways to address and offset the decreasing capabilities of a person's immune system over time.

Early Progress

While the progress made towards curing HIV has been slow, there have still been glimmers of hope along the way, indicating that scientists may be inching closer to a widely effective treatment.

The Berlin Patient

Perhaps the best-known case so far has been Timothy Brown, also known as "the Berlin Patient," who is considered to be the first person to have been "functionally cured" of HIV.

Despite his moniker, Brown was born in the United States but was diagnosed with HIV in 1995 while studying in Germany. Ten years later, he was diagnosed with acute myeloid leukemia (AML) and required a stem cell transplant in order to have any chance of surviving the cancer.

When doctors discovered that Brown matched with 267 donors (many people do not find a single match), they decided to use one who had a mutation called CCR5-delta 32, thought to be able to induce HIV immunity.

Three months after his February 2007 transplant, HIV was no longer detected in Brown's blood. And while he continued to have complications with leukemia—and required additional stem cell transplants—Brown's HIV infection did not return. That remained the case until his death in 2020 from leukemia.

Doctors at Brigham and Women's Hospital in Boston attempted to use a similar stem cell transplant technique on two patients between 2008 and 2012—though without using donors with the delta 32 mutation. Though the patients initially experienced 10 and 13 months of undetectable levels of HIV, they both subsequently went through viral rebound.

The London Patient

A 2019 study was published providing details regarding a second person—Adam Castillejo, this time known as "the London Patient"—who also appears to have been functionally cured of HIV.

His situation was similar to Brown's in that he had cancer, received chemotherapy to wipe out his immune system, and then had a stem cell transplant using donor cells with a genetic mutation that leads to HIV immunity.

So far, there is clinical evidence that Castillejo has been in HIV-1 remission for 30 months with no detectable replication-competent virus, though it's unclear whether it will continue.

And while using a stem cell transplant to produce HIV immunity may have been successful for Brown and Castillejo, it is not something that will be used in its current form in regular clinical practice any time soon.

Not only is this multistep process expensive, but it also involves too many potential risks and harms for the patient.

Because Brown and Castillejo both had cancer and needed a stem cell transplant anyway, finding a donor with the delta 32 mutation made sense. However, it's not a viable option for someone without cancer to undergo this specific course of treatment.

Despite the practical limitations of the treatment, these cases offered scientists insights that have advanced HIV cure research in significant ways.

Stem Cell-Based Gene Therapy

One type of treatment that shows initial potential is stem cell-based gene therapy—an approach largely informed by Brown's case.

Its aim is to reconstitute a person with HIV's immune system by transplanting genetically engineered hematopoietic stem cells with anti-HIV genes, which can not only self-renew, but they can also multiply and differentiate into mature immune cells.

There has been some success in early stem cell-based gene therapy research.

A 2018 study involving HIV-infected pigtail macaque monkeys found that a transplant of gene-edited stem cells was able to significantly reduce the size of their dormant "viral reservoirs" that could reactivate to produce additional copies of the virus.

Additional progress has since been made with primates. According to a 2021 study, researchers determined a formula that would predict the ideal dose of stem cells required to cure HIV.

Still Work to Be Done

Although the approach has shown promise in primates, it is by no means replicable on a global scale.

Now the goal is to replicate the effects of Brown and Castillejo's stem cell transplants in other humans, but without the toxicity of having to undergo chemotherapy first.

Broadly Neutralizing Antibodies

Some of the most promising vaccine models to-date involve broadly neutralizing antibodies (bNAbs)—a rare type of antibody that is able to target the majority of HIV variants.

BNAbs were first discovered in several HIV elite controllers—people who appear to have the ability to suppress viral replication without ART and show no evidence of disease progression. Some of these specialized antibodies, like VRC01, are able to neutralize more than 95% of HIV variants.

Currently, vaccine researchers are attempting to stimulate the production of bNAbs.

A 2019 study involving monkeys shows promise. After receiving a single shot of an HIV vaccine, six out of the 12 monkeys in the trial developed antibodies that significantly delayed infection, and, in two cases, even prevented it.

bNAbs Showing Promise

This approach is still in the early stages of human trials, though in March 2020, it was announced that for the first time, scientists were able to devise a vaccine that induced human cells into generating bNAbs.

This is a notable development, following years of past studies, which, up until this point, have been stymied by the lack of a robust or specific bNAb response.

Latency Reversal

Until scientists are able to "clear" latent HIV reservoirs, it is unlikely that any vaccine or therapeutic approach will fully eradicate the virus.

Some agents, including HDAC inhibitors used in cancer therapy, have shown promise, but have yet been unable to achieve high levels of clearance without risking toxicity. On top of this, scientists remain unsure how extensive these reservoirs actually are.

Still, it is hoped that the combination of a latency-reversing agent with a vaccine (or other sterilizing agents) can succeed with a curative, experimental strategy known as "kick-and-kill" (aka "shock-and-kill") that is currently under investigation.

Kick-and-Kill Strategy

It is a two-step process:

First, drugs called latency-reversing agents are used to reactivate latent HIV hiding in immune cells (the "kick" or "shock" part).
Then, once the immune cells are reactivated, the body's immune system—or anti-HIV drugs—can target and kill the reactivated cells.

Unfortunately, latency-reversing agents alone are not capable of reducing the size of the viral reservoirs.

Another latency reversal strategy may involve PD-1 inhibitors like Keytruda (pembrolizumab) that have shown promise in clearing viral reservoirs while potentially reversing immune exhaustion.

PD-1 acts as an immune checkpoint and is preferentially expressed at the surface of persistently infected cells. But at this point, it's still unclear whether PD-1 plays a functional role in HIV latency and reservoir persistence.

A Word From Verywell

While progress is being made toward achieving a cure for HIV, it is too soon to say when a breakthrough might occur.

Fortunately, scientists have made great strides in the prevention of HIV—particularly through pre-exposure prophylaxis (or PrEP). The idea behind PrEP is to give people at high risk of getting HIV, but are not infected, the opportunity to prevent that from happening by taking a pill once a day. When used correctly and consistently, PrEP reduces the risk of getting HIV from sex by about 99%, and from injecting drugs by 74%.

But until a cure is found, the best outcome for people with HIV is antiretroviral therapy, which can reduce the risk of HIV-associated illness and keep life expectancy—for those in the United States—at a similar length to those who don't have HIV.

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