Is HIV Curable?

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.

Herausforderungen

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

Moreover, one cohort study published in JAMA Network Open in 2020 suggested that the life expectancy for individuals with HIV in the United States may be near the life expectancy of those without HIV infection. This study, which included 39, 000 adults with HIV and 387, 785 adults without HIV, found that those with HIV who started antiretrovirals at high CD4 cell counts lived 6.8 fewer years overall.

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.

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.

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. Although ART can suppress HIV levels, it cannot eliminate latent reservoirs.

That said, a latently-infected cell can be reactivated, causing the cell to begin to produce HIV again. This persistence in latent HIV reservoirs is a large challenge in curing 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.

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.

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.

According to a 2023 article published by The Foundation of AIDS Research, Castillejo has continued to remain HIV-free since stopping ART in 2017.

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.

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 80% of diverse HIV-1 strains.

Currently, vaccine researchers are attempting to stimulate the production of 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

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.

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.