What is Functional cure of AIDS patients?

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What is Functional cure of AIDS patients?

Functional cure of AIDS’ has always been an important research direction for scientists around the world, Including stem cell transplantation, immunotherapy, gene editing, etc., may be the first in the future A major breakthrough has been made.”

On February 21 , the front page of “Nature” reported a story of an AIDS patient who was “functionally cured”.

The patient, dubbed the “Düsseldorf patient” by academic circles, is a 53-year-old man from Germany whose viral load remains “undetectable” after nearly five years of stopping HIV drug treatment state.

The “Dusseldorf patient” is the third AIDS patient in the world who has been officially confirmed to have been cured by the academic community, following the “Berlin patient” in 2008 and the “London patient” in 2019.

What is Functional cure of AIDS patients?

How to Understand “Functional Cure”?

So far, 5 infected persons who have achieved functional cure of AIDS have been reported in the world (two of them have not yet been published in official journals) , including the “Düsseldorf patient”, all of whom received a drug called “CCR5Δ32 genotypic stem cell transplantation”.

The CCR5Δ32 mutation gene is the key to the cure of these five AIDS patients.

CCR5 protein is one of the co-receptors for HIV to invade human immune cells. If it is compared to the “entrance” of HIV, when CCR5 is mutated into CCR5Δ32, the “entry” will be closed. And some people are born with this genetic mutation and may be immune to HIV for life.

Scientists have boldly imagined that if the special immune system of these people is “implanted” into the body of HIV-infected patients, whether it can completely block the replication of the virus.

In the same year that the “Berlin patient” was declared cured, the 39-year-old “Düsseldorf patient” was diagnosed with AIDS and started antiretroviral (ART) treatment in 2010. He was diagnosed again six months later For acute myeloid leukemia.

For the “Düsseldorf patient”, this is bad news, but also an opportunity. In order to completely treat leukemia, he needs to undergo hematopoietic stem cell transplantation, and if the “CCR5Δ32 hematopoietic stem cells” happen to be transplanted, HIV infection may be cured by the way.

“From the beginning, our aim was to treat leukemia and HIV infection at the same time,” says Prof. Guido Kobbe, a hematologist at the University of Düsseldorf’s Faculty of Medicine who was involved in the study. In 2013, the “Düsseldorf patient” waited for a suitable donor and underwent hematopoietic stem cell transplantation at the University Medical Faculty of Düsseldorf.

Nearly five years after the successful transplant, researchers kept him on HIV medication out of an abundance of caution and closely monitored the “Düsseldorf patient”‘s viral load, finding HIV levels in his body remained below the detection limit.

At the same time, the researchers also tried transplanting his immune cells into mice, and found that HIV failed to replicate in the mice—indicating that it had lost function.

After careful consideration, in 2018, doctors stopped administering anti-HIV drugs to the “Düsseldorf patient”. At a meeting the following year, the research team revealed that his condition had improved, but was inconclusive at the time.

The latest published research shows that since the drug was discontinued, traces of the HIV gene have been found in individual blood samples of the “Dusseldorf patient”, but the virus has no longer reproduced. “He was really cured, not just in long-term remission,” the researchers said.

Unpopular therapy

To this day, humans have still not found a universal therapy that can cure AIDS. Whether it is the “Berlin patient”, “London patient” or “Düsseldorf patient”, they are just “exceptions” outside the rules.

One reason is the scarcity of donors.

Research data show that only about 1% of whites carry a homozygous CCR5Δ32 gene mutation, while this ratio is almost zero in other regions. This means that for the approximately 36 million HIV-infected people worldwide, the probability of matching a suitable donor is less than that of any type of organ transplant.

As an alternative, in a study published in the New England Journal of Medicine in 2019, researchers used CRISPR/Cas9 gene editing technology to knock out the CCR5 gene in donor hematopoietic stem cells, which were eventually transplanted into HIV-infected, accompanied in adult patients with acute lymphoblastic leukemia.

It may be feasible to use gene editing technology to artificially modify hematopoietic stem cells, and then transplant them. However, the in vitro knockout efficiency of CCR5 in the study was low, only 17.8%, which led to patients stopping antiretroviral therapy. After taking viral drugs, the amount of HIV virus in the body also rose sharply.”

In addition, the huge health risk is the direct factor leading to its failure to popularize.

In this type of transplant treatment, the doctor will replace the immune system of a ‘naturally HIV-resistant person’.

The premise is to first destroy the original immune system of the infected person, kill a large number of HIV-infected immune cells, and then use hematopoietic stem cell transplantation. Rebuilding the immune system is risky, even fatal. Even if the operation is successful, the patient still needs to take anti-rejection drugs for life.

Hematopoietic stem cell transplantation is a very dangerous technique that is mainly used to treat leukemia. The five HIV cured patients so far all happened to suffer from malignant blood tumors.

Before and after transplantation , they all need to undergo intensive chemotherapy, during which the body’s immunity is almost zero, and they are prone to various bacterial infections.”

According to the current academic consensus, stem cell transplantation would be needed if one is not suffering from fatal cancer, and it is unethical to try this therapy on ordinary HIV-infected people and cannot be used for large-scale promotion.

How far has HIV treatment progressed?

AIDS is no longer a terminal illness.

After the advent of “Highly Efficient Antiretroviral Therapy” (HAART) , the virus level in HIV-infected patients can be effectively suppressed, and the clinical indicators can also be “non-infectious”, and the life expectancy is close to that of ordinary people.

But they need to take the medicine for life, and once the medicine is stopped, the virus level in the body will rebound quickly. In addition, life-long use of the drug may have side effects and may lead to drug resistance.

Therefore, scientists always hope to further develop safe and long-acting therapies to help tens of millions of HIV-infected people around the world, and many breakthroughs have been made now.

At the beginning of 2022, Excision BioTherapeutics of the United States announced the launch of the human phase 1/2 clinical trial of EBT-101, a therapy based on CRISPR gene editing technology, through “multiple cutting” to completely break up the HIV virus genome.

On July 27 of the same year, at the International AIDS Conference held in Canada, scientists from the University of Barcelona presented a report on a 59-year-old woman who received antiviral therapy in 2006, combined with multiple immunomodulatory therapies. After the trial, the woman stopped using all related drugs. After 15 years, no rebound of HIV viral load has been found so far.

Including the Shock and Kill treatment proposed in recent years, as well as various genetically engineered T cell transformation strategies, are promising and promising directions for functional cure of AIDS.

On the 16th of this month, the “AIDS Nucleic Acid Injection” developed by Professor Chen Zhiwei from the AIDS Research Institute of the University of Hong Kong’s Faculty of Medicine started Phase I clinical trials in Shenzhen Third Hospital. This is an immune system-dependent treatment with the same goal of “functional cure”. .

It’s just that so far, it is still impossible to determine which methods can eventually be widely promoted.

Before the emergence of ‘cure’ strategies, the development of broad-spectrum long-acting antiviral inhibitors has more application prospects in the short term and can also be used for HIV preventive treatment.

On June 1, 2022, a study published in the top journal “Nature” showed that after the combined use of two broad-spectrum neutralizing monoclonal antibodies, the level of HIV virus in infected patients can be controlled within 43 weeks of drug withdrawal And no rebound. Researchers believe that in the future, some HIV-infected patients may not need to take daily medicines, but only need to give monoclonal antibodies at a low frequency (such as once every two years), and they can return to normal life.

In fact, with the existence of cost-effective HAART therapy, in addition to the limited increase in absolute health benefits, the high price and difficulty in “mass production” have further restricted the popularity of various cutting-edge therapies.

However, some experts believes that successful cases or cases with good treatment effects provide good ideas for subsequent scientific research and formulation of clinical treatment plans. In order to realize the functional cure of the HIV-infected population, continuous scientific exploration and research are needed.

The existing HAART treatment cannot effectively solve the problems of viral reservoirs, drug withdrawal rebound, and incomplete immune reconstitution.

Therefore, even if a huge investment is made in other treatment strategies, it is still a must for the academic community.

What is Functional cure of AIDS patients?

(source:internet, reference only)

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Tags: HIV