Chinese scientist Science released important results of AIDS research: new anti-AIDS drug is expected to break the curse of lifelong medication

Once the drug is stopped, the virus will come back

In a study published in "Cell" in the early morning of the 17th, the team of Professor He Yuxian of the Institute of Pathogen Biology of the Chinese Academy of Medical Sciences and the team of Xue Jing, a researcher of the Institute of Medical Laboratory Animals of the Chinese Academy of Medical Sciences, discovered a powerful treatment and prevention of AIDS Drugs explored the "home" of the HIV virus and initially revealed the characteristics of the virus's latent pool and the immune control mechanism

Medicine that can't stop

As there are no effective radical cure drugs and vaccines, AIDS is also known as the "super cancer" and "the killer of the century

According to the World Health Organization, there will be 37.

The study of new long-term treatment and prevention methods for AIDS is not only a major scientific issue at present, but also a difficulty in research, and it is also an urgent need for patients

Currently, high-efficiency antiretroviral therapy (HAART) is the main method for the treatment of HIV-infected and AIDS patients.

Although the "cocktail" therapy greatly reduces the mortality rate of HIV-related infections, due to the existence of the virus latent pool, once the drug is stopped, HIV will rebound rapidly

In this "battle", the HIV virus is like a cunning criminal, able to integrate into the genome of the target cell, and with the target cell lurking in all corners of the body, without showing up

As a police AIDS drug, once the situation is deemed safe and the troops are returned to the camp, the latent HIV virus will be activated and continue to replicate, causing the virus to rebound

This causes AIDS patients to relapse once they stop taking the medicine

Therefore, the realization of "stable virus control after drug withdrawal", that is, functional cure, is the ideal goal in the field of AIDS prevention and treatment at this stage, and the key is to discover the virus latent pool and immune regulation mechanism behind "stable virus control"

Xue Jing told the Chinese Journal of Science, "If we can know the characteristics of the virus latent library and find the virus latent library, we can lay the foundation for the next step to accurately combat the HIV virus

The research team has developed a lipopeptide virus fusion inhibitor LP-98 with extremely high anti-HIV activity and long-acting effect, which can be used as an effective HIV treatment and prevention strategy, and reveals the virus latent pool and immune control mechanism

Membrane fusion inhibitors, also known as viral entry inhibitors, unlike other AIDS drugs play a role only after the virus-infected cells, the early stages of its major role in viral infection, like "refused enemy outside the gates"

"The newly designed lipopeptide-based fusion inhibitor not only has extremely high viral inhibitory activity, but also has a long-lasting effect in the body.

Go deep into the "poison nest"

After treating 21 infected rhesus monkeys, researchers found that low-dose monotherapy can effectively inhibit SIV (a chimeric virus of HIV and SIV) virus replication and maintain long-term effective treatment

More importantly, after long-term viral RNA monitoring of infected monkeys after drug withdrawal, the researchers found three different states after drug withdrawal.
About 20% of treated monkeys showed the most ideal "stability after drug withdrawal.
" Virus control" status
.

In addition, about 40% of the treated monkeys showed a stable virus rebound state after drug withdrawal, and about 30% of the treated monkeys showed an unstable virus rebound state after drug withdrawal
.

Next, they further explored the characteristics of the virus latent pool of the three groups of treated monkeys, and found that the virus stably controlled the monkey's viral DNA "latent" in the deep lymph nodes at a low level, and the virus rebounded after the drug withdrawal, and the monkey's viral DNA was at a higher level.
Latent” is in the superficial lymph nodes, which indicates that the location and level of the latent library of viral DNA are closely related to whether it rebounds after drug withdrawal
.

Further studies have found that the virus stably controls the monkey’s latent tissue library with less ability to produce live viruses, and there are differences in the virus-specific CD8+ T cell responses of the three groups of monkeys.
After the drug is stopped, the virus stably controls the monkey’s virus-specific CD8+ The T response is stronger, and the multifunctional CD8+T response increases
.

In order to further explore the mechanism of virus control or partial control after drug withdrawal, they will be in the state of "stable virus control after drug withdrawal" and "virus instability rebound after drug withdrawal" state after CD8+ T cells in monkeys are knocked out , Found that the viral load rebounded rapidly
.

"This means that CD8+ T cells have played a key role in the outcome of virus control after drug withdrawal, and it has brought new ideas and methods for the target selection and evaluation of subsequent functional cure drug development
.
" Xue Jing said
.

Pre-exposure prevention

Can LP-98 be used for AIDS prevention and protection?

In this regard, the researchers conducted pre-exposure prevention experiments on LP-98.
They found that the effective protection period of LP-98 pre-exposure prophylaxis is 1 week, which can effectively block SIV and SIV (simian immunodeficiency virus) from passing through the rectum, Vaginal or intravenous infections can therefore be used as a new strategy for pre-exposure prevention of AIDS
.

In fact, He Yuxian’s team has been conducting research on AIDS drugs for more than 10 years.
They have conducted in-depth and systematic studies on the structure and function of GP41, and discovered and defined multiple protein structural features
.

After repeated screening and design and countless failures, the researchers finally increased the antiviral activity of LP-98 to the current picomolar level, and had also experienced LP-11, LP-19, LP-40, LP-46 before.
, LP-52, LP-80, LP-83 and other progressive optimization stages
.

Fortunately, the new AIDS drug "lipvirtide" developed by them that targets viral membrane fusion, as a national class 1 new drug, has now entered clinical trials and made important progress
.

To study the underlying mechanism of HIV, it is necessary to construct a corresponding animal model, which is also a major difficulty in this research
.

In Xue Jing's view, animal models suitable for latent mechanism research need to accurately simulate the various stages of AIDS infection, onset, drug treatment, virus incubation, and relapse after drug withdrawal
.

To this end, they have simultaneously promoted the improvement of drugs and the optimization of animal models.
The animal models have also continuously added chronic infections, therapeutic drug evaluation, long-acting drug control, and rebound after drug withdrawal from the initial acute infection model.
This proves that LP-98 is an effective long-term HIV control drug, and can partially achieve stable virus control.
It also preliminarily clarifies the characteristics of the virus latent pool and the immune mechanism related to the control after drug withdrawal
.

In fact, in addition to LP-98, the study also found another lipopeptide virus fusion inhibitor LP-97 with strong anti-HIV activity, because it has a very similar molecular structure and antiviral activity to LP-98, so the study The staff did not carry out other research on it
.

He Yuxian said that next, the team will be committed to promoting the clinical trials of LP-98 to verify its clinical prevention and treatment effects, and will also in-depth study of the mechanism of virus latency and drug withdrawal control, so as to provide new target options for therapeutic drugs
.

Related paper information: https://doi.
org/10.
1016/j.
cell.
2021.
11.
032