Recently, two new breakthroughs have been made in HIV immunotherapy: Researchers from TSRI in the United States and Shanghai University of Science and Technology in China have successfully constructed immune cells against HIV, which are expected to cure HIV infection; Chinese scientist Hu Wenhui at Temple University and others use genes Editing technology efficiently removes human HIV virus from multiple organs and tissues of humanized mice from multiple targets.

Since the discovery of AIDS, the world has invested a lot of manpower and material resources to carry out research. Although more than a dozen vaccines and nearly a hundred therapeutic drugs have been developed, so far no specific drug has been found to completely treat AIDS. As a new weapon for the treatment of AIDS, the "cocktail" therapy immediately caused a sensation in the entire medical community as soon as it was announced. Scientists from all over the world also gave this therapy a high evaluation.

Nowadays, immunotherapy is very popular as a popular treatment for cancer, and because viral infectious diseases have certain characteristics such as strong specificity and controllable mutation rate relative to tumors, scientists have also begun to use immunotherapy to treat HIV infection.

Related research on AIDS treatment continues to advance, and new breakthroughs are continuously made. Recently, two new breakthroughs have been ushered in. So what progress has been made in cellular immunotherapy in the treatment of AIDS? This editor counts the progress of HIV immunotherapy in recent years and hopes to learn with you.

In August 2015, researchers at the California Institute of Technology discovered a special neutralizing antibody. This antibody can recognize the above-mentioned marker protein, and no matter what structure the envelope protein becomes when HIV is infected, it cannot escape the "legal eye" of this neutralizing antibody. The discovery of this neutralizing antibody opened a new chapter for the detection and elimination of the virus in AIDS patients.

The research was led by biology professor Pamela Bjorkman, and the relevant research results were published in the journal "cell".

Although neutralizing antibodies can identify the enveloped spikes on the surface of HIV, most can only identify the spikes in the closed state. In addition, each neutralizing antibody can only identify a specific target, or antigenic determinant, on the spike. Because certain antigenic determinants can eliminate HIV more effectively, certain neutralizing antibodies are more capable of destroying the virus. In 2014, Professor Bjorkman and colleagues at Rockefeller University discovered for the first time a powerful neutralizing antibody called 8ANC195 in AIDS patients whose immune system can also fight the virus. They found that this neutralizing antibody can destroy the virus by anchoring a newly discovered epitope.

They found that although many neutralizing antibodies can identify the closed state of the envelope spikes, 8ANC195 is even better. It can identify the closed and semi-open states of the envelope spikes. Scharf said: "We think it is very beneficial for this antibody to recognize the two forms of spikes."

In addition, since Scharf and others have fully grasped the complete information on how 8ANC195 is combined with the viral spike, they can begin to use genetic engineering to make it more efficient and allow it to identify more HIV drug lines.

New treatments are suspected to cure AIDS patients?

In March 2016, the results of a clinical trial of HIV treatment in the United Kingdom showed that among 50 patients receiving treatment, a 44-year-old male patient did not detect any HIV virus in his blood test. According to the media, this may mean the first time humans have eliminated HIV lurking in lymphocytes.

This result is very happy, but it is too early to talk about the cure of HIV. Professor Sarah Fidler of Imperial College London said: "The new treatment used in the experiment aims to eliminate all HIV in the body, including latent HIV. Great progress has been made in clinical trials, but it is still far from being used in clinical trials to cure cancer. long way to go."

The study selected HIV-infected patients within six months of clinical trials, using the "Kick and Kill" therapy: Kick partly relies on the Vorinostat drug to "kick" the infected dormant T cells, and simultaneously uses two vaccines to make immunity The system can identify these activated cells to complete the Kill step. This technology is hailed as "one of the most likely cures for AIDS."

Facing many media reports that “AIDS patients are suspected of being cured”, researchers from the RIVERS project issued an official statement on the website: “We will get the final research results in 2018. Until then, it is impossible to say whether the treatment is really effective. But. From the current state of the patient, we know that the human body is tolerant to this therapy, which provides the possibility for follow-up research. We look forward to the ultimate breakthrough results, but until then, we cannot conclude that AIDS has been cured.

In August 2016, a new study was published in the journal Virology. Researchers from the AIDS Institute and the AIDS Research Center of the University of California, Los Angeles, USA confirmed that the recently discovered antibody can be used as the head of the CAR. CARs build a strong immune response, and then can use this CAR-T to kill cells infected by HIV-1.

CAR-T is manufactured by genetically modifying T cells to produce receptors on their surfaces that target and kill specific cells containing viruses or tumor proteins. Chimeric receptors have become the focus of ongoing research on how gene immunotherapy can be used to fight cancer. However, Dr. Otto Yang, professor of medicine in the Department of Infectious Diseases at the David Geffen School of Medicine at UCLA, said they can also be used to generate a powerful immune response against HIV.

Although the body’s immune system did respond to HIV at first and attacked it, this complete attack on HIV was eventually lost due to the virus’ ability to hide in different T cells and replicate rapidly, and cause damage to the immune system. Damage, which makes the body vulnerable to a series of infections and diseases. Scientists have been looking for ways to strengthen the immune system against HIV, and now, it seems to indicate that CAR-T is a weapon used to fight HIV.

Researchers have obtained a new generation of antibodies and transformed them into artificial T cell receptors, which can reprogram killer T cells to kill HIV-infected cells. Others have used antibodies against cancer antigens to create artificial T cell receptors that fight cancer, and they have shown that this can help cancer treatment. The University of California, Los Angeles is the first to design this strategy against HIV.

In this new study, the researchers used seven recently discovered "widely neutralizing antibodies" that can bind to multiple invading HIV strains, instead of the earlier ones that often only bind A small number of antibodies to HIV strains. These broadly neutralizing antibodies are transformed into artificial CAR-T cell receptors that are resistant to a wide range of HIV strains. In laboratory tests, the researchers found that all of these broadly neutralizing antibodies can guide the proliferation of killer T cells, kill HIV-infected cells and inhibit virus replication in infected cells to varying degrees.

There is great hope for this immunotherapy to advance further in further research.

In October 2016, a collaborative study (WRAIR) between researchers from the Beth Israel Deaconess Medical Center (BIDMC) and Walter Reed Army Research Institute scientists has demonstrated that an experimental vaccine combined with an innate immune stimulant has Contribute to the alleviation of the virus of HIV carriers. In animal experiments, the combined method reduced the level of viral DNA in peripheral blood and lymph nodes, promoted viral suppression and delayed viral rebound after antiretroviral therapy (ART) was stopped. Related research results were published in "Nature".

Normally, the vaccine will "teach" the body to clear the virus invaders by triggering an immune response. However, the HIV virus attacks the cells of the immune system. The virus kills most of the infected immune cells, while others enter a dormant state. This kind of dormant infected cells (researchers believe that HIV is still hidden in these dormant cells during antiretroviral therapy) is the main reason why AIDS is currently incurable. Barouch and his colleagues are studying strategies to find these hidden viruses with the goal of eliminating them from the body.

In a two-year long-term study, the researchers tested the viral load of 36 rhesus monkeys infected with Simian Immunodeficiency Virus (SIV) (HIV-like virus that infects non-human primates). After using ART inhibitory drugs for 6 months,

It was found that the combination of Ad26/MVA vaccination and TLR7 stimulation proved to be more effective than a single treatment.

In order to evaluate the efficacy of vaccines and immunostimulants, researchers stopped ART on all animals and continued to monitor their viral load. Animals receiving only the vaccine demonstrated some reduction in viral load, but compared with the control group, the animals receiving the vaccine/immunostimulant combination treatment showed a reduction in plasma viral RNA levels and a 2.5-fold delay in viral rebound. All nine animals showed a reduction in viral load, and one third of the animals had no virus detected in their bodies.

Barouch said: "This is definitely the basis on which we can work."

In November 2016, "New England Journal of Medicine" published an article revealing the latest breakthroughs in immunotherapy in the field of AIDS. Scientists from the Perelman School of Medicine at the University of Pennsylvania, the University of Alabama, and the National Institutes of Health (NIH) have discovered that injection of a broadly neutralizing antibody (bNAb) can effectively inhibit the virus and moderately delay the latent HIV virus. Time to rebound.

The research team screened a broadly neutralizing antibody VRC01, and found that it can be highly expressed in patients through injection, thereby controlling the virus "rebound". Although the current research results show that this inhibition ability does not exceed 8 weeks. However, it heralds that HIV-specific antibodies can inhibit or even eliminate the HIV virus for a long time. It is expected to eliminate the dependence of patients on antiretroviral drugs (ART) and take an important step in long-term suppression of the virus.

In the early stages of AIDS drug development, taking a single antiretroviral drug can cause rapid drug resistance and viral rebound. With the introduction of cocktails and other therapeutic strategies, compound drugs can fight the virus from different angles, thereby enhancing the timeliness of virus suppression.

At present, most AIDS patients only need to take a compound ART drug once a day, which can extend the life of the patient and improve overall health indicators. However, ART drugs cannot eradicate latent HIV, and insisting on taking antiretroviral drugs daily is still a problem for many patients, especially in areas with limited medical care. Once the medication is stopped, the virus in most AIDS patients will rise again, aggravating the patient's condition.

Now, immunotherapy may be the second option. Researchers compared the blood samples of patients before participating in the test and found that antibody immunotherapy can suppress the HIV virus in a short time. Pablo Tebas of the AIDS Clinical Trial Center at the University of Pennsylvania said that the current research team is focusing on an antibody. They believe that a more powerful combination of antibodies can be screened to control the virus more effectively.

In April 2017, in a new study, researchers from the Scripps Research Institute (TSRI) and Shanghai University of Science and Technology in China developed a method to attach antibodies against human immunodeficiency virus (HIV) to the immune system. On the cell surface, thereby generating a population of cells resistant to HIV. Under laboratory conditions, their experiments confirmed that these resistant cells can quickly replace HIV-infected immune cells, thereby helping potentially cure HIV-infected patients.

In previous therapies, anti-HIV antibodies swim freely in the blood at relatively low levels. However, in this new technology developed by TSRI, anti-HIV antibodies attach to the surface of immune cells, blocking HIV from binding to a vital cellular receptor, thereby preventing the spread of HIV infection. Researchers call this the "neighbor effect". Attaching anti-HIV antibodies to the surface of immune cells is more effective than many anti-HIV antibodies flowing through the blood.

The researchers tested whether the technology can resist HIV. In order to infect humans, all HIV strains need to bind to a cell surface receptor called CD4. Therefore, they selected antibodies that could potentially protect this receptor on the surface of immune cells that are normally killed by HIV, and then tested these antibodies. They genetically modified immune cells to express antibodies that bind CD4 on the cell surface. After incubating these genetically modified immune cells with HIV, they finally obtain a population of immune cells resistant to HIV. These antibodies recognize the CD4 binding site, thereby blocking HIV binding to this receptor.

These researchers further confirmed that these tested antibodies that attach to the surface of immune cells are more effective in blocking HIV infection than free-swimming soluble antibodies.

In April 2017, the American "Molecular Therapy" magazine recently published the latest research results of the Chinese scientist Hu Wenhui of Temple University and others: They used gene editing technology to efficiently eliminate one humanized mouse from multiple targets. Human HIV virus in organs and tissues.

Hu Wenhui, colleagues at the same school, Kamal Khalili, and University of Pittsburgh Yang Wenbin and others first used HIV virus to infect humanized BLT mice, and then used adeno-associated virus (AAV) as a vector to make it known as "gene scissors" The CRISPR/Cas9 gene editing tool was delivered to latently infected mice. Two to four weeks later, they detected that the HIV genome was excised in multiple mouse organs.

As we all know, HIV virus genes are "mercury." Hu Wenhui's team proposed a new idea this time, replacing single targets with multi-target gene editing to curb virus escape. They designed 4 guide RNAs (ribonucleic acid) for the HIV transcription and structural regions to guide the Cas9 enzyme to a predetermined position to achieve multi-target excision, which significantly increased the efficiency of HIV elimination. There is another advantage of using "genetic cut" to eliminate HIV: it does not affect the survival and function of target cells, that is, "only kills virus but not cells".

Although the current gene editing therapy cannot eliminate 100% of the HIV in animals, it can significantly reduce the amount of latent virus. Therefore, the combination of antiretroviral drugs is a promising strategy for AIDS treatment.