Reporter : Zhang Jiaxing / Publisher : Science & Techology Daily / http://news.sciencenet.cn/htmlnews/2020/11/449350.shtm / Direct translation
"The youngest age for sexual infection is 13 years old, and the oldest is 86 years old."
Mentioning these two figures, Sun Lijun, director of the STD and AIDS Clinic of the Infection Center of Beijing You'an Hospital, looked sad.
13 years old, in the Mood for Love; 86 years old, old man. They shouldn't have been "captured" by HIV, and even more incredible is through sex.
Some people may think that these are just two extreme cases. However, Han Mengjie, director of the Center for STD and AIDS Prevention and Control of the Chinese Center for Disease Control and Prevention, based on the information he has, told a more worrying reality-"A recent survey organized by us showed that a small number of middle school students search for'partners' online and have sex. "Han Mengjie said that the elderly are mainly in rural areas, especially in the southwest region. Sex may happen for money. All these lay hidden worries for the sexual transmission of AIDS.
December 1, 2020 is the 33rd "World AIDS Day". Data from the frontline of diagnosis and treatment and national surveys all point to one point: AIDS has entered the stage of sexual transmission.
"Prevention and control is very difficult." Han Mengjie is used to speaking with data: Although my country reported less than 2,000 cases of HIV transmission due to drug use in 2019, which is at a low level, sexual transmission has made the situation of AIDS prevention and control still severe.
HIV spreads more "secretly".
This is only one. HIV has too many "hidden corners".
It pulled the "trigger" of the collapse of the immune system, but humans can do nothing.
The purple-red sarcoma looks like a ripe cherry.
In 1981, dozens of patients suffering from Kaposi's sarcoma appeared in New York and California at the same time. The clustered disease caused the medical community to alert: Could it be an infectious disease?
Subsequent patients showed different symptoms: bacterial or fungal infection, rare pneumonia, terribly low platelets, aggressive lymphoma...
Although the symptoms are diverse, they reflect the commonality: the immune system is "unsuccessful."
The name of AIDS comes from this: Acquired Immuno Deficiency Syndrome (AIDS). But people still don't know what triggered the "trigger" that caused the immune system to collapse.
The discovery of the source was two years later. In 1983, scholars from the Pasteur Institute in France and the National Cancer Institute in the United States independently isolated the pathogen of AIDS, the notorious HIV. Their research results were published in the journals "Science" and "Nature".
The discovery of the culprit did not stop the killing of AIDS in human society. At the end of 1986, of the nearly 29,000 American patients diagnosed with AIDS, 25,000 died.
Even the discovery of "Patient Zero" did not bring the slightest turn. A Canadian gay man who worked as a flight attendant is considered "patient zero", and it is generally believed that he was the first person to bring AIDS out of Africa.
However, continuous virus traceability and new discoveries have pushed the "No. Zero" farther.
"Later the virus traceability work has been tracked through the global network, and now we know that HIV actually started in Africa in the 1930s, from animals to humans." Bailey Martin Award winner, the eighth people of Guangzhou City Cai Weiping, director of the Hospital Infectious Diseases Center, said that the discovery of HIV may be more than 50 years later than the emergence of "patient zero" in human society.
Numerous evidences suggest that the so-called "patient zero" that people have discovered may be just an intermediate chain, and the traceability is far from over.
Whether it is “secretly” sneaking in the face of other diseases or raging after being discovered, before 1996, the frustration brought by AIDS to doctors and scholars was not alleviated by the recognition and separation of HIV. .
"The sense of frustration is very strong, and it has been fresh in my memory for 30 years." At the Xiangshan Science Conference on "AIDS Immune Reconstruction and Immune Recovery" held not long ago, Li Taisheng, director of the Department of Infectious Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, sighed with emotion. Duo: "When I went to France to study AIDS treatment in 1993, I always felt very helpless, because the patients I encountered had to be replaced in about a year, just like this time we went to Wuhan to treat patients with new coronary pneumonia. Facing the death of the patient, he was helpless."
Ghostly "Rejuvenation": Just escaping from death, and falling into the "vortex" of chronic inflammation
In 1996, Chinese-American scientist He Dayi proposed the famous "cocktail therapy", which is to treat AIDS through the combined use of three or more antiviral drugs.
Prior to this, scientists from all over the world have studied HIV behavior patterns, hobbies, invasion paths, attack methods and even weaknesses.
AIDS has a "key" to enter the human body, mainly to open the "lock" marked by "CD4".
HIV mainly attacks CD4 cells of the human body. Since it is an RNA virus, it will “bring its own” tool enzyme for reverse transcription (from RNA to DNA) after sneaking into it. DNA sneaks into the nucleus of the host cell and is permanently inserted into the host chromosome. in.
CD4 cells were occupied by HIV and became a stronghold of HIV. After "feeding" a large number of viruses, they died one after another.
From discovering, identifying, separating, and then figuring out its details and ways, every link in the HIV "chain of life" seems to have been "broken".
Nucleoside reverse transcriptase inhibitors were invented, and people have grasped the "life gate" of HIV: as long as the reverse transcriptase is inhibited, it is not allowed to reverse transcribed into DNA into the cell genome, interrupting the key link, Can shut out the "Reaper".
Unexpected things happened one after another. The most curious thing is the mutation of HIV.
Its frequent mutations have not only triggered drug resistance, but also made the birth of AIDS vaccines increasingly slim.
Harvard Medical School Professor Jerome Gropman commented: HIV is a highly mutated virus. It is cunning that through mutations, the drug cannot find its target (reverse transcriptase). This is drug resistance.
The combination of "cocktail therapy" overcame the problem of drug resistance, and for the first time made long-term control of AIDS possible and became the standard treatment for AIDS.
People are delighted to see that the viral load has been declining until the test shows "Negative", but as long as the drug is stopped for a period of time, it will make a comeback.
"Fuyang" has become a cure nightmare, which also makes AIDS patients burdened with high and long-term treatment costs and heavy treatment side effects.
Finally, people realize that HIV is lingering like a "ghost".
"Patients who have been treated for a long time generally suffer from chronic diseases, such as cardiovascular alienation and neurological, kidney, and liver problems. The elderly will also suffer from severe osteoporosis." Li Taisheng said, in the era of "post-cocktail therapy", Chronic inflammation and abnormal immune activation are the cost of suppressing the virus with drugs, and whether AIDS drugs can reduce or overcome these effects is currently an important issue for its efficacy evaluation and new drug research.
In clinical practice, doctors can give different "cocktail" plans based on comprehensive consideration of the patient's clinical status, economic status, medication contraindications, and adverse reactions.
In the development of new drugs, improving the efficacy of drugs, the convenience of taking drugs, and reducing the side effects are the goals. Currently, the focus is on the research and development of new target drugs and long-acting drugs. For example, tablets, taken once a week, these are good developments.
To reduce toxic side effects, many teams in China tried to find a breakthrough from traditional Chinese medicine.
"Our team tried to use Chinese medicine to treat rheumatoid arthritis with Tripterygium Glycoside Tablets in clinical trials on AIDS patients, and the results showed that CD4 has been significantly improved." Li Taisheng said that since 2015, the team has cooperated with companies to start Chinese medicine tablets Further research on the active ingredient (Lei Tengshu) is currently underway for patient recruitment in clinical trials.
Coincidentally. Professor Lu Hongzhou, Secretary of the Party Committee of Shanghai Public Health Clinical Center, introduced that the Shanghai public health team is exploring the possibility of "old medicine and new use" of traditional Chinese medicine, and has found active monomers in kansui, clarified the mechanism of the drug, and will start clinical drug research soon jobs.
Since the cause of everything is immunodeficiency, does the lymphocytes that have been devastated by HIV have a chance to regain their vitality?
A 12-year follow-up analysis of 100,000 patients led by Wang Fusheng, academician of the Chinese Academy of Sciences and director of the Department of Infectious Diseases of the Fifth Medical Center of the People’s Liberation Army General Hospital, showed that once the “massage” of CD4 cells by HIV crosses the “red line”, even 12 years Nor can it be restored to normal levels. They divided the level of CD4 cells in newly-treated AIDS patients into 5 groups. The results showed that if it is greater than 500 cells/mm3, after treatment, the CD4 cells will quickly recover and the entire system will also tend to be balanced; and if it is less than 200 /Cubic millimeter, then even if the virus is controlled, the patient’s immunity is still difficult to recover.
This large-scale, long-term investigation and research has given iron evidence to the destructive power of HIV: HIV not only kills CD4 cells but even destroys its ability to recuperate.
"Need to support the damaged immune system." Over the years, Wang Fusheng led the team to carry out research on overall adoptive immunotherapy, hoping to "reconstruct" the immune system of people living with AIDS, by collecting cells from healthy immediate family members and returning them to the patient's body , Enhance or improve the immunity of patients and assist in the control of disease complications.
In terms of drug prevention, AIDS treatment has also made new breakthroughs. The long-acting HIV integrase inhibitor developed by GSK is used as a preventive drug for HIV infection in African women. It only needs to be injected once every 2 months to prevent and protect It can even be used as a vaccine.
According to the recent advances in HIV frontier research summarized by the professional media "Bio Valley", "Science" published a study on the reconstruction and integration process of HIV in vitro by American scholars, further understanding the mechanism of HIV action. In addition, research on immune cell therapy and virus latent mechanism has also made breakthroughs.
In the battle of human poison, the 36 strategies in the "Art of War" are very likely to be performed from time to time
The ghostly "rejuvenation" of HIV has made scholars do everything possible to hunt down and try to find its hiding place.
The Harvard Medical School professor Jerome Gropman, who participated in the treatment of AIDS patients in 1981, recorded this history in his memoir: In the 1997 issue of Nature, Johns Hopkins Medical School Robert Siliciano, a researcher at the Howard Hughes Institute of Medical Research, published a paper using a very sensitive measurement technique he invented to find the HIV virus in memory T cells. HIV stays dormant in the DNA strands of memory T cells so that it can avoid the cocktail of drugs and reactivate later to start damaging the immune system.
"Siliciano told me that he still remembers the first time a latent virus was found in the memory T cells of a patient treated with HAART." Jerome Gropman wrote in the article: "The doctor at the time thought The patient is curable. A biopsy was performed at every imaginable part, and no signs of the virus were visible. The researchers took 20 test tubes of blood samples from the patient, separated T cells, and put them separately Into the container. Next, the researcher mixes the sample with the cells of the uninfected person. If healthy T cells are infected, the virus can multiply and be released. If the presence of the virus is detected, the color of the test tube will change to blue."
One day, a graduate student broke in and declared: The container has turned blue! This ice blue locks the last "hiding spot" of HIV, but it also confirms the fact that people don't want to believe: Even if antiretroviral therapy is used, the virus will still survive in the body and be eradicated.
"The current treatment can continue to inhibit the replication of HIV, and the effect can reach its existence undetectable, but it cannot eliminate the persistent latent virus." Professor Zhang Linqi, deputy dean of the Vanke School of Public Health and Health, Tsinghua University, said that this is now HIV The main reason for no cure.
Only by finding the "old nest" can it be eradicated.
In 2012, the method of "drawing the snake out of the hole" was proposed. By reactivating the dormant virus, the drug or the immune system can recognize and eliminate it.
What to wake up? The proponents of the theory used a drug called vorinostat. In recent years, the search for drugs to attract snakes has become the forefront of AIDS research.
Linqi Zhang’s team worked with colleagues from the School of Pharmacy of Tsinghua University. Starting from receptor agonists, through a combination strategy of computer-aided, structure-based drug design, virtual screening, and lead compound optimization, about 200 kinds of different structures and biochemical properties were synthesized. Small molecule compounds have preliminarily proved the great potential of small molecules in activating virus reservoirs and enhancing NK cell-mediated antiviral immunity. "The safety and effectiveness of new small molecules in activating and clearing the potential virus pool of AIDS patients still requires in-depth mechanism analysis and preclinical and clinical evaluation." Zhang Linqi said.
The interaction between HIV and the human body may be more complicated than imagined. In the human-toxin war, the 36 strategies in the "Art of War" are very likely to be performed from time to time.
With the advancement of biotechnological methods, more and more surprises are coming.
For example, type I interferon, which was originally thought to be an important antiviral factor in the human body, has been proved to be an accomplice of HIV destroying the immune system in animal experiments.
Su Lishan, a professor at the Institute of Human Virology at the University of Maryland School of Medicine, led a team to conduct an experiment to "test" type I interferon. "It's very interesting. After the removal, the virus replication increased by about 5-10 times, indicating that the type I interferon derivatives inhibited the virus replication, but the human immune cells were rescued: the function of T cells was back, and the hematopoiesis in the bone marrow Stem cells and the homeostasis in the intestinal tract have also returned." Su Lishan described this discovery at the Xiangshan Science Conference.
Whether the "secret" inner ghost only has type I interferon, reconnaissance continues.
Berlin patients, London patients, São Paulo patients, elite controllers... Is HIV really dying?
For several years, "cure" has not been able to be used on AIDS patients.
But the "Berlin patient" appeared...
In 2007, Timothy Ray Brown, who had both leukemia and AIDS, underwent a bone marrow transplant, and then the HIV miraculously disappeared from his body.
A defect in the CCR5 gene prevents HIV from opening the door to human cells, and Brown’s bone marrow donors are born with this defect.
The door to gene editing and cell transplantation to treat AIDS has opened.
In 2016, the "London Patient" repeated Brown's miracle.
But their luck is considered impossible to replicate.
In addition to the difficulty in finding a matching bone marrow, not all successful matches let the virus disappear. Whether the infusion of immune cells can survive and grow in the patient's body is the key. Similar treatments have also been used, and the patient's virus has not been eliminated.
It is difficult to find the natural CCR5 gene defect system, and artificial gene editing technology may be able to make up for the "short board."
On September 12, 2019, the New England Journal of Medicine published an online publication of Professor Deng Hongkui, School of Life Sciences, Peking University, my country, and Chen Hu from the Fifth Medical Center of the PLA General Hospital Professor Wu Hao from You'an Hospital affiliated to Capital Medical University and other teams cooperated to use CRISPR gene editing technology to inactivate the CCR5 gene in human hematopoietic stem cells and transplant the edited stem cells into an AIDS patient with acute lymphoblastic leukemia.
In the United States, ZNFs gene editing technology is used in the transformation of blood and bone marrow stem cells, and CCR5 inactivated stem cells are reinfused, and high hopes are placed on helping people with AIDS form an immune system that can resist the virus.
In 2020, an even more joyous news came. A man in Sao Paulo, Brazil received special medication (antiretroviral drugs + niacinamide), and 66 weeks after he stopped using the medication, he still had no HIV detection.
Among the 5 patients who received the same treatment, only the "São Paulo patient" was effective. Regardless of whether he will become the world's first AIDS patient who has recovered from drug treatment, he still gives great encouragement to the drug cure of AIDS.
The human-to-drug war has been fighting for nearly half a century! HIV has always resisted.
But among the human race, there is a group of people who can "lock up" the sequence of HIV insertion into the genome. They are called "elite controllers", and they will not get sick even if they are infected with HIV.
Associate Professor Yu Xu of Harvard Medical School recently published a study in the journal Nature, and found that among these elite controllers, viruses often integrate into specific regions of the human genome, and their transcription is inhibited.
The research team used the latest sequencing technology to accurately map the position of the complete HIV genome in the human genome, and compared the sequence of the provirus in the cells of 64 individuals who maintained HIV-1 elite controllers and 41 who were receiving ART treatment. Resident more in the "gene desert".
Berlin patients, London patients, São Paulo patients, elite controllers... Whether they are a case or a minority, their existence proves that HIV is not invincible. And what makes HIV really die can be effective treatments, advanced biotechnology, or special drugs, but the magic weapon that ultimately defeats infectious diseases must be disease prevention and control strategies.
The People's Republic of China formulated the 'Implementation Plan for Containing the Spread of AIDS' in 2019, and truly let the AIDS prevention and control work be undertaken by multiple departments." Han Mengjie said, for example, the youth student project was led by the Ministry of Education and has been accepted. To a very good effect.
It can be seen that in the absence of an effective preventive vaccine, the AIDS epidemic can only be effectively controlled by government leaders, various departments, and the participation of the society, and the implementation of comprehensive prevention and control measures focusing on health education.
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