December 1 is the thirty-fourth "World AIDS Day", in the 40 years of fighting HIV, with the continuous deepening of research and medical progress, mankind has achieved certain results in the fight against AIDS, but it is also facing great challenges.
Highly effective antiretroviral drugs have transformed AIDS from a lethal disease into a chronic disease that can be treated but is still difficult to cure; broad-spectrum neutralizing antibodies that can be blocked before HIV infected cells have begun experimental exploration for clinical treatment; but research on AIDS vaccines has been "difficult to produce" and has been fruitless.
Suppression of AIDS with long-acting agents is a trend
"Hive (HIV) destroys the body's immune function by specifically infecting the body's CD4+ T lymphocytes and spawning complications such as various bacterial, fungal or viral infections and tumors of the blood system." Tang Huamin, professor and doctoral supervisor of the Department of Immunology of Nanjing Medical University, told reporters that in recent years, with the application of highly effective antiretroviral drugs, AIDS has changed from a lethal disease to a chronic disease that can be treated but is still difficult to cure.
"At present, highly effective antiretroviral drugs can be divided into 7 categories, including nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, fusion inhibitors, CCR5 inhibitors and novel mechanism of action drugs." Dong Li, chief physician of the Department of Infectious Diseases of Jiangsu Provincial People's Hospital (the First Affiliated Hospital of Nanjing Medical University), told reporters that because AIDS patients need to take medicine for a lifetime, they are often accompanied by problems such as virus resistance and poor patient compliance.
"The use of long-acting agents to suppress AIDS is the future trend." Fu Gengfeng, director of the Institute of St. AndR and AIDS Prevention of the Jiangsu Provincial Center for Disease Control and Prevention, explained that if AIDS patients do not take medicines on time and as required, the blood concentration in the body is not enough, which will lead to a decrease in the rate of virus suppression. Once the virus accumulates, mutates, and increases in number, drug resistance develops. Long-acting preparations can reduce the frequency of administration, so that the drug has a long-term effect in the human body, and it is also conducive to improving patient compliance.
At present, there are many long-acting preparations for the treatment of AIDS in the world, such as cabotevir and rilpivirine. The former is an HIV integrase inhibitor, the latter is a non-nucleoside reverse transcriptase inhibitor, and the two can be produced into a long-acting injectable nanosuspendent. In March 2020, the long-acting injectables cabotevir and rilpivirine were approved for marketing in Canada, making it the world's first long-acting HIV injection program.
Aikonin is a synthetic polypeptide drug designed with the HIV membrane protein gp41 as the target, and is the world's first approved long-acting HIV fusion inhibitory drug, which can be administered intravenously once a week, and was approved for marketing in Mainland China in August 2018, suitable for combination with other antiretroviral drugs.
"But these long-acting agents are only used as therapeutic drugs, and there are no long-acting drugs for pre-exposure prophylaxis in people at high risk of AIDS." Fu Gengfeng said.
But not long ago, GlaxoSmithKline's ViiV Healthcare announced that the U.S. Food and Drug Administration (FDA) has granted it priority review of caboterwei new drug applications (NDA) for its research and development. The company revealed that if approved, cabotvir will become the first long-acting drug for the immunodeficiency virus in humans, namely the pre-exposure prophylaxis of people at high risk of human immunodeficiency virus (HIV).
HIV vaccine development faces multiple challenges
"Since the first cases of AIDS were detected in 1981, humanity has realized that the AIDS vaccine is one of the most effective means of ending the AIDS epidemic. Unfortunately, there is currently no effective AIDS vaccine for clinical application. Tang Huamin said.
AIDS was first detected and reported in humans in 1981, and HIV was isolated two years later, but vaccine development has been stalled ever since. In 1998, a company in the United States launched the first large-scale AIDS vaccine trial, but in 2003 it was declared ineffective; the "STEP" project in 2007 found that the AIDS vaccine HVTN502 promoted immune cells to attack HIV, which may increase the risk of immune cells being infected by HIV; in 2009, the results of the phase III clinical trial of the AIDS vaccine showed that the protective efficacy of the vaccine reached 31%, which was the first time scientists found a detectable protective effect in clinical trials In 2016, a clinical trial of the effectiveness of the HVTN702 AIDS vaccine was launched in South Africa, but in early 2020, the trial ended in failure.
"There are many types of AIDS vaccines, including inactivated vaccines, live attenuated vaccines, protein subunit vaccines, synthetic peptide vaccines, DNA vaccines, vector vaccines, etc." Dong Li introduced that due to the particularity of HIV, there are still a large number of safety problems that have not been solved. For example, incompletely inactivated HIV may lead to latent infection, and the possibility of integrating viral nucleic acids that have not been destroyed after inactivation into the chromosomes of human cells cannot be ruled out, so there is no inactivated AIDS vaccine entering the clinical trial stage.
"Due to the extremely high variability of HIV, the direction of attenuated virus mutation in live attenuated vaccines in vivo is unpredictable, and there is a risk that retroviruses will integrate into host DNA and reverse into the wild type." At present, the development of traditional live attenuated HIV vaccines is low. Dong Li said.
Why is the AIDS vaccine so "difficult to produce"? "This is because HIV mutates too quickly." Fu Gengfeng explained that HIV will undergo random mutations in each replicated generation of the human body. Vaccines or drugs need to be targeted at the appropriate sites, and as the virus mutates, drug resistance can occur and the vaccine or drug malfunction.
The lack of ideal animal models is another important reason for hindering vaccine development. Fu Gengfeng said that preclinical animal model evaluation is one of the important links in vaccine research. "HIV only infects humans, does not infect animals, can not replicate in animals, can not carry out preclinical in vitro tests of AIDS vaccines, it is difficult to verify the safety and efficacy of vaccines."
According to Fu Gengfeng, monkey immunodeficiency virus (SIV) is very similar to HIV in terms of infection, transmission and incubation period, and researchers have successfully established a model of chimeric virus (SHIV) infection of non-human primates. However, SHIV infection mode, dose, and timing parameters can significantly affect vaccine evaluation results.
"In addition, it is unclear how HIV escapes the surveillance of the human immune system, which also poses a challenge for vaccine development." Fu Gengfeng said.
Antibody therapy has been used in clinical treatment trials
In the process of "fighting wits" with AIDS, human beings have discovered a special "defender" against HIV - broad-spectrum neutralizing antibodies. It can identify areas on the surface of HIV strains that are not easily changed, so that it has the ability to capture multiple strains, inhibit viral replication in patients, and effectively reduce HIV levels in the human body.
"Broad-spectrum neutralizing antibodies are mainly isolated and purified from the blood of infected people, which can directly neutralize HIV strains, prevent viruses from invading immune cells, and can also stimulate other immune cells in the body after neutralizing the virus to jointly destroy viruses or cells infected by viruses." Wu Jie, a professor at the School of Life Sciences and Technology of China Pharmaceutical University, told reporters that antiretroviral drugs inhibit and interfere with HIV after it enters the infected cells of the human body, while broad-spectrum neutralizing antibodies block before the virus infects the cells.
However, it is very difficult for such a weapon to kill HIV in the body of HIV-infected people, Fu Gengfeng introduced, "Only 10% to 15% of people can produce neutralizing antibodies after infection with HIV, of which only 2% to 5% of patients have broad-spectrum neutralizing antibodies." These broad-spectrum neutralizing antibodies generally appear 2 to 3 years after a patient is infected with the virus and can neutralize most HIV strains at very low concentrations, where the viral load is low and disease-free, and is known as an 'elite' controller. Fu Gengfeng said.
Studies have shown that the production of broad-spectrum neutralizing antibodies may be related to factors such as viral load, viral diversity, time of infection, and host immune status.
"At present, it will take time for human research on broad-spectrum neutralizing antibodies, for example, the mechanism of its production is not fully understood, and some clinical trials are trying to induce broad-spectrum neutralizing antibodies in humans to make vaccines, but they have not yet succeeded." Tang Huamin said.
It is gratifying that in recent years, with the advancement and wide application of high-throughput neutralizing antibody screening and monoclonal antibody isolation technology, researchers have successfully isolated hundreds of broad-spectrum neutralizing antibodies from infected people.
On March 7, 2018, the FDA officially approved the first clinically available monoclonal antibody capable of binding to CD4, the main HIV receptor on the surface of T cells, to stop these cells from being invaded by the virus.
Experts from the Center for St. Mary Disease and AIDS Prevention and Control of the Chinese Center for Disease Control and Prevention said that more and more antibodies have been used for clinical treatment trials.
"In addition, scientists also use reverse vaccine technology to actively search for immunogens that can stimulate the body to produce protective HIV-specific antibodies, and try to use viral vector vaccines to carry antibody-expressing genes to induce the human body to produce antibodies, which provide new ideas and new technologies for HIV vaccine research and development." Wu Jie said.
Source/Learning Powerhouse
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