HIV (yellow) infection of human immune cells (blue) Image credit: NIH/SPL
AIDS is the last stage of human immunodeficiency virus (HIV) infection and has been discovered For nearly 40 years, from the initial "unknown panic" to today's "satisfaction", the successful development of antiretroviral drugs is inseparable. Through the "cocktail" therapy of these drugs, the virus in AIDS patients can be very Good control, the patient mortality rate has been controlled below 5%, and the life span can reach a life expectancy similar to that of normal people.
However, antiretroviral drugs can not cure AIDS patients because, taken daily Although these drugs can almost completely eliminate the HIV virus in the peripheral blood, they cannot kill the virus that is lurking in the host cell, CD4+ T lymphocytes. Once stopped, these latent HIV viruses will attack the body's immune system again.
For the past few decades, the only AIDS patient identified as a cure has only one. The American who is known as the "Berlin patient" is Timothy Ray Brown, who felt when he was in Berlin in 1995. HIV was diagnosed with acute myeloid leukemia in 2006.
TimothyRay Brown (Source: DANIEL JACK LYONS)
The most effective means of curing leukemia is hematopoietic stem cells. Transplantation. After transplantation, the patient's immune system can be reconstituted to kill cancer cells that remain in the body (the patient undergoes pretreatment with radiotherapy or chemotherapy before removal to remove tumor cells and other abnormal cells). Reaching the goal of healing and preventing recurrence.
Brown was transplanted in 2007, however, his bone marrow donor is very special, carrying a mutant version of the gene called CCR5 - CCR5Δ32. /p>
CCR5 is called C-Cchemokine receptor type 5 and is expressed on the surface of white blood cells. It is one of the main co-receptors of HIV virus invading the body cells. When it is mutated, the virus cannot enter the cell, thus Can't play a "destructive" role. People with CCR5Δ32 mutations are naturally resistant to CCR5-dependent HIV.
This special bone marrow transplant has created a miracle: Brown's leukemia and AIDS are cured He also became the first AIDS patient to be completely cured in the world, and he has not been tested for HIV since he stopped taking it.
Because for a long time, there is no cure like Brown. Successful cases, therefore, many people believe that this "one stone two birds" therapy can not be copied.
On March 5, 2019, the transfer seems to have appeared. /p>
According to Nature, a patient known as the "London Patient" has maintained an 18-month remission after receiving nearly the same treatment (ie, blood tests have not shown a virus). Rebound).
The "London Patient" was diagnosed with AIDS in 2003 and was diagnosed with Hodgkin's lymphoma in 2012. He then accepted it in May 2016. A hematopoietic stem cell transplant of a CCR5 gene mutation donor, continued to receive antiretroviral therapy for 16 months after transplantation, and stopped taking the drug in September 2017.
The scientists were surprised that the stop So far, the HIV in the blood of patients has been reduced to an undetectable level, and white blood cells in the body will not be affected. HIV infection at the CCR5 receptor.
Ravindra K Gupta, who led the study, said it is still too early to think that the "London patient" has been cured, and that it still needs to continue to monitor its disease progression. Still, "London patients" have been widely reported by domestic and foreign media. Many experts have expressed their views on the significance of this case.
Among them, many people said that although it sounds exciting, However, such treatments have very limited limitations and will not become a treatment strategy for many AIDS patients. On the one hand, at present, the drug can be used to suppress HIV virus. The choice of bone marrow transplantation is actually Taking a bigger risk. On the other hand, there are two indispensable factors for successful treatment of “London patients” and “Berlin patients”: 1) they are all infected with HIV that depends on CCR5. 2) They have found natural Bone marrow donors carrying CCR5Δ32. In fact, these two conditions are not so easy to satisfy. In the first condition, the HIV virus also has a CXCR4-dependent type. In the second condition, the CCR is naturally carried. 5Δ32 bone marrow donors are not “common”. Except for Europeans, there are almost zero people with CCR5Δ32 mutations in other parts of the world.
However, although this is not a breakthrough in “wide cure for AIDS” However, the case still has a very important enlightenment. The doctor of "Berlin patient" hopes that "London patients" can evoke academic enthusiasm for research on CCR5-based AIDS therapy. Professor Zhang Linqi, director of the Center for AIDS Comprehensive Research at Tsinghua University, accepts In an interview, the reporter said that the "London Patient" part of the verification that the "Berlin patient" was cured is not accidental. It has a very important "scientific meaning" and provides a very important reference for the purpose of killing AIDS through genetically edited stem cells. p>
Professor Zhang Linqi told reporters that the reason why AIDS is refractory is because the HIV virus has two "fatal" characteristics. First, they will produce many mutations during the replication process, resulting in the loss of the immune system and antiviral drugs. In addition, the genetic material of the virus will be integrated into the DNA of the human cell and become the host cell genome. Part of it, so it can't be removed (the existing anti-aerobic drugs are only needed when the virus is copied, and it is not effective for these latent viruses).
HIV virus can be injected once a month. Control. (Source: NIBSC/SciencePhoto Library)
The currently marketed antiretroviral small molecule drugs are very effective, but patients need to take them daily for life. Therefore, scientists are always looking for better Anti-Ai drugs. Some are combined with other antiretroviral drugs. Relatively long-acting drugs have been approved for two years, such as Trogarzo (antibody drug. once every two weeks). Akonin (polypeptide drugs. once a week) Some drugs, although not yet on the market, have achieved positive results, such as the antiretroviral drugs cabotegravir and rilpivirine . According to the latest news from Nature, more than 1,000 people participated in the twin test results showed that prevention In terms of HIV replication, a monthly combination of these two drugs can achieve the same effect as taking three common antiretroviral drugs per day.
To achieve Long-term "anti-Ai", many scientists in the field are also developing a treatment called broadlyneutralizing antibodies (bNAbs), and the results have repeatedly hit top magazines. For example, last September On the 26th, Professor Michel C. Nussenzweig of Rockefeller University in the United States led a team to publish two important papers in Nature and its sub-distribution. The study said that the results from the Phase 1b clinical trial (NCT02825797) showed that the two bNAbs (3BNC117+10- The combination of 1074) (15 participants stopped taking antiretroviral drugs and received 3 injections of the combined antibody in the next 6 weeks) was able to control the HIV virus for an average of 21 weeks in the “responders”, some of whom were able to Persist for more than 30 weeks, and the subjects did not have obvious side effects . In addition, even in patients with HIV viremia, bNAbs also showed good therapeutic effects. Of the 7 subjects, 4 The viral load in the blood of patients was controlled and maintained at a low level of 3 months .
According to Professor Zhang Linqi, Broad-spectrum comprehensive resistance The body can not only effectively inhibit the HIV virus, but also has a good effect on improving the immune response. It is a next-generation antiviral drug that is generally optimistic in the field and is expected to achieve the goal of "functional cure" by mobilizing the body's immune system.
The so-called "functional cure" means that although a small amount of HIV virus is present in patients, the replication of these viruses will be suppressed for a long time, the disease progresses significantly, and the symptoms of infection stop. The patient stopped taking the drug. The true meaning of AIDS cure is to completely eliminate the cells that are latently infected by HIV. Research progress in this area. Can the immunotherapy create a miracle to cure AIDS? Some articles have been introduced in the article. Some studies have shown that PD-1 antibodies may help to disrupt the potential of HIV and eliminate HIV latent infected cells . .
In addition to drug treatment, genes Therapy is also expected to be an effective way to cure AIDS. Some scientists have found that in the mouse model, the gene magic clip CRISPR can accurately "destroy" the genetic material of HIV, thereby inhibiting its replication .
Professor Zhang Linqi believes that in the future, the further development of new therapies such as macromolecular antibody drugs and cell therapy is an inevitable trend in the field of AIDS treatment. In addition to research in these areas, the team will continue to develop HIV preventive vaccines. We are conducting in-depth research on the virus, immune system and genetic characteristics of individuals who are infected with HIV but are still in good health. We believe this will provide an important direction for the development of new targets and therapies." He said. /p>
1]RavindraK Gupta etal. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-celltransplantation. Nature(2019).
2]David AMargolis et Al. Long-acting intramuscular cabotegravir and rilpivirinein adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. The Lancet (2017).
3]Pilar Mendoza etal. Combination therapy with anti-HIV-1 antibodies maintains viral suppression.Nature(2018).
4]YotamBar-On et al.Safety and antiviral activity of combination HIV -1 broadly neutralizingantibodies in viremic individuals. Nature Medicine(2018).
5]Rémi Fromentin et al.PD-1 blockadepotentiates HIV latency reversal ex vivo in CD4+T cellsfromART-suppressed individuals. Nature Communications (2019
6]A Guihot et al.Drastic decrease of the HIV reservoir in a patient treated with nivolumab forlung cancer. Annals of Oncology (2017).
7]Hsin-Kai Liao et Al. Use of the CRISPR/Cas9 system as an intracellular defense against HIV-1 infection in humancells. Nature Communications (2015).
8]ChaoranYinet al.InVivo Excision of HIV-1 Provirus by saCas9 and Multiplex Single-GuideRNAs in Animal Models. Molecular Therapy (2017).
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