Reviews |Shao Feng(Academician of the Chinese Academy of Sciences)., Wang FushengAIDS, also known as acquired immunodeficiency syndrome (AIDS), is caused by infection with human immunodeficiency virus (HIV). HIV-infected patients lose large amounts of CD4+ T lymphocytes, resulting in immunodeficiency. As one of the most important members of the immune system, CD4+ T lymphocytes play a key role in both cellular and humoral immune responses. CD4+ T lymphocytes in the blood of patients with advanced AIDS can be nearly completely lost, so that the immune system has completely lost its ability to defend against conventional pathogenic infections, leading to opportunistic infection and death. For more than 40 years since the outbreak of AIDS (1981), scientists have wondered why HIV infection causes such a large proportion of CD4+ T lymphocytes to die in a patient's immune system. Even though CD4+ T lymphocytes are the main target cells for HIV infection, studies have found that less than 1 in 1,000 CD4+ T lymphocytes are directly infected by HIV when the viral titer in patients is at its peak。Other studies have found that most of the dead CD4+ T lymphocytes have no detectable nucleic acids or proteins of the virus。This suggests that HIV is likely to cause massive CD4+ T lymphocyte death in a manner that is not dependent on direct infection. In fact, HIV** is associated with the primate acquired immunodeficiency virus (SIV) carried by African primates, and about 40 species of African primates are natural hosts for SIV, including the well-studied black white-browed monkey and African green monkey. SIV also predominantly infects CD4+ T lymphocytes in African primates, and the high replication level of the virus is comparable to that of HIV infection in humans. Interestingly, SIV infection does not cause the loss of CD4+ T lymphocytes in these animals, nor does it lead to immunodeficiency。Because it is not pathogenic in natural hosts, the existence of SIV was not known for a long time, until the 80s of the 20th century, in the course of experiments to study other infectious diseases, SIV in the body fluid samples of African black-browed monkeys was mistakenly transferred to Asian macaques that had never been exposed to the virus, resulting in Asian macaques suffering from immunodeficiency syndrome with a large loss of CD4+ T cells consistent with human appearanceWhy does SIV cause a large number of target cell death in the pathogenic host Asian macaque, which is also infected with CD4+ T lymphocytes, but not in the natural host, the African monkey? Why HIV infection can cause AIDS in humans? Is pathogenicity determined by the virus or the host? This series of questions has been a long-standing problem in the field of AIDS research. February 29, 2024, Washington University in St. Louis (WUSTL), USASingle girderThe professor's research group is incellThe article was published onthe card8 inflammasome dictates hiv/siv pathogenesis and disease progressionThe key role of the CARD8 inflammasome in HIV infection was revealed. 
In the early stage, Dr. Wang Qiankun from Professor Liang's group first reported the mechanism of Card8 inflammasome recognition of HIV protease (Protease) (see Bioart report for details: Expert Comments Science |The discovery of inflammasome receptors in HIV-induced pyroptosis in the single-beam group provides a new idea for AIDS**). In simple terms, the HIV protease releases a functionally active C-terminus UPA-Card domain by cleaving the N-terminus of the Card8 protein, thereby activating Caspase 1 and pyroptosis. In this latest study, Dr. Qiankun Wang and PhD student Kolin Clark explored card8 inflammasome function in different primates. Through genome sequence analysis, they found that card8 is present in the vast majority of vertebrates and that the protein sequence of the upa-card domain is highly conserved. Surprisingly, the card domain of African primate card8 contains loss-of-function mutations, and the mutations carried by different species of African monkey card8 vary. For example, the card domain of the African black white-browed monkey card8 contains a frameshift mutation, while the card domain of the African green monkey is almost completely lost. When CD4+ T lymphocytes from a pathogenic host are exposed to HIV SIV, the proteolytic enzymes in the viral particles can be rapidly introduced into the cell, resulting in card8 inflammasome activation and pyroptosis. The whole process takes no more than six hours, and the cells don't need to be infected by the virus, which explains whyClinically, it has been observed that dead CD4+ T lymphocytes do not contain the nucleic acids or proteins of the virus。Unlike pathogenic hosts, the loss of function of the Card8 inflammasome avoids pyroptosis when CD4 T lymphocytes from the natural host are exposed to SIV virus particles. To find in vivo evidence, the authors transplanted card8 knockout human hematopoietic stem cells into immunodeficient miceA humanized immune system with card8 deficiency is established。Compared with the control group, the humanized card8-deficient mice had higher HIV titers after infection, but the loss of CD4+ T lymphocytes was significantly slowed, and the number of CD4+ T lymphocytes in each organ of the card8-deficient mice was significantly higher than that of the control group, which further confirmed that the card8 inflammasome was the main cause of CD4+ T lymphocyte loss in HIV-infected patients. It can be said thatThe human immune response accelerates and deepens the pathogenicity of HIV, and the natural host of SIV has evolved over a long period of time to identify genetic mutations that produce immune tolerance to SIV. This study not only provides the most powerful explanation for the mystery surrounding the pathogenesis of AIDS for more than 40 years, but also provides a direction for how to better protect or restore CD4+ T lymphocytes in patients. Although a cocktail of HIV** has been shown to be highly effective in blocking viral replication, a significant proportion of patients still do not return to normal levels of CD4+ T lymphocytes after **. Drugs that antagonize card8 function on top of a cocktail** may be a novel strategy to help rebuild immune system function. 
Dr. Qiankun Wang, the first author of this paper, is about to join the Shenzhen Bay Laboratory as a distinguished researcher, and the research direction of the research group is viral infection immunity, and we sincerely invite associate researchers, postdoctoral fellows, research assistants and graduate students who are interested in the direction of infection immunity to join. The research group is well treated, providing applicants with sufficient scientific research guidance and good career planning, so that every member of the laboratory can learn something, welcome to contact! Expert commentary
Shao Feng(Academician of the Chinese Academy of Sciences, Beijing Institute of Biological Sciences) pyroptosis is a programmed cell necrosis mediated by membrane perforation proteins of the Gasdermin (GSDM) family, accompanied by the release of a large number of pro-inflammatory factors. As one of the earliest identified members of the GSDM family, GSDMD is a relatively well-studied pyroptosis pathway. In immune cells, GSDMD is often activated by caspase-1 cleavage of the classical inflammasome pathway, inducing pyroptosis. On the other hand, pyroptosis triggered by non-classical inflammasomeal caspase-4 5 (human) caspase-11 (mine) activated GSDMD occurs more often in non-immune cells. Inflammasomes are an important component of the innate immune system, and their mediated pyroptosis is an effective means for the host to fight bacterial and viral infections. In the past two decades, the study of pyroptosis of immune cells has mainly focused on macrophages, and whether there are inflammasomes in lymphocytes and whether pyroptosis will occur has always been a question mark. In 2020, Hornung and Bachovchin reported that a small molecule compound, Val-BoroPro (VBP), can activate caspase-1 in resting T cells to induce pyroptosis, and demonstrated that this process is mediated by Card8。However, it is unclear whether card8 is an inflammasome receptor and what kind of pathogenic signals it recognizes. A few months later, the single beam research group published an article in Science, reporting that CARD8 acts as a receptor for inflammasomes to specifically recognize the proteolytic enzyme of HIV virus and then induce T cell pyroptosis (Expert Comment Science |The discovery of inflammasome receptors in HIV-induced pyroptosis in the single-beam group provides a new idea for AIDS**). 。In this latest CELL article, the single beam research group further elucidated the biological function of the CARD8 inflammasome in HIV infection. Normally, inflammasome activation works to help the body effectively defend against pathogenic infections, but this study found that the CARD8 inflammasome plays the opposite role in HIV infection。The production of a large number of virions by HIV-infected CD4 T lymphocytes requires CD4 T lymphocytes to be in the activation stage, and the function of Card8 is inhibited by the activation signal of T cellsActivated T cells do not block viral replication by activating inflammasome pathways. Conversely, resting T cells, although they can be infected by HIV, produce little virions and therefore do not support HIV replication, but they can promote the cellular and humoral immune system to defend against viral infection. Unfortunately, card8 in resting T cells efficiently recognizes HIV viral proteolytic enzymes, leading to GSDMD activation and inducing T cell pyroptosis and rapid clearance by HIV. As a result, Card8 not only fails to inhibit HIV replication, but also causes the loss of CD4 T lymphocytes. In hundreds of millions of years of evolution, the struggle between pathogenic microorganisms and the immune system has never stopped, starting with phages infecting bacteria. The host has evolved a variety of inflammasome receptors to recognize pathogens such as DNA, RNA, proteins, polysaccharides and other substances for different pathogens. The specific antipathogenic effect of CARD8 in the evolutionary process is still unknown, but it has played a role in improving viral pathogenicity and accelerating immunodeficiency in HIV infection. More interestingly, the loss of the Card8 gene by African primates, the natural host of SIV, in order to reduce pathogenicity under selection pressure, is a solution given by nature. Expert commentary
, Wang FushengProfessor Liang's research group (Academician of the Chinese Academy of Sciences, Chief Physician, Department of Infectious Diseases, Fifth Medical Center of the PLA General Hospital) used a variety of experimental methods and animal models, such as knockout cell lines, humanized mice, and human and non-human primate samples, to systematically study the mechanism of CD T lymphopenia caused by Card8 inflammasome after SIV infection. The results showed that Card8 had inactivating gene mutations in some non-human primates (such as black-browed monkey and African green monkey), making it a natural host of SIV and non-pathogenic. In primates and humans with normal expression of Card8, when HIV enters CD4 T lymphocytes, after sensing the protease of HIV, it activates the Card8 molecule, and then forms the Card8 inflammasome complex, causing rapid pyroptosis of CD4 T cells. At the same time, it was found that activated CD4 T cells could weaken the function of Card8 and limit HIV infection to a certain extent. These important findings suggest that CD4 T cell pyroptosis caused by CARD8 inflammasome is a novel pathway for CD4 T cell reduction after HIV infection. Antiviral** drugs can be designed against the relevant targets, so the above findings are clinically significant. In the meantime, there are still some questions that deserve further attention**: Similar to the CARD8 inflammasome, CD4 T cells can also cause pyroptosis via NSDMD activation mediated by the NLRP1 pathway after HIV-1 infection, and what is the relationship between the two? Which way is the main one? Are there mutations in the Card8 domain among the people who receive ART in people living with HIV, as well as in different populations such as elite controllers and failed immune reconstitution? Further research is needed on the physiological role of card8 inflammasome and its role in the process of immune reconstitution of AIDS patients receiving antiviral**. Original link:
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