Apoptosis, also known as type I programmed cell death, is a fundamental biological process in the organism that is not accompanied by inflammation or damage to surrounding tissues; apoptosis is involved in embryonic development, hormone regulation, inflammation and tumorigenesis. Abnormal regulation of apoptosis can disrupt the balance between cell proliferation and death; a decrease in apoptosis can lead to the development of malignant tumors or autoimmune diseases; conversely, an increase in apoptosis leads to neurodegenerative pathologies or immunosuppression. Therefore, maintaining the balance of the apoptotic system is of great importance in the physiological processes of the organism.
Various physiological and pathophysiological factors can promote apoptosis, which is an energy-dependent process that uses the activation of a series of cysteine protease caspases leading to the apoptotic signaling pathway. Depending on the external stimuli, apoptotic signaling is divided into the endogenous pathway or mitochondrial pathway, which is designed to involve members of the Bcl-2 protein family and mitochondrial proteins, and the extrinsic pathway, which is mediated by The latter is mediated by extracellular stimulus signals via Death Receptors (DR). Autophagy, also known as type II programmed cell death, is a highly conserved cell death mechanism that leads to cell survival and death when cells reduce damaged organelles or intracellular components through autophagy in a starved state, a complex mechanism. Apoptosis and autophagy are not mutually exclusive and the two regulators of cell signaling pathways coordinate with each other.
External antigen stimulation of the body’s immune system induces proliferation of antigen-specific lymphocytes to clear pathogens, and apoptosis plays an important role in terminating the acquired immune process, a process that includes: Naïve T cells proliferate and differentiate into effector T cells in response to antigen stimulation; most of the differentiated effector cells enter a depleted state to prevent the development of autoimmune disease; a few T cells act as memory cells survive to function. The apoptotic process reduces activated T cells and terminates the immune response, becoming activation-induced cell death (AICD).
Different pathogens affect the cell death signaling pathway in different ways. Human immunodeficiency virus (HIV) can induce apoptosis in immune cells, especially CD4+ T cells, and the mechanisms involved in apoptosis by HIV are reviewed in this paper.
1. Structure of HIV-1.
HIV-1 is a retrovirus and a member of the lentivirus family. Lentiviral infection usually manifests as a chronic disease process, long-term clinical latency, sustained virological replication, and central nervous system involvement. Monkey immunodeficiency virus (SIV) and feline immunodeficiency virus (FIV) are typical examples of lentiviral infections. HIV-1 and HIV-2 are extremely similar under electron microscopy, but their protein molecular weights and accessory genes are completely different. HIV-2 is genetically closer to SIV found in white-lidded monkeys than HIV-1, and therefore, it can be hypothesized that HIV may have been transmitted from monkeys to humans. Both HIV-1 and HIV-2 can replicate in CD4 cells and are pathogens that cause disease in infected individuals.
HIV-1 virus particles are 100 nm in diameter and are surrounded by a lipoprotein membrane. Each viral particle contains 72 glycoprotein complexes, which are integrated into the lipid membrane. Each glycoprotein complex consists of a trimer of the extrinsic glycoprotein gp120 and the transmembrane protein gp41. gp120 and gp41 are loosely bound and can be spontaneously shed in the local environment, and glycoprotein gp120 is detected in serum and lymphoid tissue of HIV-infected patients. During viral outgrowth, it also binds different host proteins such as HLA-I or II on the host cell membrane to its own lipoprotein layer, or binds the adhesion protein ICAM-I to induce viral adsorption to other target cells. The matrix protein p17 is distributed on the inner side of the viral lipoprotein membrane and p24 viral protein contains two copies of HIV-RNA; HIV-1 viral particles also include enzymes required for viral replication, such as reverse transcriptase RT, integrase p32, and protease p11.
The typical retroviral genome structure contains mainly 5- and 3-long terminal repeat sequences (LTR), gag, pol, and env genes. Long terminal repeat sequences are the two ends of the viral genome that do not encode viral proteins and are linked to host cell DNA upon integration of viral DNA into the host cell genome. env and gag genes encode viral cytosolic glycoproteins and nucleocapsids; pol gene encodes reverse transcriptase and other enzymes. In addition, six genes are included in the HIV genome, namely vif, vpu, vpr, tat, rev, and nef.
The Tat and rev proteins are regulatory proteins that bind to specific regions of viral RNA in the nucleus, and both are transactivation response elements for the LTR and for the viral cytosolic glycoprotein gene env, respectively. tat protein is a transactivation element necessary for viral replication in in vitro culture systems and is a potential transcription factor for the LTR promoter region. The cell cycle regulatory protein T1 is a cellular cofactor essential for Tat. tat and rev proteins stimulate transcription of HIV-1 proviral DNA into RNA, initiate RNA elongation, and facilitate HIV RNA translocation from the nucleus to the cytoplasm.
Vpr proteins are required for HIV virus replication in non-dividing cells; current studies show that vpr proteins block cell cycle arrest in the G2 phase; they also translocate viral pre-integration complexes into the nucleus.
Nef proteins have multiple functions within the cell. Studies have shown that Nef proteins induce downregulation of CD4 and HLA-I molecule expression on the surface of HIV-1 infected cells. Nef proteins bind to many signaling pathway proteins and interfere with T-lymphocyte activation. Additional studies have shown that Nef gene deletion delays viral replication but does not prevent AIDS production.
Vpu protein is involved in HIV viral outgrowth. vpu gene mutations cause HIV viral particles to remain on the host cell surface. vpu is involved in the degradation of the CD4-gp120 complex in the endoplasmic reticulum, allowing gp160 to enter recirculation and form new HIV virions.
Vif protein plays an important role in HIV replication. vif-deficient HIV viruses cannot replicate in CD4+ T cells and macrophages, i.e. they cannot replicate in these “non-permissive” cells, while wild strains containing vif genes can replicate in these cells. Studies have shown that HIV replication is executed by the presence or absence of a cellular repressor, the endogenous APOBEC3G, which is an intracellular RNA editing enzyme that deaminates cytosine in mRNA to form uracil, leading to the accumulation of G and A mutants and consequently to the degradation of viral DNA. vif blocks the inhibitory activity of APOBEC3G by binding to APOBEC3G to form a complex. In the absence of vif, APOBEC3G integrates into newly formed viral particles and subsequently blocks proviral DNA formation in infected target cells; in the presence of vif protein, APOBEC3G binds to vif protein and is degraded by the ubiquitination system and fails to integrate into newly formed viral particles. The above findings suggest that APOBEC3G is a cellular self-protection mechanism, but vif is a protein that HIV virus counteracts the function of APOBEC3G, resulting in HIV virus evading the process of intracellular self-clearance.
2. HIV virus and immune cell apoptosis.
HIV virus infects immune cells, leading to a gradual decrease in CD4+ T cells, a gradual decline in the body’s immune function, and various opportunistic infections. the HIV envelope protein Env and immune cell surface CD4 molecules bind, leading to the replication of HIV virus in CD4 cells, resulting in eventual cell death. Mature CD4+ Th cells are key effector cells in the antiviral immune response, and the HIV-associated immune deficiency was previously thought to be the result of virus-mediated killing of CD4+ T cells, but this view is considered too simplistic in light of the current understanding of the mechanism of CD4+ T cell reduction. Several hypotheses have been proposed for the reduction of CD4+ T cells due to HIV: these include the production of damage to T cells in the thymus and the homing of virus-specific T lymphocytes in lymphoid tissue, which alters the proliferative balance of CD4+ T cells and leads to HIV-induced apoptosis. There is growing evidence that HIV-induced lymphocyte apoptosis is an important cause of immune system destruction due to HIV infection. Because of the continuous replication of HIV viral particles, HIV infection leads to an accelerated rate of T-cell renewal in vivo, resulting in accelerated T-cell multiplication, the latter controlling T-cell numbers by increasing apoptosis under normal physiological conditions. In addition, HIV leads to immune evasion by triggering apoptotic mechanisms in cells; the molecular mechanisms of HIV immune evasion include rapid viral mutation and down-regulation of host cell MHC molecule expression.
Molecular mechanisms of HIV-associated lymphocyte apoptosis include: direct killing of infected target cells by HIV virus; bystander cell death due to pro-apoptotic viral proteins released from infected cells; killing of HIV-specific effector cells after recruitment to infected lymphoid tissues; and alteration of intracellular apoptosis regulatory molecules.
Apoptosis is an important form of cell death that is regulated by the apoptotic cell signaling pathway, which is an important way to maintain lymphocyte homeostasis in vivo. In addition, in the immune response against foreign antigens, apoptosis requires a reduction in the majority of antigen-specific T cells in order to block the autoimmune response. Apoptosis is accomplished through two major transduction pathways: Activation-induced cell death (AICD), which is mainly mediated by death receptors (exogenous signaling pathway), and activated T-cell autonomous death (ACAD). The latter is mediated by BCL-2-related proteins (endogenous signaling pathway). The exogenous apoptotic signaling pathway is triggered by the binding of tumor necrosis factor family death receptors and their ligands; the endogenous apoptotic signaling pathway is triggered by intracellular receptors conducting signals to mitochondria.
After acute HIV infection, CD4+ T-cell lesions result in “ballooning”, formation of syncytia and apoptosis of infected cells and surrounding bystander cells. gp120-gp41, the HIV genomic cytosolic glycoprotein complex, is the major apoptosis-inducing molecule, causing apoptosis in infected cells and bystander cells. bystander cell apoptosis. Env molecules expressed in the cytosol of infected cells are able to bind to CD4 molecules and cofactors, leading to cell-cell fusion, and the resulting syncytium leads to apoptosis. HIV or SIV induces syncytium, and decreased CD4 cell counts are responsible for the development of AIDS. In lymph nodes of HIV-positive individuals, syncytia express markers of early apoptosis, and apoptosis of syncytia is not mediated by Fas and tumor necrosis factor receptor 1 conductance pathways, but HIV-infected T cells are more sensitive to Fas-mediated apoptosis conductance pathways, and this susceptibility may be induced by HIV products such as vpu. Infected cells expressing Env and cells expressing the CD4-CXCR4 complex fuse to form syncytia, which induce apoptosis via a mitochondria-dependent conductance pathway that is mediated by upregulation of the Cyclin B-CDK1 signaling pathway and the mammalian target of rapamycin (mTOR) nuclear localization is accomplished. This leads to mTOR-mediated phosphorylation of p53 protein serine 15 (p53ser15), upregulation of P53-dependent BAX protein expression and activation of the mitochondrial transduction pathway, i.e. BAX protein inserts into the mitochondrial membrane, releasing cytochrome C and activating the caspase transduction pathway and apoptosis. Some studies have shown increased expression of cyclin B and mTOR molecules in peripheral blood and lymph node cells of HIV-infected patients, with the latter correlating with p53 protein serine 15 (p53ser15) phosphorylation and viral load. Furthermore, when peripheral blood CD4+ T cells were heavily infected with HIV virus in vitro, cell death and necrosis were associated, but not with apoptosis.
In addition to the HIV viral protein Env, several other viral proteins can trigger apoptotic signaling pathways in both infected and non-infected cells. The endogenous conductance pathway is activated by the viral protein vpr, which leads to rapid decay of mitochondrial membrane potential, release of cytochrome c, and apoptosis. tat protein induces apoptosis by downregulating BCL-2 and upregulating caspase-8. In addition, the binding of HIV gp120 and CD4 molecules induced the downregulation of BCL-2 and promoted the release of cytochrome c, thus inducing apoptosis. In addition, activation of caspase-8 by the protease encoded by the HIV genome leads to degradation of BCL-2 protein, resulting in a decrease in BCL-2 levels and thus inducing apoptosis. Current studies show that HIV virus also affects apoptotic exogenous conductance pathways in both infected and bystander cells, with HIV virus gp120 and and CD4+ T cells cross-linking to activate the Fas-FasL conductance pathway; Nef-expressing T cells co-express FasL and become potential killers of HIV-uninfected lymphocytes expressing Fas molecules. Similarly, tat proteins secreted by infected cells upregulate Fas and FasL molecules in non-infected cells, enhancing the susceptibility to Fas-induced apoptosis. In conclusion, HIV virus can control apoptotic mechanisms, leading to disruption of the body’s immune system and favoring immunological evasion of the virus.
Studies have shown that HIV infection can lead to activated T-cell autonomous death (ACAD). peripheral blood T cells from HIV patients show spontaneous apoptosis when cultured in vitro without exogenous stimulation, which is associated with downregulation of BCL-2 expression. Cells expressing low levels of BCL-2 have an activated phenotype in vivo, suggesting that repeated stimulation of T cells in vivo with viral antigens leads to immune activation, altering the physiological balance of activated T cells in vivo and leading to activation of members of the pro-apoptotic BCL-2 protein (pro-apoptotic BCL-2) family. In vivo studies in gorillas show a lack of immune activation in non-pathogenic HIV infection, low levels of spontaneous T cell apoptosis, and normal intracellular BCL-2 protein expression. acad is normally blocked by cytokines, and IL-2 and IL-15 maintain T cell survival in vitro by promoting upregulation of BCL-2 expression.
T lymphocytes in HIV-infected patients can be activated-induced cell death (AICD) in vitro after stimulation with mitogen, superantigen and TCR-specific antibodies. apoptosis induced by the Fas signaling pathway is involved in the AICD process, and CD4+ T and CD8+ T cell surfaces in HIV-infected patients Increased Fas expression in HIV-infected patients increases the susceptibility to Fas-mediated apoptosis, which correlates with disease progression in HIV infection. Soluble Fas protein can be detected in serum, and its level can be used as a serological predictor of AIDS progression.FasL protein is highly expressed on the surface and in the serum of CD4+T and CD8+ T cells in HIV-infected patients; macrophage-associated FasL protein is highly expressed in the lymphoid tissue of HIV-infected patients, which correlates with the level of tissue apoptosis. Apoptosis suppressor protein FLIP expression was reduced after quiescent T cell activation, as activated lymphocytes undergo apoptosis in HIV-infected patients, and therefore it is assumed that reduced expression of apoptosis suppressor protein FLIP correlates with Fas-induced lymphocyte apoptotic susceptibility.
In HIV-infected patients, the tumor necrosis factor TNF signaling pathway is involved in lymphocyte apoptosis. Although earlier reports showed that peripheral blood T cells of HIV-infected patients are tolerant to TNF signaling pathway-induced apoptosis, recent reports have shown susceptibility to apoptosis induced by TNFR1 and TNFR2 in CD4+ T and CD8+ T cells, and this apoptotic transmission pathway and TNFR1-associated death domain (TRADD), receptor domain (TRADD), Receptor-interacting protein (RIP), and TNFR-associated factor 2 (TRAF2) expression, but is associated with the downregulation of BCL-2 expression. During apoptosis, death receptor cross-linking leads to the activation of a series of caspase proteins, including apoptosis initiator caspase-8 and effector caspase-3. Both of these active forms of caspase proteins are expressed in CD4+T and CD8+T lymphocytes of HIV-infected individuals, the latter being induced in vitro by a variety of different HIV-encoded proteins, such as Tat, Env, Nef, and Vpr; another caspase protein, ICE, is also detectable in CD4+T cells of HIV-infected individuals. Studies have shown increased caspase-3 activity in patients with progressive HIV infection, suggesting a correlation between in vivo caspase expression and HIV pathogenesis. Studies have shown that TNFR-mediated apoptosis is involved in the apoptosis of CD8+ T cells, and that the binding of HIV viral Env protein and CXCR4 molecules upregulates TNFR2 expression, leading to apoptotic susceptibility of CD8+ T cells. In HIV patients, serum TNF levels are significantly elevated and serum soluble TNFR2 levels can be elevated, and the latter can be used as a predictive marker for HIV disease progression. TRAIL is another TNF-related apoptosis-inducing ligand that is also involved in HIV-associated T-cell apoptosis, and studies have shown that T cells in HIV-infected patients are susceptible to TRAIL-mediated apoptosis; when using The function of TRAIL antibodies antagonizing TRAIL inhibits activation-induced cell death.
In HIV-infected patients, CD4+ T cells upregulate FasL protein expression through HIV infection and viral proteins such as gp120, tat and nef, which can turn into killer cells for Fas-expressing cells. In vitro studies have shown that FasL-expressing CD4+ T cells can kill Fas-expressing CD8+ T cells; FasL-expressing macrophages are also potential killers of Fas-expressing T cells, and this killing is not controlled by MHC molecules. Notably, macrophage-mediated killing mainly selects uninfected bystander T cells; HIV-specific CTL are potential killers of Fas-expressing activated lymphocytes. In HIV-infected individuals, viral protein Nef-specific CTL can mediate perforin- and Fas-mediated cytotoxic activity. Thus, certain HIV-specific effector cells are deleterious to the immune system of HIV-infected individuals, primarily infected cells by expressing FasL, which performs killing of HIV-uninfected, Fas-expressing lymphocytes, a situation that persists in the HIV-infected immune system.
3. Role of apoptotic proteins in HIV infection.
During apoptosis, many proteins are involved in the onset of apoptosis, and three of the death-inducing ligands have important roles in the onset of apoptosis, including TNF, FasL and TRAIL.
Fas/FasL has an important role in the immunopathogenesis of HIV infection. The levels of soluble and cytosolic-linked Fas/FasL are significantly higher in infected patients compared to HIV-uninfected patients, which correlates with AIDS disease progression. In HIV-infected patients, Fas molecule expression was increased in CD4+ T and CD8+ T cells; FasL expression was increased on the surface of monocytes-macrophages, Nk cells, both of which occur in the peripheral circulation and lymph nodes. Gene microarray analysis revealed increased Fas/FasL expression in HIV-infected lymph nodes. Compared to uninfected cells, HIV-infected cells were more sensitive to Fas-mediated apoptosis, but did not constitute a major part of apoptosis in vivo. In HIV-infected patients, the majority of circulating apoptotic peripheral blood mononuclear cells do not express Fas; HIV-infected macrophages induce apoptosis in T cells in HIV-infected patients, but not in non-infected patients, suggesting a “bystander” effect hypothesis, that is, the apoptosis occurring in HIV-infected The apoptosis that occurs in HIV infection involves non-infected cells in the lymphoid tissue that respond to the infection. Studies have shown that CD4+ T cells in HIV-infected chimpanzees do not induce apoptosis through Fas/FasL binding; however, CD4+ T and CD8+ T cells in chimpanzees infected with SIV virus express Fas molecules, and T and B cells express increased FasL on their surface. In nonprogressive HIV-infected individuals peripheral blood soluble Fas proteolysis is lower, lymphocytes expressing Fas/FasL molecules are reduced, and Fas molecule sensitivity is decreased. A study showed alleviation of disease progression in the acute phase of SIV infection after blocking the Fas conduction pathway using a monoclonal antibody to FasL.
The pathogenesis of TNF-α in HIV infection and related complications, particularly in HIV viral replication and in mediating CD4+ T cell apoptosis, has been extensively studied. Several studies have shown that inhibition of the TNF-α conduction pathway did not reveal a significant immunological advantage against HIV virus; instead, several experiments found significant side effects, including increased viral load. In addition, clinical trial results show that recombinant TNF-α has significant toxic side effects and cannot be used as a method to clear latent HIV.
TRAIL, a member of the TNF superfamily, mediates apoptosis of CD4+ T cells in HIV infection and functions in both infected and non-infected T cells by interacting with death receptors DR4 and DR5. Dendritic cell and macrophage HIV infection leads to increased TRAIL expression, which induces apoptosis in non-infected bystander T cells. Compared to non-infected patients, peripheral blood TRAIL serum concentrations were increased in HIV-infected bystanders with increased expression of the monocyte death receptor DR5. Expression of TRAIL by plasma cell-like dendritic cells in peripheral blood of HIV-infected bystanders induced apoptosis of CD4+ T cells in uninfected but not in HIV-infected bystanders. Increased TRAIL and DR5 expression was found in lymphoid tissues of HIV-infected individuals; reduced levels of free TRAIL in peripheral blood and reduced expression of TRAIL and DR5 by CD4+ T cells were found after HAART treatment initiation. However, reduced TRAIL expression was found in lymphoid tissues of HIV-infected patients after HAART treatment initiation, but no reduction in DR5 expression was observed.
In vitro studies showed that treatment of HIV-infected patients’ macrophages with recombinant TRAIL protein showed a significant reduction in HIV viral levels, suggesting that recombinant TRAIL protein may be a therapeutic approach for HIV infection. Monoclonal antibodies to recombinant TRAIL protein and DR4 and DR5 are currently used in phase I and phase II clinical trials for tumor therapy by inducing apoptosis of tumor cells. Theoretically, immunological treatment of HIV-infected patients with recombinant TRAIL protein is able to kill HIV-infected cells, but bystander CD4+ T cells can also undergo apoptosis; in vitro studies have shown that treatment of HIV-infected patients with PBL using recombinant TRAIL protein resulted in a decrease in the number of HIV viruses, but no changes in the number or function of lymphocytes were found.
The body’s immune system is stimulated by new antigens, and previously activated, other antigen-specific immune cells are reduced. The mechanism includes apoptosis of activated immune cells, known as activation induced cell death (AICD). Chronic activation of the immune system during HIV infection is characterized by generalized lymph node enlargement, increased levels of B-lymphocytes, activated T-lymphocytes, NK cells, antigen-presenting cells, and hypergammaglobulinemia. Studies have shown that chronic immune activation occurs during HIV infection, such as a decrease in circulating activated monocytes (HLA-DR+), activated CD8+ T cells (CD38+) and CD4+ T cells and disease progression of HIV infection. Chronic immune stimulation leads to CD4+ T cell AICD through Fas-dependent and independent mechanisms. during HIV infection, AICD is not limited to CD4+ T cells, but also acts on CD8+ T cell depletion, which is associated with the expression of programmed death 1 (PD-1) by activated CD8+ T cells during HIV infection. .
The sources of chronic immune stimulation during HIV infection are diverse and include, among others, persistently replicating viruses, circulating HIV proteins, opportunistic infectious agents and reactivation of other infectious agents; a decrease in absolute regulatory T cell counts is associated with chronic immune activation during disease progression of HIV infection. Recent studies have shown that depletion of CD4+ T cells in the gastrointestinal tract leads to microbial relocalization and increased microbial components in the circulation, including endotoxins, bacterial DNA, etc., which are associated with HIV disease progression. Systemic circulation of microbial products leads to activation of Toll-like receptor signaling pathways that promote AICD of gastrointestinal CD4+ T cells, resulting in a decrease in CD4+ T cells. Systemic circulation of microbial products also inhibits T cell proliferation and function through upregulation of PD-1 expression and IL-10 production.
4. HIV proteins and apoptosis.
Gp120 is a glycoprotein expressed by the HIV genome on the HIV plasma membrane that attaches to the CD4 receptor and CXCR4 or CCR5 co-receptors, facilitating viral attachment and entry into cells. Membrane-bound and soluble gp120 and CD4 receptors bind, leading to apoptosis of infected and uninfected CD4+ T cells. Studies have shown multiple mechanisms involved in gp120-induced apoptosis of CD4+ T cells: upregulation of Fas, FasL and TNF-α expression, molecular mimics of Fas, upregulation of TRAIL, DR4 and DR5 expression, induction of cell cycle arrest in G2 phase, production of reactive oxygen radicals, reduced BCL-2 expression, mTOR and p53 protein phosphorylation, proapoptotic protein increased expression of PUMA, and activation of P38 protein. Although it is not clear which mechanism plays a major role in HIV infection in vivo, what is clear is that the gp120 molecule is pluripotent and can induce apoptosis in CD8+ T cells, vascular endothelial cells, neuronal cells, cardiomyocytes, renal tubular cells, hepatocytes, etc.
Tat is a trans-activating protein of HIV that promotes transcription of HIV long terminal repeat sequences and is pleiotropic in the apoptosis of CD4+ T cells. tat protein is produced early in the viral life cycle and can be secreted by HIV-infected cells and taken up by non-infected cells through clathrin-mediated endocytosis. Studies have shown that Tat protein can exert apoptotic and anti-apoptotic effects in vitro depending on the cells used, the endogenous expression vector, and the dose of tat protein applied. Treatment of uninfected Jurkat T cells with low doses of tat protein resulted in tolerance to apoptosis induced by TNF, Fas, and TRAIL molecules, and reduced caspase 10 expression and increased Bcl-2 and c-FLIP expression. Treatment of uninfected T cells and mononuclear cells with high doses of tat protein increased the expression of Fas, caspase 8, Bax and RCAS-1 molecules and promoted apoptosis. tat protein also attached to intracellular microtubules, leading to their alteration and Bim-mediated mitochondria-dependent apoptosis. The mechanism of Tat induction or inhibition of apoptosis in HIV-infected patients is not yet understood. Tat is present in the body at anti-apoptotic serum concentrations; treatment of monocytes and macrophages of HIV-infected patients with Tat protein results in upregulated expression of TRAIL molecules, which induce apoptosis in uninfected “bystander” T apoptosis; however, chimpanzee T cells treated with tat protein antagonize tat-mediated apoptosis.
Vpu is a helper protein encoded by the HIV genome that downregulates CD4 receptor expression, prevents further infection of infected CD4+ T cells, and allows newly generated virus to “bud” in the cytosol. High expression of Vpu protein in Jurkat T cells leads to increased susceptibility to Fas-mediated apoptosis, which is associated with the suppression of intracellular NF-κB-mediated anti-apoptotic gene expression in HIV-infected cells expressing Vpu molecules. Removal of the Vpu component from the HIV viral structure NL4-3 reduced CD4+ T cell depletion. It was shown that Vpu proteins from different HIV viral subtype sources have different CD4+ T cell depletion rates.
The Nef protein is a multifunctional protein encoded by the HIV viral genome that is mainly expressed early in the viral life cycle and is responsible for downregulating the expression of CD4 receptors and MHC-I molecules while enhancing viral replication. T cells expressing the Nef protein upregulate Fas and FasL molecules, decrease Bcl-2 and Bcl-XL expression, increase PD-1 molecule expression, and induce apoptosis through caspase-dependent and independent pathways. Nef proteins produced by infected CD4+ T cells cause increased lysosomal permeability and release cathepsin D into the cytoplasm, which subsequently leads to rupture of the outer mitochondrial membrane.Nef molecules acting on uninfected CD4+ T cells can lead to apoptosis by a mechanism that is not yet understood but may be related to CXCR4 and SDF-1α action.
5. Immune cell apoptosis and immune damage.
5.1 CD4+ T-cell apoptosis and immune injury in.
CD4+ T cells are usually considered to be helper T cells of the immune system, facilitating the production of humoral and cellular immunity and promoting the production of antibodies and CD8+ CTL. upon encountering antigens, T helper cells differentiate into effector cells, which secrete high levels of γ-IFN, IL-4, IL-10 and other immunomodulatory molecules. the most striking feature of HIV infection is the lack of HIV-specific CD4+ T cells. The proliferation of HIV-specific CD4+ T cells that occurs after anti-retroviral therapy controls viral load confirms the important role of CD4+ T effector cells; this also confirms the rapid loss of HIV-specific CD4+ T cell responses during the acute phase of HIV infection. Several mechanisms could explain this loss: HIV-specific CD4+ T-cell precursors are destroyed in lymph nodes after HIV viral binding to the homing receptor CD62L; when natural CD4+ T-cell precursors are recruited to infected lymphoid tissue, they are killed under the guidance of HIV-infected dendritic cells. Thus, during acute HIV infection, rapidly proliferating HIV-specific CD4+ T memory cells are highly susceptible to HIV infection, and they carry more viral DNA than other memory CD4+ T cells, suggesting that HIV preferentially infects CD4+ T cells, leading to subsequent preferential destruction; destruction of activated HIV-specific CD4+ T effector cells is mediated by FasL and Low levels of HIV-specific CD4+ T cells in HIV-infected patients are associated with high levels of viremia, their “inability” to interact with peripheral blood dendritic cells or their suppression by CD4+CD25+ regulatory T cells. The “incompetence” is related to the suppression of peripheral blood dendritic cell interaction or by CD4+CD25+ regulatory T cells.
T cells are differentiated into two major classes during the immune response: Th1 cells, which secrete mainly γ-IFN, and Th2 cells, which secrete IL-4, and Th1 cells have an important role in the antiviral CTL response. Many cytokines influence the transformation of Naïve T cells into Th1 cells, such as IL-12 and γ-IFN, the former derived from pathogen-activated macrophages or dendritic cells, and the latter from pathogen-activated NK cells, which are important for Naïve T cell differentiation. HIV infection induces changes in cytokine secretion patterns. The progression of HIV infection is accompanied by a decrease in IL-2, IL-12 and γ-IFN secretion by peripheral blood mononuclear cells and an increase in IL-4 and IL-10 secretion, which are pointers to a decrease in CD4+ T cells and disease progression. analysis of peripheral blood T cells from HIV-infected patients after stimulation in vitro and short-term culture showed a significant decrease in IL-2 secreting T cells and an increase in γ-IFN producing γ-IFN-producing T cells persisted throughout the course of HIV infection. Among the different Th1 cell subclasses, certain subclasses were susceptible to activation-induced cell death (AICD), which is regulated by cellular expression of BCL-2 protein. The progressive reduction of IL-2 producing T cells correlates with both susceptibility to apoptosis and disease progression. These findings suggest a correlation between increased peripheral blood Th cell AICD and HIV-specific immune damage during HIV infection.
5.2 Altered differentiation of CD8+ T cells.
In HIV-infected patients, HIV stimulates the production of a strong CD8+ CTL response. During acute infection, CTL responses and viral load in peripheral blood increase; when CTL responses peak, viral levels decrease; during chronic infection, a negative correlation between CTL responses and viral load is found. cd8+CTL has an important role in the control of HIV viremia, and studies in chimpanzees show that depletion of CD8+ T cells after SIV infection leads to CD8+ T-cell depletion also failed to control HIV infection. In vitro analysis of virus-specific CTL showed that HIV-specific deficiencies in CTL function impaired its ability to control the virus. Although HIV-specific CD8+ CTL produce antiviral molecules such as γ-IFN and CCL4, the vast majority of CTL express low levels of perforin and fail to effectively kill target cells. altered CTL differentiation is associated with increased apoptosis, and differentially differentiated CD8+ CTL subclasses have different susceptibilities to Fas-induced apoptosis; the poor cytokine environment in vivo is detrimental to cell survival. In addition, the failure of CTL to control HIV infection is also related to immunoregulatory T cells, as studies have shown that HIV antigen induces TGF-β secretion by regulatory CD8+ T cells (Regulatory CD8+T) and reduces the γ-IFN response of HIV-specific CD8+ T cells. Therefore, activation-induced cell death (AICD) and inhibitory cytokines are important mechanisms of differentiation defects of CD8+ CTL.
6. T-cell apoptosis and AIDS disease progression.
Studies in HIV-infected patients and animal models of SIV infection have shown a correlation between the intensity of T-cell apoptosis and the progression of AIDS. First, the level of T-cell apoptosis was lower in those with long-term progression-free HIV infection; second, studies in West Africa showed that HIV-2 infection, which is less pathogenic than HIV-1, exhibited low levels of immune activation and reduced T-cell apoptosis; third, when comparing HIV-1 and HIV-2 viral infections with similar CD4+ T-cell depletion found that immune activation and CD4+ T-cell depletion were correlated; fourth, when comparing animal models of lentiviral infection with control animal models found that lymphocyte apoptosis occurred in animal models of lentiviral infection. Studies in animal models of chimpanzee SIV infection showed a progressive decrease in CD4+ T cells associated with high viral load, high immune activation and increased CD4+ T cell apoptosis. Studies in mouse research models have shown an important role for chronic immune activation in T cell immunodeficiency. The construction of transgenic mice expressing CD70 molecules, which can be consistently expressed in response to antigenic stimulation, can produce clinical features similar to HIV infection, i.e., progressive conversion of Naïve T cells to effector T cells, leading to depletion of the Naïve T cell pool and eventual apoptosis due to opportunistic infection. In conclusion, the above experimental results provide further evidence that chronic immune activation may be the main cause of abnormal CD4+ T cell function and apoptosis, the main pathological molecular mechanism of AIDS progression.
7. Virological evasion of apoptosis.
Inhibition of apoptosis favors the production of daughter HIV viral particles, and several HIV viral gene products have anti-HIV viral activity. nef, gp120, and Vpu proteins favor downregulation of CD4 molecule expression in HIV-infected cells and prevent gp120-CD4 molecule-mediated apoptosis. nef proteins downregulate MHC-I molecule expression and upregulate fasL molecule expression, a strategy protects infected cells from being killed by CTL and NK cells. Low expression of the viral protein Vpr caused upregulation of BCL-2 expression and downregulation of BAX, thereby inhibiting apoptosis. tat protein reduced TP53 protein transcription, promoted cell cycle progression, inhibited apoptosis, and contributed to the production of large numbers of viral particles by infected cells. In the lymph nodes of HIV-infected patients, in vivo apoptosis occurred mainly in non-infected bystander cells, suggesting an indirect molecular mechanism of apoptosis; it also suggested the presence of apoptotic CD8+ CTL, B cells and dendritic cells in the lymphoid tissue of HIV-infected patients. In contrast, HIV-infected cells are less susceptible to apoptosis, suggesting tolerance to HIV-induced cell killing. Thus, the HIV virus ensures its own survival by controlling apoptotic mechanisms before they are activated leading to the destruction of the immune system.