Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A previous report from this laboratory described the production of CD8+, class I-specific T cell hybridomas which developed specific cytolytic activity and the ability to secrete IL-2 upon Con A or specific Ag stimulation. Unlike normal lymphocytes or long-term CTL lines for which exposure to Ag triggers both differentiation and proliferation, T cell hybridoma lines can be activated functionally against a background of continuous proliferation. They therefore provide a unique system with which to study the molecular events involved in the induction of cytolytic function. The expression of mRNA from a series of genes was evaluated by Northern hybridization at various times after Con A stimulation of the H-2Ld-specific CD8+ 3D9 hybridoma. Induction of the c-fos proto-oncogene by 45 min poststimulation was followed shortly by c-myc induction. Perforin mRNA was expressed at a low level in the unstimulated hybridomas, but was down-regulated upon Con A stimulation to levels undetectable by PCR. Interestingly, production of granzyme A mRNA was strongly induced by 45 min after Con A stimulation. In the CD8+ RT-1.3G3 hybridoma, which is nonlytic and specific for the HIV-1 envelope glycoprotein, c-fos but not granzyme A mRNA was induced by 45 min poststimulation, and no granzyme A mRNA was detectable at any time. Thus, a significant role for granzyme A in the induction of cytolytic activity is suggested. Cytolysis by the 3D9 hybridoma involved both target cell membrane damage and DNA fragmentation, and both Ca(2+)-dependent and Ca(2+)-independent cytolysis were observed. Although TNF-alpha mRNA was induced by 4 h poststimulation, Ab to TNF-alpha failed to inhibit the Ca(2+)-independent lysis observed, leaving the basis for the observed Ca(2+)-independent lysis unexplained.
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PMID:Induction by concanavalin A of specific mRNAs and cytolytic function in a CD8-positive T cell hybridoma. 796 18

Cytotoxic CD8+ lymphocytes (CTLs) kill virally infected target cells by releasing cytotoxic granules. The primary objective of this study was to determine whether the activity of granzyme A, a serine protease in the killing granules of CTLs is altered in HIV-infected hemophiliacs. A sensitive colorimetric assay that measures cleavage of a synthetic substrate, N alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester (BLT), was used to quantitate granzyme A activity. Granzyme A activities from hemophiliacs were normalized to to granzyme A activities of healthy donors run concurrently. Granzyme A activity in CD8+ T cells from HIV-seropositive hemophiliacs was significantly lower than granzyme A activity in cells from HIV-seronegative hemophiliacs (0.48 units +/- 0.086/CD8+ T cell and 1.573 +/- 0.434 units/CD8+ T cell, respectively; p < 0.005). These results indicate that cytotoxic cells in HIV-infected hemophiliacs have reduced granzyme A activity, which may result in a defect in CTL-mediated cell killing in these patients.
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PMID:Activity of granzyme A, a serine protease in the killing granules of cytotoxic T lymphocytes, is reduced in cells from HIV-infected hemophiliacs. 883 2

Activated CTLs and NK cells induce apoptosis via multiple mechanisms, including that termed granule exocytosis. The latter pathway consists of vectorial secretion of perforin and a family of granule-associated serine proteases (granzymes) to the target cell. To establish whether granzymes are released extracellularly during cytolytic reactions in vivo, ELISAs that measure the native enzymes were developed and were found to specifically detect granzyme A (GrA) and granzyme B (GrB) at picogram concentrations. Low levels of GrA and GrB were present in plasma of healthy individuals (GrA, 33.5 pg/ml (median); GrB, 11.5 pg/ml (median)), whereas significantly higher levels were present in patients with ongoing CTL response, i.e., patients suffering from infections by EBV or HIV type 1. Markedly elevated levels were also noted in synovial fluid of patients with active rheumatoid arthritis. The measurement of soluble granzymes should be useful to assess clinical disorders associated with activated CTL and NK cells. Furthermore, these results suggest that granzymes mediate biologic effects beyond their described role in apoptotic cell death.
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PMID:Extracellular granzymes A and B in humans: detection of native species during CTL responses in vitro and in vivo. 953 25

Granzymes are a family of serine proteinases commonly found in the granules of CD8+ T cells. In HIV infection, CD8+ cells show cytotoxic and noncytotoxic antiviral activities. The latter is mediated, at least in part, by a secreted CD8+ cell antiviral factor, CAF. Because of the antiviral nature of CD8+ cells, we examined the potential anti-HIV activity of free granzymes that can be found in CD8+ cell culture fluids. Pretreatment of CD4+ T cells with granzyme A or granzyme B had no effect on their susceptibility to infection with HIV, nor did incubation of the granzymes with HIV virions alter their infectivity. Continuous culture of acutely infected CD4+ T cells with granzyme A or B showed no effect on cell viability or the replication of HIV. The findings of this study suggest that free granzymes do not control HIV infection and spread in CD4+ T cells.
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PMID:HIV virions and HIV infection in vitro are unaffected by human granzymes A and B. 1071 74

Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocyte (CTL) responses are detectable shortly after the acute phase of HIV infection, but they cannot control viral replication and prevent development of chronic immune suppression. This article describes a defect in the coexpression of perforin in granzyme A-positive CD8(+) T cells in lymphoid tissue from patients with acute HIV infection and a reduction in the perforin-dependent nuclear translocation of granzyme A. Furthermore, intracellular levels of HIV DNA and RNA found in lymphoid tissue were higher (10-100 times) than those found in blood, and blood samples showed more-coordinated cellular perforin/granzyme A expression. This suggests that mechanisms inhibiting CTL-mediated cytotoxicity are operative in lymphoid tissue early in the course of HIV infection.
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PMID:Low levels of perforin expression in CD8+ T lymphocyte granules in lymphoid tissue during acute human immunodeficiency virus type 1 infection. 1200 Oct 57

Despite the frequency of HIV-specific CD8 T cells, most HIV-infected patients do not control viral replication without antiviral drugs. Although CD8 T cells are important in containing acute HIV and simian immunodeficiency virus (SIV) infection, CD8 T-cell functions are compromised in chronic infection. To investigate whether functional deficits are specific to HIV, the phenotypic and functional properties of HIV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV)-specific CD8 T cells, labeled with HLA A2.1 or B8 tetramers, were compared in 35 HIV-infected and 9 healthy donors. Cytotoxic T lymphocytes express the cytolytic molecules perforin and granzymes, and are thought to be CD45RA(+)CD27(-). Although most HIV- specific cells are antigen experienced and express granzyme A (median, 85%), few express high levels of perforin (median, 10%) or CD45RA (median, 14%) or have down-modulated CD27 (median, 12%). Perforin expression by HIV-specific cells is not significantly different from that of EBV- or CMV-specific cells in the same donors or in healthy donors. EBV- and CMV-specific cells, like HIV-specific cells, are often not cytotoxic when tested directly ex vivo. HIV-specific T-cell expression of other phenotypic markers is similar to that of EBV- and CMV-specific CD8 T cells in healthy donors. However, CMV-specific cells (and, to a lesser extent, EBV-specific cells) in HIV-infected donors are more likely to be CD27(-), CD45RA(+), and GzmA(+). These results suggest that the chance to eradicate an infection by T-cell-mediated lysis may be undermined once an infection becomes chronic. Impaired antiviral cytotoxicity during chronic infection is not specific to HIV but likely represents the immune response to chronic antigenic exposure.
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PMID:Most antiviral CD8 T cells during chronic viral infection do not express high levels of perforin and are not directly cytotoxic. 1239 40

Because GALT is a major portal of entry for HIV-1 and reservoir for viral replication, we hypothesized that an ineffective cellular immune response in intestinal mucosa might partially explain the failure of immune control in AIDS. In this study, we demonstrate that the vast majority of CD8+ T cells in rectal tissue, including HIV-1-specific cells, fail to express the cytolytic protein, perforin. However, rectal CD8+ T cells do express granzyme A, and are also capable of releasing IFN-gamma upon stimulation with cognate peptide. Confocal microscopy showed that granzyme A was located in intracellular granules in the absence of perforin. The majority of rectal CD8+ T cells exhibit an effector memory phenotype, expressing CD45RO but not CCR7. Quantitative real-time PCR analysis demonstrated that perforin RNA is expressed in rectal CD8+ T cells from healthy and HIV-1-positive individuals. In HIV-1-positive individuals, similar amounts of perforin RNA were detected in CD8+ T cells from rectal tissue and PBMC, despite a relative absence of perforin protein in rectal tissue. These findings demonstrate an important difference in perforin expression between CD8+ T cells in blood and mucosa. Furthermore, the relative absence of armed effector cells may serve to protect the integrity of rectal mucosa under normal conditions, but might also provide an early advantage to HIV-1 and other sexually transmitted viruses.
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PMID:Abundant expression of granzyme A, but not perforin, in granules of CD8+ T cells in GALT: implications for immune control of HIV-1 infection. 1521 Aug 27

The observation that HIV-1 replication is concentrated in lymphoid follicles (F) compared to extrafollicular (EF) lymphoid tissue is not fully understood. The purpose of this study was to quantify HIV-1 replication in these compartments and evaluate the hypothesis that heightened replication in F occurs because of diminished antiretroviral mechanisms. In situ hybridization for HIV-1 RNA and immunohistochemical staining for CD4, CD8, CD20, and multiple antiretroviral proteins was performed in lymph nodes from 15 HIV-1-infected individuals who were not receiving antiretroviral therapy. A median of 70% of virus-producing cells were detected in F, defined morphologically by CD20 staining, although only a minority of tissue (median, 19%) consisted of F. Frequencies of virus-producing cells were higher in F (median, 1.35 cells/mm2) compared to EF (median, 0.35 cells/mm2; p < 0.0001). A CD4+ cell in F had a median 31-fold greater likelihood of harboring HIV-1 RNA than a CD4+ cell in EF (p = 0.0006). The most highly expressed antiretroviral proteins were alpha-defensins 1, 2, and 3 (median, 4.6% tissue staining), RANTES (median, 728.4 cells/mm2), and granzyme A (median, 412.6 cells/mm2). Less alpha-defensins (p = 0.0127), RANTES (p = 0.0007), granzyme A (p = 0.0018), MIP-1alpha (p = 0.0054), interferon (IFN)-alpha (p = 0.0186), and CD8 (p < 0.0001) was expressed in F compared to EF; amounts in F ranged from 0.15 to 0.50 of those in EF. Expression of IFN-gamma (median, 3.1 cells/mm2) and perforin (median, 4.0 cells/mm2) was low and not significantly different in F and EF. Deficiencies of multiple antiretroviral proteins within F may contribute to heightened replication at that site.
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PMID:Lymphoid follicles are sites of heightened human immunodeficiency virus type 1 (HIV-1) replication and reduced antiretroviral effector mechanisms. 1592 98

Lentivirus infections including HIV and feline immunodeficiency virus (FIV) cause neurovirulence, which is largely mediated by innate immunity. To investigate the interactions between neurovirulence and repeated conditioning by innate immune activation, models of lentivirus infection were exposed to LPS. Gene expression in HIV-infected (HIV+) and control (HIV-) patient brains was compared by real time RT-PCR and immunocytochemistry. Supernatants from mock and HIV-infected monocyte-derived macrophages exposed to LPS were applied to human neurons. FIV-infected (FIV+) and control (FIV-) animals were exposed repeatedly to LPS postinfection together with concurrent neurobehavioral testing, viral load, and host gene analyses. Brains from HIV+ individuals exhibited induction of CD3epsilon, CXCL10, and granzyme A expression (p < 0.05). Supernatants from HIV+ monocyte-derived macrophages induced CXCL10 expression in neurons, which was diminished by IL-10 treatment (p < 0.05). LPS-exposed FIV+ animals demonstrated lower plasma and brain viral loads (p < 0.05). Neuronal CXCL10 expression was increased in FIV+ animals but was suppressed by LPS exposure, together with reduced brain CD3epsilon and granzyme A expression (p < 0.05). In conjunction with preserved NeuN-positive neuronal counts in parietal cortex (p < 0.05), FIV+ animals exposed to LPS also showed less severe neurobehavioral deficits (p < 0.05). Repeated LPS exposures suppressed CXCL10 in the brain and ensuing T cell infiltration with a concomitant reduction in neurovirulence. Thus, innate immune chronic conditioning exerted beneficial effects on neurovirulence through suppression of a specific chemotactic factor, CXCL10, mediated by IL-10, leading to reduced leukocyte infiltration and release of neurotoxic factors.
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PMID:Regulation of lentivirus neurovirulence by lipopolysaccharide conditioning: suppression of CXCL10 in the brain by IL-10. 2004 80

Recent data suggest that CD8+ T-cell effector activity is an important component in the control of HIV replication in elite controllers (ECs). One critical element of CD8+ T-cell effector function and differentiation is the T-box transcription factor T-bet. In the present study, we assessed T-bet expression, together with the effector proteins perforin, granzyme A (Grz A), granzyme B (Grz B), and granulysin, in HIV-specific CD8+ T cells from ECs (n = 20), chronically infected progressors (CPs; n = 18), and highly active antiretroviral therapy (HAART)-suppressed individuals (n = 19). Compared with the other cohort groups, HIV-specific CD8+ T cells among ECs demonstrated a superior ability to express perforin and Grz B, but with no detectable difference in the levels of Grz A or granulysin. We also observed higher levels of T-bet in HIV-specific CD8+ T cells from ECs, with an ensuing positive correlation between T-bet and levels of both perforin and Grz B. Moreover, HIV-specific CD8+ T cells in ECs up-regulated T-bet to a greater extent than CPs after in vitro expansion, with concomitant up-regulation of perforin and Grz B. These results suggest that T-bet may play an important role in driving effector function, and its modulation may lead to enhanced effector activity against HIV.
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PMID:Increased HIV-specific CD8+ T-cell cytotoxic potential in HIV elite controllers is associated with T-bet expression. 2128 10


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