Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reactive oxygen species (ROS) such as hydrogen peroxide serve as second messengers in the induction of the transcription factor NF-kappaB, and hence in the activation and replication of human immunodeficiency virus type 1 (HIV-1) in human cells. During inflammatory reactions, many oxidative species are produced, one of which is hypochlorous acid (HOCl), which is responsible for the microbicidal effects of activated human polymorphonuclear leukocytes. Treatment of a T-lymphocytic cell line with micromolar concentrations of HOCl promoted the appearance of transcription factor NF-kappaB (the heterodimer p50/p65) in the nucleus of the cells, even in the absence of de novo protein synthesis. Western blot analysis of the NF-kappaB inhibitory subunits (IkappaB) demonstrated that both IkappaB-alpha proteolysis and p105 processing were induced by the treatment. NF-kappaB activation was very effective when cells were subjected to hyperthermia before being treated with HOCl. Various antioxidants, such as pyrrolidine dithiocarbamate, p-bromophenacyl-bromide and nordihydroguaiaretic acid could strongly reduce NF-kappaB translocation, demonstrating the importance of oxidative species in the transduction mechanism. Moreover, ACH-2 cells treated with HOCl or H2O2 released tumour necrosis factor-alpha (TNF-alpha) in the supernatants. The importance of TNF-alpha release in NF-kappaB induction by HOCl or H2O2 was demonstrated by the fact that: (1) the nuclear appearance of NF-kappaB was promoted in untreated cells; and (2) synergism between TNF-alpha and HOCl was detected. Collectively, these results suggest that HOCl should be considered as an oxidative species capable of inducing NF-kappaB in a T-lymphocytic cell line through a transduction mechanism involving ROS, and having a long-distance effect through subsequent TNF-alpha release.
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PMID:Activation of the NF-kappaB transcription factor in a T-lymphocytic cell line by hypochlorous acid. 903 66

The silicon phthalocyanine HOSiPcOSi(CH3)2(CH2)3 N(CH3)2 (Pc 4), is being studied as a photosensitizer for virus inactivation in red blood cell concentrates (RBCC). The RBCC spiked with cell-free human immunodeficiency virus (HIV) or with HIV actively replicating in the T-lymphocytic cell line CEM can be successfully inactivated (> or = 6 log10) when exposed to 2 microM Pc 4 and 90 J/cm2 red light (600-800 nm). Inactivation of > or = 6 log10 inducible HIV in the latently infected promonocytic cell line U1 occurred at 22.5 J/cm2 (H. Margolis-Nunno et al., Transfusion 36, 743-750, 1996). In order to understand the reason for the increased susceptibility of U1 to photosensitized inactivation we looked for induction of apoptosis by photodynamic treatment (PDT). Agarose gel electrophoresis was used to observe the appearance of a characteristic 180-200 base pair DNA ladder, which can indicate apoptosis. Using this assay it is shown that Pc 4 treatment induced apoptosis in U1 cells in a light dose-dependent manner, starting 30 min after light exposure. Using the ApopTag Plus kit (which attaches a fluorescent label to the 3'-OH ends of the degraded DNA) and flow cytometry, the percentage of cells undergoing apoptosis was quantitated. At 10.5 J/cm2, 3 h after light exposure, about 92.5% of the cells were apoptotic. Under these conditions 99% of the cells eventually die. The CEM cells similarly treated underwent apoptosis at slower kinetics and required higher light doses. Other cell lines latently infected with HIV (ACH-2 and OM 10.1) were as sensitive as U1 to HIV inactivation by Pc 4-PDT (H. Margolis-Nunno et al., Transfusion 36, 743-750, 1996) and underwent apoptosis at a similar kinetic. These results suggest that the enhanced inactivation of HIV in latently infected cells compared to CEM cells by Pc 4-PDT may be due, at least in part, to apoptosis in the former.
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PMID:Silicon phthalocyanine Pc 4 and red light causes apoptosis in HIV-infected cells. 907 31

To develop a rapid and sensitive means of detecting cell-associated human immunodeficiency virus (HIV), donor cells from HIV seropositive patients were treated with the potent viral activator sodium-n-butyrate (NaB) and subsequently assayed by both in situ RNA hybridization and a reverse transcriptase polymerase chain reaction (RT-PCR). The sensitivity of RT-PCR was estimated to be equivalent to 1 x 10(-16) grams (0.1 fg) or approximately 64 copies of the input standard viral RNA per reaction. The present study takes advantage of the ability of NaB to introduce changes in chromatin structure of latently infected cells, leading to increased HIV gene expression. Human ACH-2 and U1 cell lines were used as representatives of T-lymphocytic and monocytoid cells harboring latent inducible proviruses. HIV gene expression was readily detected when these cells were treated with NaB. Viral gag RNA was detected by both in situ and RT-PCR assays. When peripheral blood mononuclear cells (PBMCs) from acquired immunodeficiency syndrome (AIDS) patients, who were all negative for in situ hybridization and serum/plasma p24 assays, were used for detection of viral gene expression, four categories with distinct patterns of induction were observed. The first set of patients showed HIV-positive PBMCs by RT-PCR without any added NaB, and suppression by added NaB or PHA. The second set of samples showed induction of viral RNA by NaB alone. The third set could be induced with PHA, but not NaB, and the fourth set required both NaB and PHA for induction of HIV gene expression. Our results suggest that direct treatment of the cells with HIV activators may be useful in increasing sensitivity of the RT-PCR intended to be used for detection of cell-associated viral RNAs. This approach may be used to confirm true status of the HIV infection when p24 results are negative or HIV RNAs in serum/plasma are below the threshold of detection. Moreover, this method may identify the presence of latent proviral genomes possibly reflecting the true rate of cell-associated viral load in vivo and without possible mutations brought about by long-term co-cultivation assays with cells from seronegative donors.
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PMID:Rapid and sensitive detection of cell-associated HIV-1 in latently infected cell lines and in patient cells using sodium-n-butyrate induction and RT-PCR. 917 66

Monocytes/macrophages have been known to play an important role in the initiation and propagation of human immunodeficiency virus 1 (HIV-1) infection. To analyze the function of these cells during the clinical asymptomatic period of infection, we examined the effect of murine peritoneal macrophages and human peripheral blood macrophages on two cell lines latently infected with HIV-1, a promonocytic cell line, U1, and a T-cell line, ACH-2. Monokines of the murine peritoneal macrophages induced significant viral expression in U1, but not in ACH-2 cells. Experiments employing transient transfection of U937 and CEM cells with HIV long terminal repeat (LTR)-chloramphenicol acetyl transferase (CAT) plasmids indicated that the effect of these monokines was due to specific activation of the HIV LTR. In contrast, supernatants of human macrophages induced viral expression in both ACH-2 and U1 cells. These results suggest that several monokines are active in regulating the transition from the clinical asymptomatic period of HIV infection to progression to acquired immunodeficiency syndrome (AIDS).
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PMID:Contribution to the regulation of virus replication in cells latently infected with human immunodeficiency virus 1. 919 10

The role of the N-myristoylation of the human immunodeficiency virus type 1 (HIV-1) gag protein in ACH-2 cells was studied. The infectivity of HIV-1 from the cells stimulated with phorbol 12-myristate 13-acetate (PMA) was suppressed by pretreatment with N-myristoyl glycinal diethylacetal (N-Myr-GOA), a potent N-myristoylation inhibitor, and the blockage of myristoylation resulted in accumulation of immature gag precursors. The viral particles which budded from the non-N-Myr-GOA-treated ACH-2 cells stimulated with PMA exhibited a typical viral phenotype, whereas those which budded from the N-Myr-GOA-treated ACH-2 cells stimulated with PMA were twisted, as observed electron microscopically. In electron microscopic analyses with gold-labeled monoclonal antibodies to gag and env, gag and env were detected adjacent to each other in the PMA-stimulated ACH-2, but no env was detected in the cells treated with N-Myr-GOA. Taken together, the results suggest that the myristoylation of HIV-1 gag seems to be responsible for both maturation of gag and acquisition of HIV-1 infectivity.
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PMID:Blockage of N-myristoylation of HIV-1 gag induces the production of impotent progeny virus. 929 93

Transition from latency to active replication is a crucial stage for the process of human immunodeficiency virus type 1 (HIV-1) infection and life cycle. HIV-1 replication in latently infected cells can be strongly induced by the cytokine tumor necrosis factor alpha (TNF-alpha) and the proliferation-arresting chemical sodium butyrate (NaB). We have investigated the ability of the drug 9-nitrocamptothecin (9NC), a potent cellular topoisomerase I (topo I) inhibitor currently in clinical trials in cancer patients, to regulate HIV-1 replication in latently infected lymphocytic ACH-2 cells on reactivation with either TNF-alpha or NaB. Treatment of ACH-2 cells with 9NC alone resulted in increased levels of viral transcripts, while there was a slight reduction or no change in the levels of host cell transcripts. However, pretreatment of ACH-2 cells with 9NC inhibited TNF-alpha-induced extracellular HIV-1 p24 levels up to approximately 95% and nearly 80% of the cell-associated viral RNAs. The quantitative decrease in viral products was concomitant with a decrease in cellular gene expression and induction of apoptosis in the host cells. 9NC blocked the infected cells at the boundary of the S and G2 phases, resulting in an accelerated apoptosis that was further enhanced with TNF-alpha treatment. Similar results were observed following concurrent exposure to TNF-alpha and 9NC, but 9NC failed to inhibit upregulation of HIV-1 mRNA in ACH-2 cells exposed to TNF-alpha before 9NC treatment. Further, 9NC had no inhibitory effect on NaB-induced apoptosis and upregulation of HIV-1 mRNA expression regardless of whether 9NC and NaB were used concurrently or in various treatment sequences. In uninfected lymphocytic CEM cells derived from a common parental cell line, a slight downregulation of cellular gene expression was detected along with low-level apoptosis. These results demonstrate that 9NC impairs TNF-alpha-induced, but not NaB-induced, HIV-1 activation, and suggest a means of inhibiting active HIV-1 viremia arising as a result of elevated TNF-alpha levels.
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PMID:9-Nitrocamptothecin inhibits tumor recrosis factor-mediated activation of human immunodeficiency virus type 1 and enhances apoptosis in a latently infected T cell clone. 945 50

We have previously reported that 9-nitrocamptothecin (9NC) inhibited human immunodeficiency type 1 (HIV-1) replication in latently HIV-1-infected T lymphocytic ACH-2 cells stimulated with the cytokine tumor necrosis factor alpha (TNF-alpha) (Moulton et al., AIDS Res Hum Retroviruses 1998;14:39). 9NC induced an accelerated apoptosis in HIV-1-infected, but not uninfected, lymphocytic cells. The present study demonstrates that 9NC selectively inhibits release of HIV-1 from freshly infected monocytoid U937 cells in a dose-response manner. Significant inhibition was achieved with concentrations of 9NC that were not toxic. In contrast, HIV-1 replication in 9NC-resistant monocytoid cells, derived from U937, was not inhibited by similar doses of 9NC. Importantly, sensitivity of HIV-1 replication to 9NC correlated with the effect of 9NC on topoisomerase I (topo I) activity. In a 9NC-sensitive subline, 9NC induced posttranslational activation of the nuclear transcription factor kappaB (NF-kappaB) after the drug treatment. This activation was neither related to selective 9NC suppression of HIV-1 replication, nor was it sufficient for the 9NC-induced toxicity in the drug-sensitive monocytoid cells. Taken together, the selective inhibition of HIV-1 replication in both lymphoid and monocytoid cells lends further credence to the potential development of 9NC as an alternative drug for treating HIV-1 infection.
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PMID:9-nitrocamptothecin selectively inhibits human immunodeficiency virus type 1 replication in freshly infected parental but not 9-nitrocamptothecin-resistant U937 monocytoid cells. 1005 54

We analysed the expression of CD95/CD95L in two widely used models for studying the cellular effects of chronic infection with human immunodeficiency virus type 1 (HIV-1), i.e. ACH-2 cells, derived from the lymphocytic cell line A301, and U1, derived from monocytic U937 cells. A301 and ACH-2 mounted the same amount of plasma membrane CD95, while U1 had a consistent decrease in CD95 expression. Using different antibodies, we failed to detect the plasma membrane form of its ligand, CD95L, but we could see the intracellular presence of that molecule in A301 cells and, to a lesser extent, in ACH-2 cells, but not in U937 or U1 cells. To confirm the cytofluorimetric data and quantify the expression of CD95L at the RNA level, we developed a quantitative competitive RT-PCR assay. The HUT78 cell line had about 50,000 copies mRNA/1000 cells, three times more after induction with a phorbol ester and ionomycin. ACH-2 expressed about 400- (basal) or 10- (induced) fold less CD95L mRNA than the parental cell line A301; U937 and U1 were below the limit of detection. In cells of lymphoid origin (ACH-2) chronic HIV infection inhibits the expression of CD95L, the phenomenon occurring at the transcriptional level. In cells of monocytic origin (U1) the infection decreases the plasma membrane expression of CD95. This suggests that HIV could trigger different anti-apoptotic strategies which likely depend upon the cell line which is infected. In monocytic cells which act as a viral reservoir, the expression of the molecule whose binding triggers apoptosis decreases, while in lymphoid cells, capable of exerting cytotoxicity, the expression of a molecule which induces apoptosis is reduced.
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PMID:Differential down-regulation of CD95 or CD95L in chronically HIV-infected cells of monocytic or lymphocytic origin: cellular studies and molecular analysis by quantitative competitive RT-PCR. 1048 Oct 67

In a search for effective HIV-1 transcription inhibitors, we have evaluated more than 75,000 compounds for their inhibitory effects on Tat-induced human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR)-driven reporter gene expression and found that EM2487, a novel small-molecule substance produced by a Streptomyces species, is a potent and selective inhibitor of HIV-1 replication in both acutely and chronically infected cells. Its 50% effective concentration for acute HIV-1 infection was 0.27 microM in peripheral blood mononuclear cells (PBMCs), while the 50% cytotoxic concentration for mock-infected PBMCs was 13.3 microM. EM2487 proved inhibitory to a variety of HIV-1 strains and HIV-2 in acutely infected T-cell lines (MOLT-4 and MT-4). The compound could suppress tumor necrosis factor alpha (TNF-alpha)-induced HIV-1 production in latently infected cells (OM-10.1 and ACH-2) as well as constitutive viral production in chronically infected cells (MOLT-4/III(B) and U937/III(B)) without showing any cytotoxicity. EM2487 did not affect early events of the HIV-1 replication cycle, as determined by proviral DNA synthesis in acutely infected MOLT-4 cells. In contrast, the compound selectively prevented viral mRNA synthesis in OM-10.1 cells, suggesting that HIV-1 inhibition occurs at the transcriptional level. Furthermore, EM2487 did not inhibit TNF-alpha-induced HIV-1 LTR-driven reporter gene expression but did inhibit that induced by Tat, irrespective of the presence or absence of the nuclear factor kappaB binding sites in the LTR. These results suggest that the mechanism of action is attributable in part to the inhibition of Tat function.
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PMID:Inhibition of human immunodeficiency virus type 1 replication in acutely and chronically infected cells by EM2487, a novel substance produced by a Streptomyces species. 1050 5

Six serinal derivatives were synthesized and tested for their anti-human immunodeficiency virus type-1 (HIV-1) activity against HIV-1-infected cells. Of the 6 serinal derivatives tested, only N,O-didecanoyl serinal dimethylacetal (DDSD) was found to strongly suppress progeny virus production from acute HIV-1-infected CEM cells, while not suppressing the HIV-1 p24 production from latent HIV-1-infected ACH-2 cells after stimulation with phorbol 12-myristate 13-acetate. DDSD also inhibited the synthesis of HIV-1 proviral DNA at 20-50 microM, not only 1 h but also 24 h after HIV-1 infection. Taken together, DDSD is a potent inhibitor of HIV-1 production, and may become a unique leading compound for chemotherapy of acquired immunodeficiency syndrome.
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PMID:Blockage of HIV-1 production through inhibition of proviral DNA synthesis by N,O-didecanoyl serinal dimethylacetal. 1069 Jun 44


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