Mechanistic effects of kijimicin on inhibition of human immunodeficiency virus replication

Kijimicin represents an important type of ionophore compound. In veterinary medicine, it is becoming important as anticoccidiostatic agent and feed supplement. We examined Kijimicin for its HIV inhibitory activity. The compound exhibited concentration-dependent inhibition of HIV replication in primary infected cultures of human T-lymphoblastoid H9 cells. Substantial inhibition of viral replication was observed at concentrations of Kijimicin that showed little cytotoxicity. The ratio of IC₅₀ values for the MTT to RT assays was 40. Anti HIV activity was also observed in cultures of monocytic lineage U937 cells chronically infected with HIV. Moreover, in attempting to define the inhibitory mechanism of Kijimicin, we investigated its effect on each step of HIV replication. The infectivity of progeny viral particles was reduced by Kijimicin treatment. This decrease may be due to incompletely glycosylated forms of gp120.     

Anti-HIV effect of gramicidin in vitro: Potential for spermicide use

Gramicidin, cation channel forming ionophore with antibacterial properties, was studied in vitro for inhibition of human immunodeficiency virus (HIV) infection of MT-4 lymphocytes. Effective antiviral concentrations required for complete HIV inactivation were three orders of magnitude lower than 10 μg/ml cytotoxic dose. Gramicidin, routinely used as a contraceptive agent, should be considered for clinical application as a spermicide with antiviral activity.     

Ellagitannins from Tuberaria lignosa as entry inhibitors of HIV

Screening of plants from the Iberian Peninsula for anti-human immunodeficiency virus (-HIV) activity revealed that aqueous extract of Tuberaria lignosa gave positive results. Following an activity-guided procedure, the crude extract was counterextracted, and the subsequent fractions obtained tested for their anti-HIV activity in vitro. The bioassay-guided fractionation of the extract afforded an ellagitannin enriched fraction (EEF) isolated for the first time from this species. This EEF exhibited antiviral activity against HIV in MT-2 infected cells, with an IC₅₀ value of 2.33 μg/ml (selectivity index greater than 21). Inhibition of HIV infection by EEF appears to be mediated by CD4 down-regulation, the main receptor for HIV entry. CXCR4 and CCR5 receptors were not affected by EEF, explaining why EEF is able to inhibit R5 and X4 infections.     

Antiviral action of membranotropic compounds modified by adamantane and norbornene pharmacophores exerted on different HIV-1 strains

The anti-HIV activity of new membranotropic compounds, i.e. of the polycarboxylate matrix and of its derivatives modified by adamantane and norbonene, was studied in respect of HIV-1 strains, whose tropicity to coreceptors CCR5 and CXCR4 was different, as well as in respect of HIV-1 variants resistant to azidothymidine (AZT) in a continuous culture of human lymphoid cells (MT-4) and in mononuclear cells of peripheral blood from healthy donors. Testing of complex compounds in a culture of infected MT-4 human lymphoid cells showed an effective inhibition of viral reproduction of LAV.04 (CXCR4-tropic variant) and of HIV11(EVK) as well as AZT-resistant variants. The studied pharmacophores-modified compounds displayed, in infection of the primary culture of human mononuclear cells of the HIV-1 R5 and X4 strains, a notable antiviral activity with their HIV efficiency significantly exceeding the one of the original matrix.     

树舌多糖Fb、Fc的结构研究

从树舌子实体中分离纯化出另两个级分Ｆｂ、Ｆｃ,经超速离心,电泳,ＳｅｐｈａｒｏｓｅＣＬ－４Ｂ柱层析等确定其均为质点、极性均一级分。经ＧＣ、ＩＯ＿４～－氧化,Ｓｍｉｔｈ降解,部分酸水解,甲基化及其产物ＧＣ,ＧＣ－ｍｓ分析,ＩＲ等分析确定Ｆｂ是由１→３甘露糖基构成主链,分枝点率及分枝率均较大;Ｆｃ由１→６和１→４甘露糖基构成主链,分枝点率及分枝率较少。     

Antimyristoylation of the gag proteins in the human immunodeficiency virus-infected cells with N-myristoyl glycinal diethylacetal resulted in inhibition of virus production

The gag proteins of human retroviruses such as human immunodeficiency virus (HIV-1) are specifically myristoylated in their amino termini (1, 2, 3). N-myristoyl glycinal diethylacetal (N-Myr-GOA) and other N-Myr-compounds (N-Myr-Gly-GOA, N-Myr-Gly-Gly-GOA and N-Myr-Gly-Gly-Gly-GOA) were newly synthesized and investigated for activity of antimyristoylation of these gag proteins and for influence on viral replication. Of the N-Myr-compounds tested, N-Myr-GOA most severely inhibited the protein myristoylation; N-Myr-Gly-GOA also inhibited it, but moderately. Furthermore, it was observed that N-Myr-GOA at 20 microM caused noticeable inhibition (about 80%) of the production of mature HIV in the HIV-1-infected MT-4 cells. In this system, N-Myr-GOA substantially inhibited more than 90% of the N-myristoylation of p17 gag protein produced in the HIV-1-infected MT-4 cells. These results suggest that the N-myristoylation of p17 gag protein of HIV-1 may be essential in its structural assembly or maturation.     

Non-induced leukocyte extract reduces HIV replication and TNF secretion

According to UNAIDS, the global HIV/AIDS epidemic increased to 40 million the number of people living with the virus around the world. Dialyzable leukocyte extract obtained by our group is a low molecular weight dialyzable material from peripheral human leukocytes previously in vitro induced with Sendai virus (DLE-ind), and more recently, from non-induced leukocytes (DLE n/i). Previous results have shown the ability of DLE-ind to inhibit HIV in vitro replication in MT4 cell; to reduce TNFalpha secretion, and to delay in vivo progression to AIDS in early stage of HIV infection. In this work we present evidences that DLE n/i also inhibits HIV in vitro replication and reduces TNFalpha secretion in human whole blood like DLE obtained from induced leukocytes. Taking together these results show that both properties of DLE, HIV in vitro inhibition and TNF production modulation, are not dependent on in vitro Sendai virus induction of leukocytes.     

Inhibition of HIV-1 IIIb replication in AA-2 and MT-2 cells in culture by two ligands of poly (ADP-ribose) polymerase: 6-amino-1,2-benzopyrone and 5-iodo-6-amino-1,2-benzopyrone

The effects of two adenosine diphosphoribose transferase (ADPRT) enzyme inhibitory ligands, 6-amino-1,2-benzopyrone and its 5-iodo-derivative, were determined in AA-2 and MT-2 cell cultures on the replication of HIV-1 IIIb, assayed by an immunochemical test for the HIV protein p24, and syncytium formation, characteristic of HIV-infected cells. Intracellular concentrations of both drugs were sufficient to inhibit poly(ADP-ribose) polymerase activity within the intact cell. Both drugs inhibited HIV replication parallel to their inhibitory potency on ADPRT, but distinct differences were ascertained between the two cell lines. In AA-2 cells both p24 and syncytium formation were depressed simultaneously, whereas in MT-2 cells only syncytium formation was inhibited by the drugs, and the p24 production, which remained unchanged during viral growth, was unaffected. Both drugs only moderately depressed the growth rate of the AA-2 and MT-2 cells and there was no detectable cellular toxicity. Results suggest the feasibility of the development of a new line of ADPRT ligand anti-HIV drugs that fundamentally differ in their mode of action from currently used chemotherapeutics.     

A biological response modifier, PSK, inhibits human immunodeficiency virus infection in vitro

PSK, a biological response modifier (BRM), was studied to determine its anti-viral activity on human immunodeficiency virus (HIV) in vitro. Either a novel infection system using human T-cell lymphotropic virus type I (HTLV-I)-carrying MT-4 cells or a coculture system using MOLT-4 cells and its virus-producing cells MOLT-4/HIVHTLV-IIIB which induces multinucleated giant cells very efficiently was used. PSK almost completely blocked the cytopathic effect such as giant cell formation and HIV-specific antigen expression both in MT-4 cells and MOLT-4 cells at a concentration of 0.4 and 0.8 mg/ml, respectively. Pretreatment of the virus with PSK may specifically interfere with early stages of HIV infection by modifying the viral receptor.     

Announcements

Both in vitro sensitization and in vitro expression of a cell-mediated CBA/H anti-DBA/2 response are suppressed by antibody directed against the stimulator or target DBA/2 cells, respectively. Induction of cytotoxicity and the suppression of sensitization or effector phases of the in vitro cell-mediated immune response by antibody are immunologically specific. Specific suppression by antibody-containing serum is (i) highly dependent on the number of stimulating cells used for sensitization, (ii) most marked when antibody is given at the initiation of the sensitization cultures, (iii) more effective in inhibiting the sensitization phase than the effector phase, (iv) interfered with by absorption with cells which contain stimulating or target cell antigens, (v) limited to the 7S fraction of antibody-containing serums, (vi) not markedly dependent on the Fc portion of antibody, and (vii) not augmented, but inhibited slightly, by the formation of antigen-antibody complexes. The characteristics of suppression by antibody in this in vitro system suggest that inhibition occurs mainly through an antigen-masking mechanism and that antibody feedback inactivation of T cells, equivalent to that of B cells, does not take place. The resistance to antibody feedback of T cells involved in the production of cytotoxic effector cells is similar to the resistance of T cells which operate in helper activities in T cell-dependent antibody responses.     

Macrophage--T cell interactions. I. The uptake by T cells of Fc receptors released from macrophages.

Using a rosette assay for the detection of cells carrying Fc receptors (Fc+) we have been able to show that in nylon wool (NWC), separated spleen cells from different strains of mice 12 to 18% are Fc+.Within 4 hr of culture in vitro at 37 °C, 75 to 85% of the Fc+ cells lose their Fc receptors and remain Fc receptor negative even after culture for 24 hr. However the addition of 5 to 10% syngeneic (but not allogeneic) peritoneal macrophages in the NWC, resulted in the preservation of the Fc receptors on 75 to 85% of the Fc+ cells originally present.Brief exposure of NWC which have been cultured in vitro for 4 hr (lost their Fc receptors) to supernates from 3 hr cultures of peritoneal macrophages reconstituted the fc+ cells by 75 to 85%. Only the supernates from syngeneic, but not allogeneic macrophages are active. Evidence is presented which indicates that these supernates contain Fc receptor molecules of small molecular weight. These molecules can be removed by antisera directed against the I region of the major histocompatibility complex.