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)

The human immunodeficiency virus (HIV) is a lentivirus which replicates within critical cells of the immune system, particularly CD4+ T-cells and monocyte/macrophages, leading to a progressive loss of helper T-cells and profound immunosuppression. This condition is known as the acquired immunodeficiency syndrome (AIDS). A rational screening strategy was adopted to evaluate new anti-HIV agents. Primary in vitro evaluation of antiviral compounds and studies of the relationship between structure and antiviral activity were carried out in a CD4+ T-cell line (MT-4). These cells develop a cytopathic effect (CPE) within a few days after infection. Initially, protection against the HIV-induced cytopathic effect as well as the MT-4 host cell cytotoxicity was determined by a highly automated evaluation system. Promising lead compounds emerging from these studies were then further investigated for their anti-HIV properties in other target cells and against different HIV-1 and HIV-2 strains. This strategy allowed the identification of several potent and selective inhibitors of HIV replication in vitro. Following the 3'-azidothymidine (AZT) lead, we synthesized and evaluated other 2',3'-dideoxynucleoside analogues with modifications in the base and/or sugar moiety. Based on their selectivity indexes in vitro, several congeners of this group, including 2',3'-thymidine (ddeThd, D4T) and 5-chloro-3'-fluoro-2',3'-dideoxyuridine (FddClUrd), seem at least as promising as AZT. From a series of phosphonylmethoxyalkylpurines and -pyrimidines, 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) emerged as a new class of broad-spectrum anti-retrovirus agents. Sulfated polysaccharides and sulfated polymers represent another class of compounds achieving high therapeutic indexes in vitro. Comparative studies allowed to define the structural requirements for anti-HIV activity. Finally, a rational screening strategy allowed the identification of tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and -thione (TIBO) derivatives which represent a complete new class of anti-HIV-1 agents.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Development of new potent and selective agents against HIV (human immunodeficiency virus). 181 6

A series of human immunodeficiency virus type 1 (HIV-1) mutants in vif, vpr, vpu, and nef were constructed from an infectious plasmid (pNL 432) containing the full-length HIV-1 DNA by frameshift mutations. The capacities for replication and cell killing of these mutant viruses were examined in a clonal cell line (M 10) isolated from HTLV-I-transformed MT-4 cells. In all cases, the mutant viruses replicated, expressed HIV-1 antigens, and induced drastic cytopathic effects. However, some M 10 cells survived infection with vif, vpr, and vpu mutant viruses and became persistently HIV-1-infected, whereas no cells survived infection with the nef mutant as well as the wild-type virus. The HIV-1 particles produced from the surviving cells after infection with the vif, vpr, or vpu mutant viruses were fully replicative in M 10 cells without apparent cytopathic effects.
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PMID:Human immunodeficiency virus type 1 vif, vpr, and vpu mutants can produce persistently infected cells. 183 72

Fifteen heteropolyoxotungstates were tested for their effects on the proliferation of human immunodeficiency virus type 1 (HIV-1) using an in vitro system consisting of MT-4 cells and HTLV-IIIb. Eight heteropolyoxotungstates (HPOTs) with the Keggin structure or dimerized deficient Keggin structure proved to be potent inhibitors of HIV-1. In contrast, seven non-Keggin HPOTs including HPA 23 did not have significant effects on HIV-1 proliferation at non-toxic doses. [PTi2W10O40]7- (PM-19) was the most potent inhibitor of HIV-1 among the 15 HPOTs tested. The inhibition of HIV-1 replication by PM-19 presumably results from impaired virus adsorption and/or penetration into target cells. Viral spread of HIV-1 and HIV-2 on cell-to-cell basis was also susceptible to PM-19. In combination, PM-19 and 3'-azido-3'-deoxythymidine were synergistic in inhibiting HIV-1 proliferation.
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PMID:Inhibition of proliferation of human immunodeficiency virus type 1 by novel heteropolyoxotungstates in vitro. 185 2

An antimicrobial peptide, tachyplesin I, isolated from hemocytes of the Japanese horseshoe crab (Tachypleus tridentatus) was examined for its inhibitory effects on human immunodeficiency virus (HIV) infection in vitro. At a concentration of 7.5 micrograms/ml, tachyplesin I suppressed the development of cytopathic effects (CPE) by more than 70% in MT-4 cells infected with HIV (lymphadenopathy-associated virus). This inhibitory effect was observed only when the drug was added during the adsorption period of the virus to the cells. In cocultures of MOLT-4 and persistently HIV-infected cells (MOLT-4/HIV), tachyplesin I at the same concentration completely inhibited multinucleated giant cell formation. Infectivity of HIV was reduced by 10(-2.5) in medium free from fetal calf serum containing tachyplesin I at a concentration of 200 micrograms/ml. Tachyplesin I did not show any inhibitory effect on reverse transcriptase activity of HIV at concentrations of 9-80 micrograms/ml at which tachyplesin I inhibited HIV infection. These results suggest that the anti-HIV action of tachyplesin I was due to the inhibition of virus adsorption.
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PMID:Inhibitory effect of tachyplesin I on the proliferation of human immunodeficiency virus in vitro. 188 8

Toward gene therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infections in AIDS, Moloney murine leukemia virus-derived retroviral vectors were engineered to allow constitutive and tat-inducible expression of an HIV-1 5' leader sequence-specific ribozyme (Rz1). These vectors were used to infect the human CD4+ lymphocyte-derived MT4 cell line. The stable MT4 transformants expressing an HIV-1 RNA-specific ribozyme, under the control of the herpes simplex virus thymidine kinase (tk) promoter, were found to be somewhat resistant to HIV-1 infection as virus production was delayed. In cells allowing ribozyme expression under control of the simian virus 40 or cytomegalovirus promoter, the rate of HIV-1 multiplication was slightly decreased, and virus production was delayed by about 14 days. The highest level of resistance to HIV-1 infection was observed in MT4 cells transformed with a vector containing a fusion tk-TAR (trans activation-responsive) promoter to allow ribozyme expression in a constitutive and tat-inducible manner; no HIV-1 production was observed 22 days after infection of these cells. These results indicate that retroviral vectors expressing HIV-1 RNA-specific ribozymes can be used to confer resistance to HIV-1 infection.
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PMID:Resistance to human immunodeficiency virus type 1 (HIV-1) infection in human CD4+ lymphocyte-derived cell lines conferred by using retroviral vectors expressing an HIV-1 RNA-specific ribozyme. 189 2

cis-acting elements for the transcription of human immunodeficiency virus type 1 DNA were analyzed in cell-free transcription and DNA transfection assays. Besides previously identified cis elements, a region adjacent to the enhancer element was found to regulate transcription in both assays. Loss of this region caused 4.3- and 1.6-fold transcription inhibition in a transfection assay with a T-cell line, MOLT-4, and a monocyte line, U937, respectively, whereas the same region appeared to function negatively with other T-cell lines, MT-4 and Jurkat. These results suggest that this novel cis element regulates the transcription of proviral DNA in a cell-type-specific manner.
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PMID:A novel cis-acting element that controls transcription of human immunodeficiency virus type 1 DNA, depending on cell type. 192 Jun 36

We describe a novel nucleoside analog, 2'-deoxy-3'-thiacytidine (BCH-189), in which the 3' carbon of the ribose ring of 2'-deoxycytidine has been replaced by a sulfur atom. In MT-4 T cells, this compound had significant time- and dose-dependent antiviral activity against five different strains of human immunodeficiency virus type 1 (HIV-1) (mean 50% inhibitory dose, 0.73 microM); known 3'-azido-3'-deoxythymidine (AZT)-resistant HIV-1 variants did not exhibit cross-resistance to it. BCH-189 also suppressed HIV-1 replication in the U937 monocytoid cell line as well as in primary cultures of human peripheral blood mononuclear cells; in these latter systems, suppression was fuller and longer lasting than that induced by AZT. Moreover, BCH-189 was less toxic than AZT in cell culture. BCH-189 may be a promising drug for the treatment of HIV-1-associated disease.
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PMID:Anti-human immunodeficiency virus type 1 activity and in vitro toxicity of 2'-deoxy-3'-thiacytidine (BCH-189), a novel heterocyclic nucleoside analog. 192 98

A novel 6-substituted acyclouridine derivative, 5-ethyl-1-ethoxymethyl-6-(phenylthio)uracil (E-EPU), has recently proved to be a highly potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) in vitro. Combinations of 3'-azido-2',3'-dideoxythymidine (AZT) and E-EPU synergistically inhibit the replication of HIV-1 in MT-4 cells, whereas the cytotoxic effects of AZT and E-EPU on mock-infected MT-4 cells are not enhanced by the drug combination. Synergistic inhibition of HIV-1 replication has also been observed in peripheral blood lymphocytes. These results indicate that the combination of AZT and E-EPU should be further pursued in the treatment of AIDS.
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PMID:Synergistic inhibition of human immunodeficiency virus type 1 replication by 5-ethyl-1-ethoxymethyl-6-(phenylthio)uracil (E-EPU) and azidothymidine in vitro. 192 4

Ribavirin enhances the anti-human immunodeficiency virus activity of 2',3'-dideoxyinosine (ddIno) in MT-4, CEM and peripheral blood lymphocyte cells. Ribavirin causes an increase in the levels of IMP, the presumed phosphate donor for the conversion of ddIno to ddIMP by 5'-nucleotidase. Consequently, ribavirin stimulates the conversion of ddIno to its antivirally active metabolite ddATP. Ribavirin also causes a marked depletion of the guanine nucleotide pools. The increase in IMP pool levels may result from (i) a direct inhibitory effect of ribavirin 5'-monophosphate on IMP dehydrogenase (which converts IMP to XMP) and (ii) an indirect inhibition of adenylosuccinate synthetase by the decreased GTP and dGTP pools (since GTP is an obligatory cofactor in the conversion of IMP to succinyl AMP). GTP depletion plays a key role in the accumulation of IMP and the resultant higher rate of ddIno phosphorylation to ddIMP and eventually ddATP. Our findings are in agreement with the observations that guanosine and 2'-deoxyguanosine, but not 2'-deoxyadenosine, reverse (i) the stimulatory effect of ribavirin on the anti-human immunodeficiency virus activity of ddIno and (ii) the accumulation of endogenous IMP pools as well as accumulation of [3H]IMP from exogenous [3H]hypoxanthine in ribavirin-treated cells.
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PMID:Mechanism of the potentiating effect of ribavirin on the activity of 2',3'-dideoxyinosine against human immunodeficiency virus. 193 81

Sulfated schizophyllans of differing sulfur content were prepared and their mitogenic activities and effects on human immunodeficiency virus (HIV) were investigated in vitro. The sulfated schizophyllans were found to possess mitogenic activity. Anti-viral activity was evaluated in terms of cytopathic effect, and by the fluorescence antibody technique, reverse transcriptase assay and cell proliferation assay. Schizophyllans with a higher sulfur content showed potent anti-HIV effects on Molt-4 clone No. 8 or MT-4 cells infected with HIV as well as on lymphocytes from AIDS patients. It is suggested that the sulfur content of schizophyllans is the most important factor for inhibiting growth of HIV, rather than molecular weight or kinds of sugar component. Thus, sulfated schizophyllans appear applicable as anti-HIV drugs.
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PMID:Immunopharmacological study of sulfated schizophyllan (SPG). I.--Its action as a mitogen and anti-HIV agent. 197 Mar 38


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