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1.
AIDS Res Hum Retroviruses ; 23(1): 123-34, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17263642

RESUMO

Two major interferon (IFN)-mediated antiviral defense enzymes are double-stranded (ds)RNA-dependent 2',5'-oligoadenylate (2-5A) synthetase (2-5OAS) and p68 kinase (PKR). When activated by dsRNA, 2-5OAS synthesizes 2-5A, which binds to and activates RNase L. Activated RNase L hydrolyzes single-stranded viral RNA, thereby inhibiting viral protein synthesis. HIV-1 inhibits the IFN-mediated intracellular antiviral pathways. We have reported the synthesis and characterization of a nuclease-resistant 2-5A agonist (2-5A(N6B)) that overcomes the HIV-1 induced blockades by restoring the 2-5OAS/RNase L antiviral pathway (Homan JW, et al., J Acquir Immune Defic Syndr 2002;30:9-20). The objective of this study was to test the effect of 2-5A(N6B) on chronically infected CD4(+) T lymphocytes and CD14(+) monocytes derived from HIV-1-seropositive individuals. Wild-type HIV-1 replication was effectively inhibited by 2-5A(N6B) in CD4(+) T lymphocytes and CD14(+) monocytes purified from HIV-1 seropositive individuals (n = 18) compared to untreated cells. We also assessed the cytotoxicity of 2-5A(N6B) and report that 2-5A(N6B) exerts its anti-HIV-1 activity with no evidence of cytotoxicity (IC(90) > 100,000 nM). Furthermore, 2-5A(N6B) did not alter the cellular RNA profile, affect CCR5 or CXCR4 coreceptor expression, or activate caspase-dependent apoptosis. Evidence is also provided to show that 2-5A(N6B), and naturally occurring 2-5A(4), act as ligands to activate human Toll-like receptor 4. These results indicate that the 2-5A agonist 2-5A(N6B) has the potential to enhance host cell innate and acquired immune defense mechanisms against HIV-1 infection.


Assuntos
Nucleotídeos de Adenina/farmacologia , Fármacos Anti-HIV/farmacologia , Linfócitos T CD4-Positivos/virologia , Infecções por HIV/metabolismo , HIV-1/efeitos dos fármacos , Receptores de Lipopolissacarídeos , Oligorribonucleotídeos/farmacologia , Nucleotídeos de Adenina/agonistas , Nucleotídeos de Adenina/síntese química , Adulto , Idoso , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo , Infecções por HIV/tratamento farmacológico , Soropositividade para HIV , HIV-1/fisiologia , Humanos , Fatores Imunológicos/farmacologia , Masculino , Pessoa de Meia-Idade , Monócitos/citologia , Monócitos/imunologia , Oligorribonucleotídeos/agonistas , Oligorribonucleotídeos/síntese química , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor 4 Toll-Like/metabolismo , Replicação Viral/efeitos dos fármacos
2.
J Acquir Immune Defic Syndr ; 30(1): 9-20, 2002 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-12048358

RESUMO

Opioids potentiate HIV-1 infection in vitro at least partly by suppressing immunoresponsive processes in human lymphocytes and monocytes. For example, it appears that morphine inhibits the interferon (IFN)-alpha, -beta, and -gamma-mediated natural antiviral defense pathways in human peripheral blood mononuclear cells (PBMC). In this study, we show that restoration of a key component of the antiviral pathway reverses morphine-potentiated HIV-1 infection of human PBMC. The data show that HIV-1 replication is potentiated and RNase L activity is inhibited after morphine administration. Because HIV-1 inhibits the antiviral pathway at the level of 2',5'-oligoadenylate (2-5A) synthetase and p68 kinase, antiviral enzymes that require double-stranded RNA, we overcame this blockade by the addition of the nuclease-resistant, nontoxic 2-5A agonist, 2-5A(N6B), to PBMC in culture. Addition of 2-5A(N6B), but not zidovudine or saquinavir, to morphine-treated PBMC completely reversed the morphine-induced potentiation of HIV-1 infection. Further, 2-5A(N6B) significantly enhanced expression of both IFN-alpha and IFN-gamma. Also, increased expression of IFN-gamma was associated with a significant increase in expression of RANTES and monocyte chemotactic protein (MCP)-1, chemokines that may inhibit HIV-1 infection by blocking viral attachment to CCR2 and CCR5 co-receptors. Our results suggest that reactivation of the antiviral pathway by 2-5A agonists may be useful to inhibit opioid-potentiated HIV-1 replication.


Assuntos
Nucleotídeos de Adenina/farmacologia , Antivirais/farmacologia , HIV-1/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Morfina/farmacologia , Entorpecentes/farmacologia , Oligorribonucleotídeos/farmacologia , Replicação Viral/efeitos dos fármacos , Nucleotídeos de Adenina/agonistas , Nucleotídeos de Adenina/síntese química , Células Cultivadas , Quimiocina CCL2/análise , Quimiocina CCL2/biossíntese , Quimiocina CCL5/análise , Quimiocina CCL5/biossíntese , Endorribonucleases/biossíntese , Endorribonucleases/metabolismo , Ativação Enzimática/efeitos dos fármacos , Inibidores da Protease de HIV/farmacologia , HIV-1/fisiologia , Humanos , Interferon-alfa/análise , Interferon-alfa/biossíntese , Interferon gama/análise , Interferon gama/biossíntese , Leucócitos Mononucleares/efeitos dos fármacos , Morfina/antagonistas & inibidores , Oligorribonucleotídeos/agonistas , Oligorribonucleotídeos/síntese química , Inibidores da Síntese de Proteínas/agonistas , Inibidores da Transcriptase Reversa/farmacologia , Saquinavir/farmacologia , Zidovudina/farmacologia
3.
Br J Pharmacol ; 123(1): 71-80, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9484856

RESUMO

1. Hippocampal slices (450 microm) generate epileptiform bursts of an interictal nature when perfused with a zero magnesium medium containing 4-aminopyridine (50 microM). The effect of adenine nucleotides on this activity was investigated. 2. ATP and adenosine depressed this epileptiform activity in a concentration-dependent manner, with both purines being equipotent at concentrations above 10 microM. 3. Adenosine deaminase 0.2 u ml(-1), a concentration that annuls the effect of adenosine (50 microM), did not significantly alter the depression of activity caused by ATP (50 microM). 4. 8-Cyclopentyl-1,3-dimethylxanthine (CPT), an A1 receptor antagonist, enhanced the discharge rate significantly and inhibited the depressant effect of both ATP and adenosine such that the net effect of ATP or adenosine plus CPT was excitatory. 5. Several ATP analogues were also tested: alpha, beta-methyleneATP (alpha, beta-meATP), 2-methylthioATP (2-meSATP) and uridine triphosphate (UTP). Only alpha, beta-meATP (10 microM) produced an increase in the frequency of spontaneous activity which suggests a lack of involvement of P2Y or P2U receptors. 6. Suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), P2 receptor antagonists, failed to inhibit the depression produced by ATP (50 microM). The excitatory effect of alpha, beta-meATP (10 microM) was inhibited by suramin (50 microM) and PPADS (5 microM). 7. ATP therefore depresses epileptiform activity in this model in a manner which is not consistent with the activation of known P1 or P2 receptors, suggesting the involvement of a xanthine-sensitive nucleotide receptor. The results are also indicative of an excitatory P2X receptor existing in the hippocampal CA3 region.


Assuntos
Nucleotídeos de Adenina/fisiologia , Epilepsia/fisiopatologia , Hipocampo/fisiopatologia , Nucleotídeos de Adenina/agonistas , Nucleotídeos de Adenina/antagonistas & inibidores , Adenosina/farmacologia , Adenosina Desaminase/metabolismo , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Animais , Estimulação Elétrica , Epilepsia/enzimologia , Hipocampo/citologia , Hipocampo/enzimologia , Técnicas In Vitro , Masculino , Neurônios/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacologia , Ratos , Ratos Wistar , Suramina/farmacologia , Teofilina/análogos & derivados , Teofilina/farmacologia
4.
J Invest Dermatol ; 104(6): 976-81, 1995 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-7769269

RESUMO

Previous investigations have shown disparate effects of adenine nucleotides on epidermal cell proliferation. Our present study demonstrates that adenosine and its related nucleotides (ATP, ADP, AMP) are antiproliferative for normal human epidermal keratinocytes cultured in the absence or presence of exogenous epidermal growth factor. Furthermore, the inhibitory effects of these compounds occur at concentrations less than 100 microM, are reversible, and do not affect the viability of the keratinocyte cultures. Our current investigation also demonstrates that both selective and nonselective adenosine receptor agonists are themselves approximately as potent as keratinocyte proliferation inhibitors, but are all less potent inhibitors than adenosine. These observations are consistent with the theory that adenosine mediates its antiproliferative response via a novel or more poorly characterized adenosine purinoreceptor subclass. Moreover, our present study demonstrates that ATP and ATP-gamma-S are significantly more potent antiproliferative agents than either alpha,beta-methylene ATP or beta,gamma-methylene ATP. Based on previous studies that have demonstrated that P2y purinoreceptors possess this type of ligand specificity and that the P2y purinoreceptor may be expressed by keratinocyte cultures, we propose that ATP may mediate its antiproliferative effects via this purinoreceptor. Collectively, our results indicate that adenosine and adenine nucleotides abrogate exogenous epidermal growth factor-dependent and -independent keratinocyte proliferation at submillimolar concentrations and may be important physiologic regulators of keratinocyte growth in vivo. Further, these results suggest that these or related compounds may have application as treatments for epidermal growth factor receptor-signaling pathway has been activated.


Assuntos
Nucleotídeos de Adenina/farmacologia , Adenosina/farmacologia , Fator de Crescimento Epidérmico/antagonistas & inibidores , Fator de Crescimento Epidérmico/farmacologia , Queratinócitos/citologia , Nucleotídeos de Adenina/agonistas , Adenosina/agonistas , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Marcadores de Afinidade , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Células Clonais/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Recém-Nascido , Masculino , Células-Tronco/efeitos dos fármacos
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