Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
BMC Res Notes ; 7: 752, 2014 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-25338959

RESUMO

BACKGROUND: Approximately one-third of the AIDS cases in the United States have been attributed to the use of injected drugs, frequently involving the abuse of opioids. Consequently, it is critical to address whether opioid use directly contributes to altered susceptibility to HIV-1 beyond the increased risk of exposure. Previous in vitro and in vivo studies addressing the role of µ-opioid agonists in altering levels of the co-receptor CXCR4 and subsequent HIV-1 replication have yielded contrasting results. The bone marrow is believed to be a potential anatomical sanctuary for HIV-1. METHODS: The well-characterized CD34+CD38+ human bone marrow-derived hematopoietic progenitor cell line TF-1 was used as a model to investigate the effects of the µ-opioid receptor-specific peptide DAMGO (D-Ala2,N-Me-Phe4, Gly5-ol-enkephalin) on CXCR4 expression as well as infection of undifferentiated human hematopoietic progenitor cells. RESULTS: The results revealed the presence of the µ-opioid receptor-1 isoform (MOR-1) on the surface of TF-1 cells. Furthermore, immunostaining revealed that the majority of TF-1 cells co-express MOR-1 and CXCR4, and a subpopulation of these double-positive cells express the two receptors in overlapping membrane domains. Three subpopulations of TF-1 cells were categorized based on their levels of surface CXCR4 expression, defined as non-, low-, and high-expressing. Flow cytometry indicated that treatment with DAMGO resulted in a shift in the relative proportion of CXCR4+ cells to the low-expressing phenotype. This result correlated with a >3-fold reduction in replication of the X4 HIV-1 strain IIIB, indicating a role for the CXCR4 high-expression subpopulation in sustaining infection within this progenitor cell line. CONCLUSIONS: These experiments provide insight into the impact of µ-opioid exposure with respect to inhibition of viral replication in this human TF-1 bone marrow progenitor cell line model.


Assuntos
Células da Medula Óssea/citologia , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , HIV-1/fisiologia , Células-Tronco Hematopoéticas/virologia , Receptores CXCR4/metabolismo , Receptores Opioides mu/agonistas , Replicação Viral/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , HIV-1/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Transporte Proteico/efeitos dos fármacos , Receptores Opioides mu/metabolismo
2.
J Acquir Immune Defic Syndr ; 66(3): 256-64, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24732878

RESUMO

BACKGROUND: This study evaluated the relationship between illicit drug use and HIV-1 disease severity in HIV-1-infected patients enrolled in the DREXELMED HIV/AIDS Genetic Analysis Cohort. Because cocaine is known to have immunomodulatory effects, the cytokine profiles of preferential nonusers, cocaine users, and multidrug users were analyzed to understand the effects of cocaine on cytokine modulation and HIV-1 disease severity. METHODS: Patients within the cohort were assessed approximately every 6 months for HIV-1 clinical markers and for history of illicit drug, alcohol, and tobacco use. The Luminex human cytokine 30-plex panel was used for cytokine quantitation. Analysis was performed using a newly developed biostatistical model. RESULTS: Substance abuse was common within the cohort. Using the drug screens at the time of each visit, the subjects in the cohort were categorized as preferential nonusers, cocaine users, or multidrug users. The overall health of the nonuser population was better than that of the cocaine users, with peak and current viral loads in nonusers substantially lower than those in cocaine and multidrug users. Among the 30 cytokines investigated, differential levels were established within the 3 populations. The T-helper 2 cytokines, interleukin-4 and -10, known to play a critical role during HIV-1 infection, were positively associated with increasing cocaine use. Clinical parameters such as latest viral load, CD4 T-cell counts, and CD4:CD8 ratio were also significantly associated with cocaine use, depending on the statistical model used. CONCLUSIONS: Based on these assessments, cocaine use seems to be associated with more severe HIV-1 disease.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/imunologia , Citocinas/metabolismo , Infecções por HIV/imunologia , HIV-1 , Adulto , Negro ou Afro-Americano , Transtornos Relacionados ao Uso de Cocaína/virologia , Estudos de Coortes , Feminino , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Carga Viral
3.
J Virol ; 86(16): 8472-81, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22647699

RESUMO

The HIV-1 capsid (CA) protein plays essential roles in both early and late stages of virl replication and has emerged as a novel drug target. We report hybrid structure-based virtual screening to identify small molecules with the potential to interact with the N-terminal domain (NTD) of HIV-1 CA and disrupt early, preintegration steps of the HIV-1 replication cycle. The small molecule 4,4'-[dibenzo[b,d]furan-2,8-diylbis(5-phenyl-1H-imidazole-4,2-diyl)]dibenzoic acid (CK026), which had anti-HIV-1 activity in single- and multiple-round infections but failed to inhibit viral replication in peripheral blood mononuclear cells (PBMCs), was identified. Three analogues of CK026 with reduced size and better drug-like properties were synthesized and assessed. Compound I-XW-053 (4-(4,5-diphenyl-1H-imidazol-2-yl)benzoic acid) retained all of the antiviral activity of the parental compound and inhibited the replication of a diverse panel of primary HIV-1 isolates in PBMCs, while displaying no appreciable cytotoxicity. This antiviral activity was specific to HIV-1, as I-XW-053 displayed no effect on the replication of SIV or against a panel of nonretroviruses. Direct interaction of I-XW-053 was quantified with wild-type and mutant CA protein using surface plasmon resonance and isothermal titration calorimetry. Mutation of Ile37 and Arg173, which are required for interaction with compound I-XW-053, crippled the virus at an early, preintegration step. Using quantitative PCR, we demonstrated that treatment with I-XW-053 inhibited HIV-1 reverse transcription in multiple cell types, indirectly pointing to dysfunction in the uncoating process. In summary, we have identified a CA-specific compound that targets and inhibits a novel region in the NTD-NTD interface, affects uncoating, and possesses broad-spectrum anti-HIV-1 activity.


Assuntos
Fármacos Anti-HIV/farmacologia , Proteínas do Capsídeo/antagonistas & inibidores , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Desenvelopamento do Vírus/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/toxicidade , Calorimetria , Linhagem Celular , Humanos , Testes de Sensibilidade Microbiana , Ligação Proteica , Reação em Cadeia da Polimerase em Tempo Real , Transcrição Reversa/efeitos dos fármacos , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Ressonância de Plasmônio de Superfície , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
4.
Biomed Pharmacother ; 64(10): 723-32, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21106331

RESUMO

Previous investigations showing that polydisperse biguanide (PDBG) molecules have activity against human immunodeficiency virus type 1 (HIV-1) also suggested a relationship between PDBG biologic activity and the lengths of hydrocarbon linkers surrounding the positively charged biguanide unit. To better define structure-activity relationships, PDBG molecules with select linker lengths were evaluated for cytotoxicity, anti-HIV-1 activity, and in vivo toxicity. Results of the in vitro experiments demonstrated that increases in linker length (and, therefore, increases in compound lipophilicity) were generally associated with increases in cytotoxicity and antiviral activity against HIV-1. However, a relationship between linker length asymmetry and in vitro therapeutic index (TI) suggested structural specificity in the mechanism of action against HIV-1. Polyethylene hexamethylene biguanide (PEHMB; biguanide units spaced between alternating ethylene and hexamethylene linkers) was found to have the highest in vitro TI (CC50/IC50) among the compounds examined. Recent improvements in PEHMB synthesis and purification have yielded preparations of PEHMB with in vitro TI values of 266 and 7000 against HIV-1 strains BaL and IIIB, respectively. The minimal toxicity of PEHMB relative to polyhexamethylene biguanide (PHMB; biguanide units alternating with hexamethylene linkers) in a murine model of cervicovaginal microbicide toxicity was consistent with considerable differences in cytotoxicity between PEHMB and PHMB observed during in vitro experiments. These structure-activity investigations increase our understanding of PDBG molecules as agents with activity against HIV-1 and provide the foundation for further preclinical studies of PEHMB and other biguanide-based compounds as antiviral and microbicidal agents.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Biguanidas/química , Biguanidas/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Animais , Fármacos Anti-HIV/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Biguanidas/síntese química , Linhagem Celular , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Camundongos , Modelos Animais , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Polietilenos/química , Polietilenos/farmacologia , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...