RESUMEN
BACKGROUND: In vitro and clinical observations in HIV-infected patients receiving interferon alpha therapy have shown a reduction in HIV loads. Limited investigations have explored the innate or adaptive immune responses of IFN-alpha on SIV replication in vivo. METHODS: Seven chronically infected rhesus macaques were given pegylated IFN-alpha 2a (n = four) or saline (n = three) injections once weekly for 14 weeks. Weekly peripheral blood samples were taken for safety parameters, viral load determinations, and measurements of innate and adaptive immune responses. RESULTS: Pharmacokinetic measurements demonstrated therapeutic peg-IFN-alpha levels for the initial period of therapy and IFN-alpha inducible antiviral molecules were increased sporadically in the PBMC mRNA of the treatment group. Despite the demonstrable effect of the IFN-alpha injections, the treatment had no effect on plasma viral RNA levels. CONCLUSIONS: This work demonstrates that while short term IFN-alpha therapy induces innate antiviral immunity, it does not dramatically enhance or suppress viral replication. However, studies in the SIV model to determine therapeutic potential of chronic IFN-alpha therapy for the treatment of HIV will require macaque specific cytokines.
Asunto(s)
Antivirales/uso terapéutico , Interferón-alfa/uso terapéutico , Macaca , Enfermedades de los Monos/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Interferón alfa-2 , Interferón-alfa/farmacocinética , Interferón-alfa/farmacología , Polietilenglicoles/farmacocinética , Polietilenglicoles/farmacología , Proteínas Recombinantes , Viremia , Replicación Viral/efectos de los fármacosRESUMEN
The goal of this study was to optimize the hydroxyurea dosage in HIV-infected patients, and to minimize the toxicity and maximize the antiviral efficacy of the hydroxyurea-didanosine combination. In a randomized, open-label study (RIGHT 702, a multicenter trial performed in private and institutional practices), three daily doses (600 microg, 800-900 microg, and 1200 microg) of hydroxyurea were administered in combination with didanosine and stavudine to 115 chronically HIV-infected patients, one-third antiretroviral drug naive, with viremia between 5000 and 200,000 copies/ml regardless of CD4+ cell count. The primary efficacy end point was the proportion of patients with plasma HIV-1 RNA levels below 400 copies/ml after 24 weeks of therapy. In the RIGHT 702 intent-to-treat population the lowest (600 mg) dose of hydroxyurea was better tolerated, associated with fewer adverse events, and more potent by all efficacy parameters, including the primary end point (76 versus 60% patients with viremia<400 copies/ml at week 24 for the 600-mg and 800- to 900-mg dose groups, respectively; p=0.027), the mean area under the curve (60.3 versus 65.8; p=0.016), and the mean log10 decrease (-1.95 versus -0.77; p=0.001). Patients receiving 600 mg of hydroxyurea daily also had the highest CD4+ cell count, CD4+/CD8+ cell ratio, and lowest CD8+ cell count and percentage (p=0.035). The RIGHT 702 trial provides an explanation for the increased toxicity and decreased efficacy of hydroxyurea when it was used at high dosage (1200 mg daily). At the optimal dosage of 600 mg daily, hydroxyurea, in combination with didanosine, deserves reevaluation for the long-term management of HIV/AIDS worldwide, because of its excellent resistance profile, durability, and affordability.
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Fármacos Anti-VIH/administración & dosificación , Didanosina/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Hidroxiurea/administración & dosificación , Hidroxiurea/efectos adversos , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Relación CD4-CD8 , Didanosina/uso terapéutico , Quimioterapia Combinada , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , VIH , Infecciones por VIH/virología , Humanos , Hidroxiurea/uso terapéutico , Masculino , ARN Viral/sangre , Estavudina/administración & dosificación , Estavudina/uso terapéutico , Carga Viral , ViremiaRESUMEN
The safety and efficacy of hydroxyurea with didanosine in combination with stavudine in nucleoside reverse-transcriptase inhibitor (NRTI)-experienced patients was investigated. Entry criteria included HIV-1 infected, NRTI-experienced adults, with CD4(+) counts 50-550 cells/mm(3) and viral loads >or=12,500 copies/mL. Subjects were treated with didanosine 200 mg twice a day (BID), stavudine 40 mg BID, and hydroxyurea 1000 mg daily for 16 weeks. Thirty-one HIV-1 subjects with mean bDNA viral load 1x10(5) log(10) copies/mL and mean CD4(+) T-cell counts of 231 cells/mm(3) were enrolled. A 1.3 log(10) decrease in mean viral load was seen at 12 weeks of therapy. Prior didanosine use resulted in a more rapid response to therapy compared with prior zidovudine use. Side effects consisting of neutropenia, pancreatitis, and peripheral neuropathy occurred in four subjects and resolved upon withdrawal of therapy. This non-randomized study in subjects with a mean CD4(+) T-cell count of 230 cells/mm(3) demonstrates the antiviral activity of hydroxyurea+didanosine and stavudine. Toxicities related to therapy need to be followed closely. The results support the need for a randomized, prospective study to determine the safety and efficacy of hydroxyurea plus didanosine in antiretroviral-experienced patients with CD4(+) cell counts below 300 cells/mm(3).
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Antineoplásicos/administración & dosificación , Didanosina/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Hidroxiurea/administración & dosificación , Estavudina/administración & dosificación , Adulto , Fármacos Anti-VIH/efectos adversos , Antineoplásicos/efectos adversos , Terapia Antirretroviral Altamente Activa , Didanosina/efectos adversos , Esquema de Medicación , Quimioterapia Combinada , Femenino , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/aislamiento & purificación , Humanos , Hidroxiurea/efectos adversos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Estavudina/efectos adversos , Carga Viral , Zidovudina/administración & dosificaciónRESUMEN
OBJECTIVE: To investigate the effects of Z-100, an arabinomannan extracted from Mycobacterium tuberculosis, on the LP-BM5 murine leukemia virus (LP-BM5 MuLV) infection in mice. METHODS: C57BL/6 mice infected intraperitoneally with 4.5 x 10(2) PFU/mouse of LP-BM5 MuLV (MAIDS mice) were treated intraperitoneally with a 10-mg/kg dose of Z-100 every other day beginning 1 day after the viral infection. MAIDS mice treated with Z-100 were compared with control mice (MAIDS mice treated with saline) for their survival and splenomegaly after LP-BM5 infection. Cytokine-producing profiles of splenic T cells from these two groups of mice were also compared. RESULTS: When MAIDS mice treated with Z-100 were compared with those of control mice, a decrease in splenomegaly and lymphadenopathy was observed. Splenomegaly was markedly enhanced in MAIDS mice treated intraperitoneally with IL-4 or IL-10. When MAIDS mice were treated with Z-100, their survival rates were significantly increased compared to those of controls. Splenic T cells from control mice produced type-2 cytokines (IL-4 and IL-10). However, a decreased production of type-2 cytokines by splenic T cells from MAIDS mice treated with Z-100 was demonstrated. CONCLUSION: Z-100 could decrease the severity of the LP-BM5 MuLV infection through the regulation of MAIDS-associated type-2 T-cell responses.
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Fármacos Anti-VIH/uso terapéutico , Virus de la Leucemia Murina/fisiología , Lípidos/uso terapéutico , Mananos/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida del Murino/tratamiento farmacológico , Animales , Antagonismo de Drogas , Interleucina-10/biosíntesis , Interleucina-10/farmacología , Interleucina-4/biosíntesis , Interleucina-4/farmacología , Virus de la Leucemia Murina/patogenicidad , Enfermedades Linfáticas/tratamiento farmacológico , Enfermedades Linfáticas/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Síndrome de Inmunodeficiencia Adquirida del Murino/mortalidad , Tamaño de los Órganos/efectos de los fármacos , Organismos Libres de Patógenos Específicos , Bazo/efectos de los fármacos , Bazo/metabolismo , Bazo/patología , Esplenomegalia/tratamiento farmacológico , Esplenomegalia/patología , Tasa de Supervivencia , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Linfocitos T/patologíaRESUMEN
Thermally injured patients are very susceptible to infection with cytomegaloviruses. In this study a role of burn-associated type 2 T cell responses on the cytomegalovirus infection was examined in a mouse model of thermal injury. A predominance of type 2 T cell responses in splenic lymphocytes of thermally injured mice has been previously demonstrated. SCID mice inoculated with splenic T cells from thermally injured mice were susceptible to infection with a small amount (5 PFU/mouse) of murine cytomegalovirus (MCMV). Conversely, SCID mice inoculated with splenic T cells from normal mice were resistant to the same infection. High levels of IL-4 and IL-10, but not IFN-gamma and IL-2, were detected in sera of thermally injured mice (TI-mice) infected with MCMV when those were compared with sera of normal mice infected with MCMV. IL-4 and IL-10 (type 2 cytokines) were produced by splenic T cells from MCMV-infected TI-mice, when they were stimulated in vitro with anti-CD3 mAb. Type 1 cytokines (IFN-gamma and IL-2), however, were not produced by these T cells after the same stimulation. In contrast, splenic T cells from MCMV-infected normal mice produced type 1 cytokines by the stimulation with anti-CD3 mAb. These results suggest that the susceptibility of mice to MCMV infection is markedly influenced by burn-associated type 2 T cell responses.
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Quemaduras/complicaciones , Quemaduras/inmunología , Infecciones por Citomegalovirus/inmunología , Linfocitos T , Traslado Adoptivo/métodos , Animales , Citocinas/sangre , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Huésped Inmunocomprometido , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Factores de Riesgo , Bazo/inmunologíaRESUMEN
PURPOSE: The objective of this analysis was to assess the efficacy of nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing, protease inhibitor (PI)-sparing, three-drug highly active antiretroviral therapy (HAART) in HIV- 1-infected, treatment-naive patients with high and low baseline viral loads. METHOD: A composite analysis was performed of clinical studies including the NNRTI nevirapine that were presented at international conferences between 1998 and October 2000. In all of the studies, nevirapine was administered in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). For a study to be included in the analysis, more than 25% of participants must have had baseline viral loads >100,000 copies/mL, and more than 25% of participants must have had viral loads <100,000 copies/mL. RESULTS: After 6 months, 139 of 156 (89%) and 82 of 99 (83% ) patients in the low and high baseline viral load groups, respectively, had on-treatment viral loads <200 to 500 copies/mL (depending on assay used). After 12 months, 95 of 124 patients (77%) with lower baseline viral loads and 63 of 76 patients (83%) with high baseline viral loads had on-treatment viral loads below the limit of quantification. CONCLUSION: Baseline viral load does not affect virologic outcome in HIV-1-infected, antiretroviral-naive participants treated with nevirapine-containing, PI-sparing HAART.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Infecciones por VIH/tratamiento farmacológico , VIH-1/aislamiento & purificación , Nevirapina/uso terapéutico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Infecciones por VIH/virología , VIH-1/fisiología , Humanos , ARN Viral/sangre , Carga ViralRESUMEN
AIDS Clinical Trials Group (ACTG) 246/946 was a double-blinded, randomized, controlled trial of HIV-1 MN rgp160 ImmunoAG vaccine in HIV-infected patients with CD4(+) T cell counts >or=500 and 200-400/mm(3). The main objectives were to study the safety and immunogenicity of this vaccine and to study the persistence of the immune responses after vaccination over a longer period of time. Fifteen patients with CD4(+) T cell counts of >or=500/mm(3) were enrolled in the ACTG 246 study. ACTG 246 patients received a monthly injection of vaccine or control for 6 months and then injections every 2 months. After completion of this study, seven new patients with CD4(+) T cell counts of 200-400/mm(3) entered into the ACTG 946 study. These study patients received highly active antiretroviral therapy (HAART) (ritonavir, didanosine, and stavudine) for 9 weeks to stabilize their viral load and then each patient received a monthly injection of vaccine or control substance for 6 months with HAART. The study of these two relatively small populations showed that the vaccine was safe without any adverse effect both in the patients with CD4(+) T cell counts of >or=500 and 200-400/mm(3). The vaccine was also immunogenic in patients with CD4(+) T cell counts of >or=500/mm(3) as measured by gp160-specific lymphocyte proliferative responses, and it persisted after they had received more than six vaccine injections, for a longer period of time.
Asunto(s)
Vacunas contra el SIDA/uso terapéutico , Proteínas gp160 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/terapia , VIH-1/inmunología , Vacunas Sintéticas/uso terapéutico , Vacunas contra el SIDA/efectos adversos , Vacunas contra el SIDA/inmunología , Animales , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Chlorocebus aethiops , Seguridad de Productos para el Consumidor , Método Doble Ciego , Proteínas gp160 de Envoltorio del VIH/efectos adversos , Proteínas gp160 de Envoltorio del VIH/inmunología , Infecciones por VIH/prevención & control , Humanos , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/uso terapéutico , Linfocitos T Citotóxicos/inmunología , Vacunación , Vacunas Sintéticas/efectos adversos , Vacunas Sintéticas/inmunología , Células VeroRESUMEN
Monocyte chemoattractant protein (MCP)-1 has a pathogenic role in herpesvirus-induced encephalomyelitis (HSM). Anti-MCP-1 antibody greatly decreased HSM severity in mice infected with herpes simplex virus type 2 (HSM mice), compared with its effect in control HSM mice treated with rabbit immunoglobulin. HSM severity was markedly enhanced in mice previously treated with a mixture of interleukin (IL) 4 and -10. In response to stimulation with antigen, HSM mouse cells isolated from cerebrospinal fluids (CSF cells) produced IL-4 in culture fluids; however, IL-4 production decreased in CSF cells derived from HSM mice previously treated with anti-MCP-1 antibody. A macrophage population isolated in CSF cells from HSM mice (CSF-Mphi) produced MCP-1 in culture fluids. In response to stimulation with herpesvirus antigen, a population of T cells isolated from CSF cells from HSM mice (CSF-T cells) produced IL-4 into their culture fluids, although MCP-1 was not produced by CSF-T cells stimulated by this antigen. IL-4 production by CSF-T cells was markedly enhanced when they were stimulated with viral antigen in the presence of murine recombinant MCP-1 (rMCP-1). Furthermore, IL-4 was produced in naive splenic T cells cocultured with CSF-Mphi. These results indicate that the severity of HSM is influenced by MCP-1, which stimulates Th2 responses.
Asunto(s)
Quimiocina CCL2/fisiología , Encefalomielitis/inmunología , Encefalomielitis/virología , Herpes Simple/inmunología , Herpesvirus Humano 2/patogenicidad , Células Th2/inmunología , Animales , Anticuerpos/farmacología , Células Cultivadas , Líquido Cefalorraquídeo/inmunología , Quimiocina CCL2/inmunología , Quimiocina CCL2/farmacología , Chlorocebus aethiops , Encefalomielitis/líquido cefalorraquídeo , Herpes Simple/líquido cefalorraquídeo , Interleucina-4/biosíntesis , Cinética , Macrófagos/inmunología , Ratones , Ratones Endogámicos BALB C , Tasa de Supervivencia , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Células VeroRESUMEN
The Viral Activation Transfusion Study (VATS) was a randomized trial that compared leukocyte-reduced transfusions with unfiltered red blood cell transfusions in HIV and cytomegalovirus (CMV) antibody-positive patients with anemia who were undergoing their first blood transfusion. The relations of the baseline qualitative and quantitative polymerase chain reaction (PCR) measures of plasma CMV viremia, HIV RNA, CD4(+) cell counts, and quality of life in these study subjects were examined. The 511 study subjects had a median CD4(+) cell count equal to 15 cells/mm3, and 110 (21.5%) had CMV viremia by qualitative assay. In multivariate models, frequency of positive qualitative CMV increased with decreasing CD4(+) cell counts (p =.04 trend), higher HIV RNA (p <.001), and a history of CMV disease (p <.001). Quantitative CMV PCR were performed on the 110 qualitative assay-positive study subjects. Median CMV viral load was 1780 copies/ml. In multivariate regression models, lower CD4(+) cell count (p =.03), and a history of CMV disease (p <.001) correlated with the level of CMV load. HIV RNA load and CMV load were not correlated. A lower Karnofsky score was associated with both the presence and quantity of CMV DNA.
Asunto(s)
Transfusión Sanguínea , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/virología , Citomegalovirus/genética , Citomegalovirus/aislamiento & purificación , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , Adulto , Recuento de Linfocito CD4 , Citomegalovirus/fisiología , Infecciones por Citomegalovirus/tratamiento farmacológico , ADN Viral/análisis , ADN Viral/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/terapia , VIH-1/genética , VIH-1/fisiología , Humanos , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Calidad de Vida , ARN Viral/análisis , ARN Viral/genética , Análisis de Regresión , Factores de Tiempo , Carga ViralRESUMEN
To understand the nature of naive and memory T cell depletion in human immunodeficiency virus (HIV) immunopathogenesis, their homeostasis in peripheral blood (PB) and lymph node (LN) compartments of HIV-infected patients was examined. Although the percentage of naive CD4+ cells was higher in LN than in PB mononuclear cells (LNMC and PBMC, respectively), the memory cells were higher in PBMC than in LNMC. The ratio of naive:memory CD4+ cells from PB positively correlated with that in LNs and with the absolute CD4+ cell counts and recall antigen responses, and the ratio inversely correlated with the cellular virus load from the corresponding compartment. These findings indicate that although the pattern of naive and memory cells in the LN and PB compartments appear divergent, their relationship is nonrandom and is significant. The naive&rcolon;memory ratio in PB appears to reflect the lymphoid microenvironment and may potentially be useful as a surrogate marker for treatment efficacy and immune reconstitution.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , VIH/inmunología , Leucocitos Mononucleares/inmunología , Tejido Linfoide/inmunología , Subgrupos de Linfocitos T/fisiología , Adulto , Biomarcadores , Relación CD4-CD8 , Recuento de Células , Femenino , VIH/genética , Infecciones por VIH/sangre , Homeostasis , Humanos , Memoria Inmunológica , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Resultado del Tratamiento , Carga ViralRESUMEN
Mice 6 days after thermal injury (TI-mice) did not respond to lipopolysaccharide (LPS) stimulation for production of serum interleukin 12 (IL-12; 2 h after LPS stimulation, <20 pg/ml in TI-mice; 1091+/-162 pg/ml in normal mice). However, 2 h after LPS stimulation, 1456+/-118 pg/ml of IL-12 were demonstrated in sera of TI-mice previously treated with a 10 mg/kg i.p. dose of glycyrrhizin (GR). IL-12 was not induced by LPS in sera of normal mice inoculated with burn-associated type 2 T cells (IL-4/IL-10-producing CD8+CD11b+TCRgamma/delta+T cells isolated from spleens of TI-mice). However, IL-12 production was induced by LPS in sera of these mice previously treated with GR or a mixture of monoclonal antibodies (mAbs) for type 2 cytokines. Also, IL-12 production was induced by LPS in TI-mice inoculated with CD4+T cells from spleens of GR-treated normal mice (GR-CD4+T cells, 5x10(6)cells/mouse). Since GR-CD4+T cells have been shown to be antagonistic cells against production of type 2 cytokines by burn-associated type 2 T cells, these results indicate that IL-12 unresponsiveness shown in TI-mice is recovered by GR through the regulation of burn-associated type 2 T cell responses.
Asunto(s)
Quemaduras/metabolismo , Ácido Glicirrínico/farmacología , Interleucina-12/biosíntesis , Traslado Adoptivo , Animales , Antiinflamatorios no Esteroideos/farmacología , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Quemaduras/inmunología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Interleucina-10/inmunología , Interleucina-12/inmunología , Interleucina-4/inmunología , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Células Th2/efectos de los fármacos , Células Th2/inmunología , Células Th2/metabolismo , Células Th2/trasplanteRESUMEN
An unresponsive state for the production of interleukin-12 (IL-12) is commonly observed in animals and patients with severe thermal injuries. In the present study, the participation of corticosteroids, prostaglandin E(2) (PGE(2)), and type 2 cytokines, which appeared in association with thermal injury, on the burn-associated IL-12 unresponsiveness was studied. These substances have been described as inhibitors of IL-12 production. Less than 20 pg/ml serum IL-12 was produced in thermally injured mice (TI-mice) after stimulation with lipopolysaccharide (LPS), while 1037 pg/ml IL-12 was detected in sera of unburned mice equally stimulated with LPS. Almost complete restoration of the impaired IL-12 production was witnessed in TI-mice after treatment with soluble IL-4 receptor (50 ng/mouse, 2 h and 2 days after thermal injury). However, IL-12 was not induced by LPS stimulation in TI-mice treated with an inhibitor of PGE(2) (indomethacin, 0.1-5 mg/kg) or an inhibitor of corticosteroid production (ketoconazole, 10 mg/kg). LPS-stimulated IL-12 production was also impaired in normal mice inoculated with burn-associated type 2 T cells. In addition, in the presence of 1 microg/ml LPS, naive macrophages cocultured with burn-associated type 2 T cells did not produce IL-12 in their culture fluids, while IL-12 was produced by LPS-stimulated naive macrophages that were cocultured with naive splenic CD8(+) T cells. These results suggest that the IL-12-unresponsive state demonstrated in TI-mice is associated mainly with type 2 cytokines released from burn-associated type 2 T cells.
Asunto(s)
Quemaduras/metabolismo , Interleucina-12/metabolismo , Corticoesteroides/fisiología , Animales , Quemaduras/patología , Citocinas/clasificación , Citocinas/fisiología , Dinoprostona/fisiología , Interleucina-12/antagonistas & inhibidores , Ratones , Ratones Endogámicos BALB C , Valores de Referencia , Linfocitos T/fisiología , Linfocitos T/trasplanteRESUMEN
OBJECTIVES: Lymphoid tissue is a major reservoir for virus replication in HIV-infected subjects. The relationship of CCR5 and CXCR4 coreceptor density and HIV replication in peripheral blood mononuclear cells (PBMC) and lymph node (LN) mononuclear cells (LNMC) of HIV-infected subjects was examined. METHODS: PBMC and cervical LNMC from 12 HIV-infected patients were examined for virological and immunological parameters including chemokine receptor density, HIV plasma and cellular viral load, coreceptor usage and CD38/HLA-DR expression. RESULTS: The number of CCR5 and CXCR4 molecules on CD4 lymphocytes in the LN were significantly higher than in PBMC. In contrast the number of CD4 molecules/CD4 T cell was higher in PBMC than in LNMC. The CXCR4/CD4 and CCR5/CD4 ratios in the LN were significantly higher than in the PBMC. This was associated with a cellular viral load in the LN that was approximately 110-fold higher than in PBMC. The absolute number of coreceptor molecules per cell did not correlate with the viral load. However, the CCR5/CD4 and CXCR4/CD4 ratios in the LN positively correlated with HIV cellular and plasma RNA. Characterization of the viral isolates suggested an association between clinical isolates using a distinct coreceptor and the upregulation of the corresponding chemokine receptor. CONCLUSIONS: The ratios of chemokine receptors to CD4 molecules in CD4 T cells from LN is higher than in PBMC and may account for the relative difference in cellular viral load in these compartments. Additionally, the coreceptor/CD4 ratios, particularly in the lymphoid tissue, were highly related to HIV replication.
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Antígenos CD4/metabolismo , Infecciones por VIH/virología , VIH-1/fisiología , Leucocitos Mononucleares/virología , Ganglios Linfáticos/virología , Receptores CCR5/metabolismo , Receptores CXCR4/metabolismo , Replicación Viral , Adulto , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Infecciones por VIH/sangre , Infecciones por VIH/inmunología , VIH-1/genética , VIH-1/inmunología , Humanos , Leucocitos Mononucleares/inmunología , Ganglios Linfáticos/inmunología , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Receptores CCR5/biosíntesis , Receptores CXCR4/biosíntesis , Carga ViralRESUMEN
A pathogenic role of Th2 cells and their cytokine products (IL-4 and IL-10, Th2 cytokines) on the development of herpes simplex myelitis (HSM) was studied in mice exposed to footpad injection of herpes simplex virus type 2 (HSV-2). Morbidity and mortality of mice with HSM (HSM mice) increased when they were treated with a mixture of Th2 cytokines. Additionally, survival rates of HSM mice increased when they were treated with a mixture of mAbs for Th2 cytokines. As compared with HSM mice treated with saline, the growth of HSV-2 in spinal cords of HSM mice treated with the mixture of Th2 cytokines increased. Th2 cells (myelitis-associated Th2 cells, MTh2 cells) were demonstrated among cerebrospinal fluid cells from HSM mice. After the stimulation with HSV-2 antigen (Ag), MTh2 cells from HSM mice previously treated with the mixture of Th2 cytokines produced enhanced amounts of Th2 cytokines into their culture fluids, as compared with the amount of Th2 cytokines produced by MTh2 cells. Th2 cells were also demonstrated in mononuclear cells from spleens of HSM mice. When compared with HSM mice inoculated with splenic CD4(+) T cells from normal mice, morbidity and mortality of HSM mice inoculated with MTh2 cells markedly increased. These results indicated that the severity of HSM induced in mice by footpad injection of HSV-2 was influenced by MTh2 cells or Th2 cytokines released from these MTh2 cells. Th2 responses manifested in mice by HSV-2 infection may act as a pathogenic enhancer of HSM severities.
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Encefalitis por Herpes Simple/inmunología , Encefalitis por Herpes Simple/patología , Herpesvirus Humano 2 , Células Th2/inmunología , Células Th2/metabolismo , Traslado Adoptivo , Animales , Anticuerpos Monoclonales/farmacología , Líquido Cefalorraquídeo/citología , Líquido Cefalorraquídeo/inmunología , Líquido Cefalorraquídeo/virología , Encefalitis por Herpes Simple/mortalidad , Interleucina-10/biosíntesis , Interleucina-10/farmacología , Interleucina-4/biosíntesis , Interleucina-4/farmacología , Ratones , Ratones Endogámicos BALB C , Morbilidad , Células Th2/virologíaRESUMEN
The protective effect of a new antifungal compound, lanoconazole, against Cryptococcus neoformans infection in C57BL/6 mice exposed to LP-BM5 murine leukaemia virus (MuLV) (MAIDS mice) was investigated. Mice were infected intratracheally with C. neoformans, strain 613D, 40 days after infection with LP-BM5 MuLV. They were treated orally with various doses of lanoconazole or with fluconazole 10 mg/kg (a positive control) once daily beginning 1 day after the fungal infection and continuing until the end of the experimental period. The number of C. neoformans cells in the lungs and brains of infected mice was determined. Lanoconazole and fluconazole had a similar inhibitory effect on the growth of C. neoformans in the brains and lungs of normal mice. Whereas lanoconazole inhibited the growth of C. neoformans in the brains and lungs of MAIDS mice, the pathogen grew in the brains of MAIDS mice treated with fluconazole. Lanoconazole reduced the number of C. neoformans in the brains of normal mice treated with a type 2 cytokine mixture, whereas fluconazole did not. A predominance of type 2 T-cell responses was demonstrated in MAIDS mice. Splenic T cells from MAIDS mice, but not those from normal mice, released interleukins 4 and 10 into the culture medium when they were stimulated with an anti-CD3 monoclonal antibody. These results suggest that lanoconazole may have the potential to inhibit the growth of C. neoformans in AIDS patients with a predominance of type 2 T-cell responses.
Asunto(s)
Antifúngicos/uso terapéutico , Criptococosis/tratamiento farmacológico , Cryptococcus neoformans/crecimiento & desarrollo , Encefalitis/tratamiento farmacológico , Compuestos Heterocíclicos/uso terapéutico , Imidazoles/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida del Murino/complicaciones , Infecciones Oportunistas/tratamiento farmacológico , Animales , Encéfalo/microbiología , Criptococosis/complicaciones , Criptococosis/inmunología , Criptococosis/microbiología , Citocinas/biosíntesis , Citocinas/uso terapéutico , Encefalitis/complicaciones , Encefalitis/inmunología , Encefalitis/microbiología , Fluconazol/uso terapéutico , Pulmón/microbiología , Ratones , Ratones Endogámicos C57BL , Síndrome de Inmunodeficiencia Adquirida del Murino/inmunología , Síndrome de Inmunodeficiencia Adquirida del Murino/microbiología , Infecciones Oportunistas/complicaciones , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/microbiología , Bazo/citología , Células Th2/inmunologíaRESUMEN
The role of type 2 T cell responses on the severity of post-infectious encephalitis was investigated in a mouse model of influenza virus infection. When mice were infected intracerebrally with 3.0 LD(50) of A/NWS33 strain of influenza virus, they all showed clinical signs of encephalitis, and 90% of them died within 10 days of the infection. However, the post-infectious encephalitis was not demonstrated in mice exposed to 0.5 LD50 of the same virus. The mortality rates of mice infected with 0.5 LD(50) of the virus were increased to levels observed in mice exposed to 3.0 LD(50) of influenza virus infection, after the administration of a mixture of interleukin (IL)-4 and IL-10 (2 ng/mouse each; immediately, 1 and 2 days after the infection). In contrast, mortality rates of mice exposed to 3.0 LD(50) of influenza virus were substantially decreased when these mice were treated with a mixture of monoclonal antibodies directed against IL-4 and IL-10. A predominance of type 2 T cell responses was demonstrated in splenic T cells of mice infected with 3.0 LD(50) of influenza virus, although these responses were minimal in mice infected with 0.5 LD(50) of the virus. After the treatment with the mixture of type 2 cytokines, an increase in the type 2 T cell responses in mice exposed to 0.5 LD(50) of the virus was shown. These results indicate that type 2 T cell responses associated with the viral infection play an important role in the severity of post-infectious encephalitis induced in mice by the intracerebral infection of influenza A virus.
Asunto(s)
Encefalitis Viral/inmunología , Infecciones por Orthomyxoviridae/inmunología , Orthomyxoviridae/inmunología , Células Th2/inmunología , Animales , Interleucina-10/administración & dosificación , Interleucina-10/inmunología , Interleucina-4/administración & dosificación , Interleucina-4/inmunología , Ratones , Ratones Endogámicos BALB CRESUMEN
Human immunodeficiency virus (HIV)-infected subjects receiving zidovudine were randomized either to add stavudine (d4T) or didanosine (ddI) to their current regimen or to switch to ddI or d4T monotherapy. After 16 weeks of therapy, the mean reduction in HIV RNA from baseline was 0.14 log(10) copies/mL in patients receiving d4T or zidovudine plus d4T. In subjects receiving ddI or ddI plus zidovudine, reductions were 0.39 and 0.56 log(10), respectively. CD4 cell counts remained stable or showed modest increases in all arms except the zidovudine plus d4T arm. Patients receiving zidovudine plus d4T showed progressive declines in CD4 cell counts with a median of 22 cells/mm(3) below baseline by 16 weeks. Examination of intracellular levels of d4T-triphosphate in 6 subjects was consistent with previous in vitro studies demonstrating pharmacologic antagonism between zidovudine and d4T. Analysis of these data suggests that zidovudine and d4T should not be prescribed in combination and that ddI provides greater antiviral activity than d4T in zidovudine-treated patients.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Estavudina/uso terapéutico , Zidovudina/uso terapéutico , Adulto , Recuento de Linfocito CD4 , Quimioterapia Combinada , Femenino , VIH/efectos de los fármacos , VIH/genética , Humanos , Masculino , ARN Viral/efectos de los fármacos , ARN Viral/metabolismo , Estavudina/antagonistas & inhibidores , Zidovudina/antagonistas & inhibidoresRESUMEN
The relationship of the neutralizing activity (NA) profile of sera from human immunodeficiency virus (HIV)-infected individuals to the HIV viral load and the absolute CD4 count was examined. The NA of 24 serum samples against autologous isolates (AI) and HIV type 1 strain MN was examined. Three NA patterns were recognized. Nine sera neutralized both AI and MN (+/+), six sera neutralized MN but not AI (-/+), and nine sera failed to neutralize both AI and MN (-/-). The identification of the three neutralization patterns (+/+, -/+, and -/-) indicated that resistance to neutralization was progressive. A reciprocal relationship between the viral burden of the patients and the NA profiles was observed. The nine subjects with a -/- NA profile had a plasma viral load of > or =5 x 10(4) copies/ml and a cellular viral burden of > or =1,122 infectious units per million viable cells, which were significantly different from those of the other groups (P < 0.02). These patterns were independent of the phenotypic characteristics of the virus. Longitudinally, subjects with a -/- profile at baseline gained their HIV-specific NA by 24 weeks of antiretroviral therapy when this was associated with a >/=1-log(10) decline in the plasma HIV viral load. The sera from week 24 from some patients were able to neutralize both the 24-week and the baseline dominant virus isolates. A change in CD4 cell count of 50 or more in either direction predicted a -/- or +/+ profile. The verification of the autologous NA profile might be important in selecting patients who may benefit from immune-based therapies involving neutralizing monoclonal antibodies.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/diagnóstico , Síndrome de Inmunodeficiencia Adquirida/inmunología , Recuento de Linfocito CD4 , Antígenos VIH/análisis , VIH/inmunología , Carga Viral , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Fármacos Anti-VIH/uso terapéutico , Anticuerpos Antivirales/administración & dosificación , Anticuerpos Antivirales/sangre , Biomarcadores , Progresión de la Enfermedad , Femenino , VIH/genética , Humanos , Inmunoglobulinas Intravenosas , Inmunofenotipificación , Masculino , Mutación , Pruebas de Neutralización , ARN Viral/sangre , Especificidad de la Especie , Viremia/diagnóstico , Viremia/tratamiento farmacológico , Viremia/inmunologíaRESUMEN
Compared with normal mice, MAIDS mice (mice infected with LP-BM5 murine leukemia virus) exhibited an increase up to 100 times greater in susceptibility to infection with Candida albicans. The impaired resistance of MAIDS mice to the infection was recovered to levels observed in normal mice by the administration of glycyrrhizin (GR), an active component of licorice roots. MAIDS mice inoculated with CD4(+) T cells from GR-treated mice were also resistant to C. albicans infection. Normal mice inoculated with CD4(+) T helper type 2 cells (Th2 cells) from MAIDS mice were susceptible to C. albicans infection at the same levels shown in MAIDS mice. The susceptibility of normal mice inoculated with type 2 T cells was reversible by (i) administration of GR and (ii) inoculation of CD4(+) T cells from GR-treated mice and injection of a mixture of mAbs targeted against type 2 cytokines (IL-4 and IL-10). Type 2 cytokines were not detected in sera of MAIDS mice inoculated with CD4(+) T cells from GR-treated mice, while they were present in sera of MAIDS mice treated with saline. These results suggest that, by inducing CD4(+) T cells which suppress type 2 cytokine production by MAIDS-associated Th2 cells, GR improves the resistance of MAIDS mice to C. albicans infection.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/inmunología , Antifúngicos/farmacología , Candidiasis/inmunología , Ácido Glicirrínico/farmacología , Síndrome de Inmunodeficiencia Adquirida del Murino/inmunología , Células Th2/inmunología , Animales , Anticuerpos Monoclonales/farmacología , Formación de Anticuerpos , Linfocitos T CD4-Positivos/inmunología , Candida albicans/efectos de los fármacos , Susceptibilidad a Enfermedades/inmunología , Inmunidad Innata/efectos de los fármacos , Interleucina-10/inmunología , Interleucina-4/inmunología , Ratones , Ratones Endogámicos C57BLRESUMEN
Factors affecting patient adherence to therapy, such as frequent daily dosing and complex dosing schedules, are widely understood to be key obstacles to the durability of effective anti-HIV therapy. Didanosine, a nucleoside analogue reverse transcriptase inhibitor (NRTI) that is a core component of combination antiretroviral regimens, is currently indicated for twice-daily dosing. However, the active metabolite of didanosine (2',3'-dideoxyadenosine-5'-triphosphate) has a long intracellular half-life that supports the use of didanosine in a more patient-friendly, once-daily dosing schedule. Clinical studies in which didanosine was administered either once or twice daily, as monotherapy or in combination with another NRTI, have demonstrated the equivalence of both dosing schedules, with respect to safety and tolerability, virologic and immunologic endpoints, and short-term clinical effects (e.g., weight gain). Preliminary results from recent studies support the clinical efficacy and utility of once-daily didanosine in combination antiretroviral regimens that provide maximal drug exposure, while allowing for once- or twice-daily dosing of all component drugs.