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1.
J Virol ; 75(22): 11227-33, 2001 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11602763

RESUMEN

Twenty-four of over 24,000 patients genotyped over the past 3 years were found to have human immunodeficiency virus (HIV) isolates that possess an insert in the protease gene. In this report, we evaluated the spectrum of protease gene insertion mutations in patient isolates and analyzed the effect of these various insertion mutations on viral phenotypes. The inserts were composed of 1, 2, 5, or 6 amino acids that mapped at or between codons 35 and 38, 17 and 18, 21 and 25, or 95 and 96. Reduced susceptibility to protease inhibitors was found in isolates which possess previously reported drug resistance mutations. Fitness assays, including replication and competition experiments, showed that most of the isolates with inserts grew somewhat better than their counterparts with a deletion of the insert. These experiments demonstrate that, rarely, insertion mutations can develop in the HIV type 1 protease gene, are no more resistant than any other sequences which have similar associated resistance mutations, and can provide a borderline advantage in replication.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/virología , Proteasa del VIH/genética , Mutagénesis Insercional , Genotipo , VIH-1/clasificación , VIH-1/efectos de los fármacos , VIH-1/fisiología , Humanos , Recombinación Genética , Replicación Viral
2.
AIDS Res Hum Retroviruses ; 17(15): 1371-8, 2001 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-11679149

RESUMEN

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 Vero
3.
Antimicrob Agents Chemother ; 45(8): 2276-9, 2001 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-11451685

RESUMEN

The T69D mutation in the human immunodeficiency virus type 1 reverse transcriptase (RT) gene has been associated with reduced susceptibility to dideoxycytosine (ddC); however, several other mutations at codon 69 have been observed in antiretroviral drug-treated patients. The Stanford HIV RT and Protease Sequence Database was interrogated and showed that 23% of patients treated with nucleoside RT inhibitors (NRTI) had mutations at codon 69. These variants included T69N, -S, -A, -G, -E, -I, and -K mutations that were present in patients treated with NRTI but not in drug-naive patients. Treatment history information showed that a substantial percentage of these codon 69 changes occurred in patients administered non-ddC-containing regimens. Different and specific patterns of other RT gene mutations were associated with the various codon 69 mutations. Drug susceptibility assays showed that viral constructs containing codon 69 variants could have reduced susceptibility to ddC and other RT inhibitors. These results suggest that the T69D mutation is not the only codon 69 variant associated with drug resistance and that ddC is not the only drug affected.


Asunto(s)
Transcriptasa Inversa del VIH/genética , VIH-1/efectos de los fármacos , Mutación , Inhibidores de la Transcriptasa Inversa/farmacología , Codón , Farmacorresistencia Microbiana , Variación Genética , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/química , VIH-1/enzimología , Humanos , Inhibidores de la Transcriptasa Inversa/uso terapéutico
4.
J Clin Microbiol ; 39(4): 1522-9, 2001 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11283081

RESUMEN

We assessed the reproducibility of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and protease sequencing using cryopreserved plasma aliquots obtained from 46 heavily treated HIV-1-infected individuals in two laboratories using dideoxynucleotide sequencing. The rates of complete sequence concordance between the two laboratories were 99.1% for the protease sequence and 99.0% for the RT sequence. Approximately 90% of the discordances were partial, defined as one laboratory detecting a mixture and the second laboratory detecting only one of the mixture's components. Only 0.1% of the nucleotides were completely discordant between the two laboratories, and these were significantly more likely to occur in plasma samples with lower plasma HIV-1 RNA levels. Nucleotide mixtures were detected at approximately 1% of the nucleotide positions, and in every case in which one laboratory detected a mixture, the second laboratory either detected the same mixture or detected one of the mixture's components. The high rate of concordance in detecting mixtures and the fact that most discordances between the two laboratories were partial suggest that most discordances were caused by variation in sampling of the HIV-1 quasispecies by PCR rather than by technical errors in the sequencing process itself.


Asunto(s)
Proteasa del VIH/genética , Transcriptasa Inversa del VIH/genética , VIH-1/enzimología , Laboratorios/normas , Mutación , Análisis de Secuencia de ADN , Secuencia de Aminoácidos , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Secuencia de Bases , Farmacorresistencia Microbiana/genética , Quimioterapia Combinada , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Proteasa del VIH/sangre , Proteasa del VIH/química , Transcriptasa Inversa del VIH/sangre , Transcriptasa Inversa del VIH/química , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , ARN Viral/sangre , Reproducibilidad de los Resultados , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/uso terapéutico
5.
AIDS Res Hum Retroviruses ; 17(5): 401-7, 2001 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-11282008

RESUMEN

The objective of this work was to test the antiviral activity of a potent nucleoside reverse transcriptase inhibitor, 3'-fluoro-3'-deoxythymidine (FLT), on both a wild-type human immunodeficiency virus (HIV-1) isolate and multidrug-resistant HIV-1 patient isolates. Drug-resistant viral isolates were selected on the basis of four different categories of well-characterized and representative multidrug-resistant mutants. The isolates included three variants containing 151M alone or in combination; three variants containing 215Y and 41L, 67N, 184V, 210W, and 219N in combination; two insertion mutant viruses (69 + EA and 69 + SA); and two deletion mutant viruses (del67NG and del67GS), the latter two groups both also containing other significant mutations. The activity of FLT and AZT against these isolates was determined by drug susceptibility assays and by measuring viral antigen p24 by ELISA. The cytotoxicity of FLT and AZT was assessed in PHA-stimulated PBMCs. Development of resistant mutants under FLT pressure was attempted by passaging HIV-1 isolates in SupT1 cells and stepwise increasing the concentration of FLT. The multidrug-resistant mutant HIV-1 isolates exhibited 7-fold to >100-fold increased resistance to AZT, but showed IC(50) values for FLT of 0.0014-0.0168 microM, which were lower than or similar to that of wild type (0.0075 microM). The cellular cytotoxicities of FLT and AZT fell into a similar range in PBMCs. The development of HIV mutants resistant to FLT appeared to be slower than for other RT inhibitors. HIV isolates with mutations resulting in multidrug resistance had no evidence of resistance to FLT. FLT may be useful in salvage therapies for patients harboring resistant strains and a reassessment of its therapeutic potential seems required.


Asunto(s)
Células Clonales/virología , Didesoxinucleósidos/farmacología , Resistencia a Múltiples Medicamentos/genética , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-1/genética , Inhibidores de la Transcriptasa Inversa/farmacología , Zidovudina/farmacología , Didesoxinucleósidos/uso terapéutico , Evaluación Preclínica de Medicamentos , Farmacorresistencia Microbiana/genética , Infecciones por VIH/genética , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/genética , VIH-1/aislamiento & purificación , Humanos , Mutación , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Replicación Viral/efectos de los fármacos , Replicación Viral/genética
6.
J Virol ; 74(22): 10707-13, 2000 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11044115

RESUMEN

Point mutations and inserts in the beta3-beta4 region of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) are associated with resistance to nucleoside analog inhibitors. This report describes HIV-1 strains from seven patients that were found to have a 3-bp deletion in the beta3-beta4 region of the RT gene. These patient strains also had a mean of 6.2 drug resistance-associated mutations in their RT genes (range, 3 to 10 mutations). The deletion was most frequently found in strains with the Q151M mutation. Nonnucleoside RT inhibitor mutations were found in six of seven strains. Culture-based drug sensitivity assays showed that deletion-containing isolates had reduced susceptibility to four to eight RT inhibitors. Site-directed mutagenesis experiments showed that the deletion alone conferred reduced susceptibility to nucleoside analogs. Changes in the three-dimensional models of the RT deletion mutants were consistently observed at the beta3-beta4 loop and at helices C and E in both the presence and the absence of dTTP. Loss of hydrogen bonds between the RT and dTTP were also observed in the RT deletion mutant. These results suggest that the deletion in the RT gene contributes to resistance to several nucleoside analogs through a complex interaction with other mutations in the RT gene.


Asunto(s)
Transcriptasa Inversa del VIH/química , Transcriptasa Inversa del VIH/genética , VIH-1/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/farmacología , Eliminación de Secuencia , Farmacorresistencia Microbiana , Genotipo , Infecciones por VIH/virología , VIH-1/enzimología , VIH-1/genética , Humanos , Modelos Moleculares , Fenotipo , Conformación Proteica , Estructura Secundaria de Proteína , Alineación de Secuencia , Homología de Secuencia de Aminoácido
7.
J Infect Dis ; 182(5): 1357-64, 2000 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11023459

RESUMEN

The potential role of human immunodeficiency virus type 1 (HIV-1)-specific immune responses in controlling viral replication in vivo has stimulated interest in enhancing virus-specific immunity by vaccinating infected individuals with HIV-1 or its components. These studies were undertaken to define patient populations most likely to respond to vaccination, with the induction of novel HIV-1-specific cellular immune responses, and to compare the safety and immunogenicity of several candidate recombinant HIV-1 envelope vaccines and adjuvants. New lymphoproliferative responses (LPRs) developed in <30% of vaccine recipients. LPRs were elicited primarily in study participants with a CD4 cell count >350 cells/mm(3) and were usually strain restricted. Responders tended to be more likely than nonresponders to have an undetectable level of HIV-1 RNA at baseline (P=.067). Induction of new cellular immune responses by HIV-1 envelope vaccines is a function of the immunologic stage of disease and baseline plasma HIV-1 RNA level and exhibits considerable vaccine strain specificity.


Asunto(s)
Vacunas contra el SIDA/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida/terapia , Proteínas del Envoltorio Viral/inmunología , Vacunas contra el SIDA/efectos adversos , Vacunas contra el SIDA/inmunología , Síndrome de Inmunodeficiencia Adquirida/inmunología , Síndrome de Inmunodeficiencia Adquirida/virología , Método Doble Ciego , Femenino , Humanos , Activación de Linfocitos , Masculino , ARN Viral/análisis
8.
AIDS Res Hum Retroviruses ; 16(14): 1357-69, 2000 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-11018855

RESUMEN

This study examines sequential lymph nodes from 13 drug-naive patients before and after 24 weeks of highly active antiretroviral therapy (HAART). A multipronged approach was used to study changes in HIV-1 RNA in each paired lymph node in relation to tissue architecture and frequency of naive T cells. After 24 weeks, all patients showed significant suppression of plasma viral load and 12 of 13 showed concordant viral suppression in the lymph node (p = 0.001). Using in situ hybridization and quantitative image analysis, we showed that HIV-1 RNA was reduced to below detectable levels (two copies per cell) in follicular dendritic cell (FDC) and mononuclear cell pools. Independent immunohistochemical analysis of lymph node sections revealed that 5 of 13 patients displayed increased FDC networks and 6 of 13 showed no change and all patients showed increases in tissue-resident CD4+ cells. All lymph node biopsies at 24 weeks showed increased proportions of CD4+ and CD8+ cells coexpressing the naive markers CD45RA and CD62L when compared with baseline values. Significant correlations existed between viral load suppression and loss of activated CD8+ T cells after 24 weeks in both lymph node and blood, which was mirrored by significantly lowered frequencies of activated peripheral Gag peptide/MHC tetramer+ CD8+ cells. Overall, these data show that a potent and successful treatment strategy that significantly suppresses and removes FDC-resident HIV-1 results in improvements in lymphoid architecture and by so doing provides the structures available for increased numbers of naive cells to interact with cognate antigen. In addition, our article shows that suppression of HIV-1 replication results in diminished frequencies of peripherally activated antigen-specific CD8+ cells.


Asunto(s)
Terapia Antirretroviral Altamente Activa , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/fisiología , Ganglios Linfáticos/virología , Subgrupos de Linfocitos T/inmunología , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/inmunología , Humanos , Inmunohistoquímica , Leucocitos Mononucleares/inmunología , Activación de Linfocitos/inmunología , ARN Viral/sangre , Carga Viral
9.
Cell Transplant ; 9(3): 307-17, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-10972330

RESUMEN

Peripheral blood samples from HIV-seropositive individuals enrolled in a pilot clinical trial investigating the use of allogeneic dendritic cell therapy were evaluated for mixed chimerism. In this study, dendritic cells from HLA-identical, HIV-seronegative siblings were used. Patients received an infusion of dendritic cells pulsed with HIV MN gp160 protein or with peptides from HLA-A2 restricted epitopes of env, gag, and pol proteins every month for 6-9 months. Of the five allogeneic dendritic cell recipients, two showed increases in HIV antigen-specific immune responses. Allele-specific polymorphisms were identified in three sib-pairs that allowed infused donor cells to be detected using sensitive PCR-based molecular methods. Analysis of blood samples from patients showed similar patterns of donor cell persistence after the first infusion, in that cells were detectable for at least 1 week. Also, differences were observed in the kinetics of cell survival between the first and subsequent infusion cycles in all three patients. This suggests variation in HIV-specific immune responses detected among these three patients was not due to differences in persistence of infused donor cells.


Asunto(s)
Traslado Adoptivo , ADN/genética , Células Dendríticas/trasplante , Infecciones por VIH/terapia , Repeticiones de Minisatélite , Supervivencia Celular , ADN/sangre , Femenino , Marcadores Genéticos , Globinas/genética , Humanos , Inmunoterapia Adoptiva , Masculino , Núcleo Familiar , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Quimera por Trasplante , Cromosoma Y/genética
10.
AIDS ; 14(9): F83-93, 2000 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-10894268

RESUMEN

OBJECTIVE: To determine the short-term effects of using genotypic antiretroviral resistance testing (GART) with expert advice in the management of patients failing on a protease inhibitor and two nucleoside reverse transcriptase inhibitors. DESIGN: Prospective randomized controlled trial. SETTING: Multicenter community-based clinical trials network. PATIENTS: One-hundred and fifty-three HIV-infected adults with a threefold or greater rise in plasma HIV-1 RNA on at least 16 weeks of combination antiretroviral therapy. INTERVENTIONS: Randomization was either to a GART group, where genotype interpretation and suggested regimens were provided to clinicians, or to a no-GART group, where treatment choices were made without such input. MAIN OUTCOMES MEASURES: Plasma HIV-1 RNA levels and CD4 cell counts were measured at 4, 8, and 12 weeks following randomization. The primary endpoint was change in HIV-1 RNA levels from baseline to the average of the 4 and 8 week levels. RESULTS: The average baseline CD4 cell count was 230 x 10(6) cells/l and the median HIV-1 RNA was 28,085 copies/ml. At entry, 82 patients were failing on regimens containing indinavir, 51 on nelfinavir, 11 on ritonavir, and nine on saquinavir. HIV-1 RNA, averaged at 4 and 8 weeks, decreased by 1.19 log10 for the 78 GART patients and -0.61 log10 for the 75 no-GART patients (treatment difference: -0.53 log, 95% confidence interval, -0.77 to -0.29; P = 0.00001). Overall, the best virologic responses occurred in patients who received three or more drugs to which their HIV-1 appeared to be susceptible. CONCLUSION: In patients failing triple drug therapy, GART with expert advice was superior to no-GART as measured by short-term viral load responses.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Microbiana/genética , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Síndrome de Inmunodeficiencia Adquirida/sangre , Síndrome de Inmunodeficiencia Adquirida/inmunología , Adulto , Recuento de Linfocito CD4 , Quimioterapia Combinada , Femenino , Genotipo , Infecciones por VIH/sangre , Infecciones por VIH/inmunología , Inhibidores de la Proteasa del VIH/uso terapéutico , Transcriptasa Inversa del VIH/genética , VIH-1/aislamiento & purificación , Humanos , Masculino , Mutación , ARN Viral/sangre , ARN Viral/genética , Carga Viral
11.
Antivir Ther ; 5(1): 57-63, 2000 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10846594

RESUMEN

The frequency of protease and reverse transcriptase (RT) gene mutations was determined in HIV-1 strains from 153 patients entering the CPCRA 046 (GART) study who were failing triple-drug regimens consisting of one protease inhibitor (PI) and two RT inhibitors. Population-based sequence analyses showed that nearly all patients had similar RT gene mutations regardless of prior drug exposure, although the M184V mutation was significantly less prevalent in patients not recently treated with lamivudine. Whilst typical inhibitor-specific ('signature') protease gene mutations were found in patients failing their first PI, these mutations were significantly less likely to be found in patients exposed to two or more PIs. Protease gene mutations associated with multi-PI resistance were more likely to be observed in patients treated with more than one PI. These results suggest sequential treatment with PIs select for a relatively limited number of protease gene mutations that likely originated during early PI therapy. These protease gene mutations and a similarly limited set of RT gene mutations appear to be responsible for treatment failure in antiretroviral therapy.


Asunto(s)
Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/genética , Mutación , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Microbiana/genética , Quimioterapia Combinada , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Proteasa del VIH/genética , Transcriptasa Inversa del VIH/genética , VIH-1/enzimología , Humanos , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Insuficiencia del Tratamiento
12.
Ann Intern Med ; 131(11): 813-21, 1999 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-10610625

RESUMEN

BACKGROUND: Tests for resistance to HIV drugs are available for clinical use; however, their predictive value has not been fully assessed. OBJECTIVES: To determine HIV-1 genotypic predictors of a virologic response to saquinavir-ritonavir therapy in patients in whom at least one previous protease inhibitor-containing regimen had failed and to compare the predictive value of baseline genotype with that of standard clinical evaluation. DESIGN: Retrospective clinical cohort study. SETTING: University-based HIV clinic. PATIENTS: 54 HIV-1-infected adults treated with saquinavir-ritonavir who had experienced virologic failure while receiving a protease inhibitor-containing regimen for at least 3 months. MEASUREMENTS: HIV-1 reverse transcriptase and protease gene sequences, CD4 cell counts, clinical characteristics, detailed antiretroviral treatment history, and plasma HIV-1 RNA levels at baseline and at three follow-up time points (median, 4, 12, and 26 weeks). Virologic failure was defined as a plasma HIV RNA level greater than 1000 copies/mL. RESULTS: In 22 patients (41%), a plasma HIV-1 RNA level less than 500 copies/mL was achieved by week 12; in 15 patients (28%), this response was maintained through week 26. Clinical characteristics predicting a poorer response included a diagnosis of AIDS, lower CD4 cell count, and higher plasma HIV RNA level (P<0.03). Number of previous nucleoside reverse transcriptase inhibitors, previous protease inhibitor therapy, and duration of previous protease inhibitor therapy were predictors of poorer response (P<0.01). Multivariate regression models revealed that protease mutations present at the initiation of saquinavir-ritonavir therapy were the strongest predictors of virologic response. A model of clinical features explained up to 45% of the variation in virologic outcomes by week 12, whereas the explained variance was 71% when genotypic predictors were included. CONCLUSIONS: In patients in whom protease inhibitor-containing antiretroviral therapy fails, HIV-1 genotype is predictive of virologic response to subsequent therapy. This predictive capacity adds to that of standard clinical evaluation.


Asunto(s)
Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/genética , Ritonavir/uso terapéutico , Saquinavir/uso terapéutico , Adulto , Recuento de Linfocito CD4 , Estudios de Cohortes , Farmacorresistencia Microbiana/genética , Quimioterapia Combinada , Endopeptidasas/genética , Femenino , Humanos , Modelos Lineales , Masculino , Valor Predictivo de las Pruebas , ADN Polimerasa Dirigida por ARN/genética , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
13.
Antimicrob Agents Chemother ; 43(8): 2046-50, 1999 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-10428934

RESUMEN

We assessed the effects of hydroxyurea (HU) at a concentration of 50 microM on the in vitro activities of 2',3'-dideoxyinosine (ddI), 9-[2-(phosphonylmethoxy)ethyl]adenine (PMEA), and 9-[2-(phosphonylmethoxy)propyl]adenine (PMPA) against a wild-type human immunodeficiency virus (HIV) type 1 (HIV-1) laboratory isolate and a panel of five well-characterized drug-resistant HIV isolates. Fifty micromolar HU significantly increased the activities of ddI, PMEA, and PMPA against both the wild-type and the drug-resistant HIV-1 isolates. In fixed combinations, both ddI and PMEA were synergistic with HU against wild-type and drug-resistant viruses.


Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/farmacología , Didanosina/farmacología , VIH-1/efectos de los fármacos , Hidroxiurea/farmacología , Organofosfonatos , Compuestos Organofosforados/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Adenina/farmacología , Adenina/toxicidad , Fármacos Anti-VIH/toxicidad , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , ADN Viral/biosíntesis , ADN Viral/genética , Didanosina/toxicidad , Farmacorresistencia Microbiana , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/clasificación , VIH-1/genética , Humanos , Hidroxiurea/toxicidad , Concentración 50 Inhibidora , Pruebas de Sensibilidad Microbiana , Compuestos Organofosforados/toxicidad , Inhibidores de la Transcriptasa Inversa/toxicidad , Tenofovir , Timidina/metabolismo , Timidina/farmacocinética
14.
AIDS ; 13(6): 661-7, 1999 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-10397560

RESUMEN

OBJECTIVES: To assess the in-vitro drug susceptibility of a panel of five well-characterized drug-resistant HIV variants to recently developed anti-HIV compounds including seven reverse transcriptase (RT) inhibitors and seven protease inhibitors. METHODS: Drug-resistant viral strains were selected on the basis of the prevalence of these mutants in patient samples from local area HIV clinics. The isolates included one multinucleoside-resistant virus containing the Q151M mutation, and four clinical isolates containing multiple RT and protease resistance mutations. The activity of the experimental compounds against these isolates was determined using drug susceptibility assays and measuring the viral antigen p24 end-point. RESULTS: These clinically relevant highly drug-resistant viruses were resistant to many of the new compounds in clinical development. In most cases the resistance mutations of the clinical isolate were different from those selected in vitro for the particular experimental compound. CONCLUSIONS: It is critical to expand the preclinical development of new drugs to include the assessment of their activity against currently circulating highly drug-resistant clinical strains, in order to develop appropriate salvage therapies for patients harboring resistant strains.


Asunto(s)
Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/genética , Inhibidores de la Transcriptasa Inversa/farmacología , Farmacorresistencia Microbiana/genética , Resistencia a Múltiples Medicamentos , Proteasa del VIH/genética , Transcriptasa Inversa del VIH/genética , VIH-1/aislamiento & purificación , Humanos , Pruebas de Sensibilidad Microbiana , Mutación , Análisis de Secuencia
15.
Circulation ; 100(1): 61-6, 1999 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-10393682

RESUMEN

BACKGROUND: Coronary artery disease occurs in an accelerated fashion in the donor heart after heart transplantation (TxCAD), but the cause is poorly understood. The risk of developing TxCAD is increased by cytomegalovirus (CMV) infection and decreased by use of calcium blockers. Our group observed that prophylactic administration of ganciclovir early after heart transplantation inhibited CMV illness, and we now propose to determine whether this therapy also prevents TxCAD. METHODS AND RESULTS: One hundred forty-nine consecutive patients (131 men and 18 women aged 48+/-13 years) were randomized to receive either ganciclovir or placebo during the initial 28 days after heart transplantation. Immunosuppression consisted of muromonab-CD3 (OKT-3) prophylaxis and maintenance with cyclosporine, prednisone, and azathioprine. Mean follow-up time was 4.7+/-1.3 years. In a post hoc analysis of this trial designed to assess efficacy of ganciclovir for prevention of CMV disease, we compared the actuarial incidence of TxCAD, defined by annual angiography as the presence of any stenosis. Because calcium blockers have been shown to prevent TxCAD, we analyzed the results by stratifying patients according to use of calcium blockers. TxCAD could not be evaluated in 28 patients because of early death or limited follow-up. Among the evaluable patients, actuarial incidence of TxCAD at follow-up (mean, 4.7 years) in ganciclovir-treated patients (n=62) compared with placebo (n=59) was 43+/-8% versus 60+/-10% (P<0.1). By Cox multivariate analysis, independent predictors of TxCAD were donor age >40 years (relative risk, 2.7; CI, 1.3 to 5.5; P<0.01) and no ganciclovir (relative risk, 2.1; CI, 1.1 to 5.3; P=0.04). Stratification on the basis of calcium blocker use revealed differences in TxCAD incidence when ganciclovir and placebo were compared: no calcium blockers (n=53), 32+/-11% (n=28) for ganciclovir versus 62+/-16% (n=25) for placebo (P<0.03); calcium blockers (n=68), 50+/-14% (n=33) for ganciclovir versus 45+/-12% (n=35) for placebo (P=NS). CONCLUSIONS: TxCAD incidence appears to be lower in patients treated with ganciclovir who are not treated with calcium blockers. Given the limitations imposed by post hoc analysis, a randomized clinical trial is required to address this issue.


Asunto(s)
Antivirales/uso terapéutico , Enfermedad de la Arteria Coronaria/prevención & control , Ganciclovir/uso terapéutico , Trasplante de Corazón/efectos adversos , Complicaciones Posoperatorias/prevención & control , Análisis Actuarial , Adulto , Anciano , Anticuerpos Antivirales/sangre , Bloqueadores de los Canales de Calcio/uso terapéutico , Causas de Muerte , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/etiología , Enfermedad de la Arteria Coronaria/virología , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Terapia de Inmunosupresión/efectos adversos , Incidencia , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/virología , Modelos de Riesgos Proporcionales , Reoperación , Riesgo , Estudios Seroepidemiológicos , Resultado del Tratamiento
16.
J Infect Dis ; 179(6): 1356-64, 1999 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10228055

RESUMEN

The efficacy of sequential protease inhibitor therapy was studied in 16 human immunodeficiency virus (HIV) 1-infected persons in whom saquinavir with multiple nucleoside reverse transcriptase (RT) inhibitors (NRTI) had failed. Nelfinavir plus two NRTIs (new or continued) resulted in minimal (0.59 log RNA copies/mL) and transient (8 weeks) suppression of plasma HIV RNA levels. Rapid failure was surprisingly associated with baseline presence of protease gene mutation L90M (P=.04) in the absence of D30N and with RT mutations D67N (P<.01), K70R/S (P=.02), and K219Q/W/R/E (P<.01). Ten patients were subsequently switched to indinavir plus nevirapine and 2 NRTIs, resulting in a median 1.62 log reduction in plasma HIV RNA, with 3 patients maintaining 400 copies/mL for 24 weeks. These results suggest that nelfinavir may have limited utility after saquinavir failure, particularly without potent concomitant therapy. Combining an NRTI with a new protease inhibitor for rescue may improve response.


Asunto(s)
Inhibidores de la Proteasa del VIH/uso terapéutico , Seropositividad para VIH/tratamiento farmacológico , VIH-1 , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Adulto , Resistencia a Medicamentos , Proteasa del VIH/genética , Transcriptasa Inversa del VIH/genética , Seropositividad para VIH/virología , VIH-1/genética , Humanos , Indinavir/uso terapéutico , Masculino , Persona de Mediana Edad , Nelfinavir/efectos adversos , Nelfinavir/uso terapéutico , Nevirapina/uso terapéutico , Polifarmacia , Pronóstico , ARN Viral/sangre , Saquinavir/uso terapéutico
17.
AIDS ; 13(3): 359-65, 1999 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-10199226

RESUMEN

OBJECTIVES: To determine the clinical efficacy of the HIV-1 protease inhibitor indinavir (IDV) in saquinavir (SQV)-experienced patients and delineate the developing drug-resistance patterns. DESIGN: Open-label prospective clinical trial. SETTING: University hospital research center. PATIENTS: Ten patients who had completed a SQV monotherapy study in which they had received SQV at a dose of 3600 or 7200 mg daily (two and fourfold the standard dose). INTERVENTIONS: At enrollment patients received IDV for 4 weeks as monotherapy, after which zidovudine (ZDV) and lamivudine (3TC) were added to their drug regimen. Patients then received combination therapy (IDV-ZDV-3TC) for an additional 20 weeks to complete a total of 24 weeks of therapy. MAIN OUTCOME MEASURES: Plasma HIV RNA viral load and CD4+ T-cell counts were monitored. Sequencing of the HIV protease gene was performed to determine the development of resistance mutations. Plasma samples for sequencing were taken before initial SQV therapy, after SQV therapy before starting IDV, and after 24 weeks of IDV therapy. RESULTS: The average duration of high-dose SQV before starting IDV was 58+/-29.2 weeks. A 0.58 log10 RNA copies/ml increase was noted during the 3-week washout phase followed by a mean reduction in plasma HIV RNA viral load of 1.2 log10 RNA copies/ml after 4 weeks of IDV. After the addition of ZDV and 3TC at week 4, HIV RNA continued to fall reaching a mean reduction of 1.96 log10 RNA copies/ml at week 24. Plasma HIV RNA was below 400 RNA copies/ml in six out of nine patients at week 24. CD4+ T-cell counts showed a gradual rise from 328 x 10(6)/l to 453 x 10(6)/l by week 24. SQV therapy had resulted in multiple mutations in the protease gene. Six of the patients had developed five or more mutations: L90M in two, G48V in four (of which three also contained L101), and V82A in three. Patients in whom plasma HIV RNA was not durably suppressed by subsequent IDV combination therapy developed multiple (up to four) additional mutations within 24 weeks, including codons 54, 82 and 93 amongst others. No clear correlation was found between the mutations that had developed in individual patients after SQV and the subsequent efficacy of IDV. CONCLUSION: Prolonged use of SQV at potent doses in the presence of elevated viral load levels resulted in the development of multiple resistance mutations. Individual resistance patterns varied greatly between patients, as did their virological response to therapy. Resistance assays may be useful in identifying which patients will benefit from salvage therapy with a second protease inhibitor.


Asunto(s)
Farmacorresistencia Microbiana/genética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/genética , Indinavir/farmacología , Saquinavir/farmacología , Recuento de Linfocito CD4 , Resistencia a Múltiples Medicamentos/genética , Quimioterapia Combinada , Infecciones por VIH/virología , Proteasa del VIH/genética , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/fisiología , Humanos , Indinavir/uso terapéutico , Lamivudine/uso terapéutico , Mutación , Estudios Prospectivos , ARN Viral/sangre , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Saquinavir/uso terapéutico , Carga Viral , Zidovudina/uso terapéutico
18.
J Infect Dis ; 179(3): 709-13, 1999 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-9952383

RESUMEN

The safety and antiviral activity of the second-generation nonnucleoside inhibitor HBY 097 was investigated in asymptomatic or mildly symptomatic human immunodeficiency virus (HIV)-1-infected patients in a randomized, double-blinded, dose-escalation study. Mean maximum virus load decreases ranged from -1.31 log10 copies/mL of plasma at week 1 in the group receiving HBY 097 monotherapy (250 mg three times daily) to -2.19 log10 copies/mL at week 4 in the group receiving zidovudine plus HBY 097 (750 mg three times daily). After 12 weeks, these patients had viral RNA copy numbers 1.05 log10 below baseline. Genotypic analysis of resistance development revealed reverse transcriptase K103N variants in most patients, which was associated with less durable efficacy of HBY 097 treatment. Fewer patients receiving combination therapy with high-dose HBY 097 developed the K103N variant (P<.01). HBY 097 caused pronounced acute suppression of HIV-1 replication both in combination with zidovudine and alone. Therefore, sustained antiviral activity can be expected from multiple combination therapy regimens including a quinoxaline derivative.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Antivirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Zidovudina/uso terapéutico , Adulto , Antivirales/efectos adversos , Recuento de Linfocito CD4 , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/inmunología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/aislamiento & purificación , Humanos , Masculino , Quinoxalinas , ARN Viral/sangre , Inhibidores de la Transcriptasa Inversa/efectos adversos , Factores de Tiempo , Carga Viral
19.
J Immunol ; 162(3): 1780-8, 1999 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-9973442

RESUMEN

Peptide/MHC tetrameric complexes were used to enumerate the frequency of HLA class I-restricted epitope-specific CD8+ T cells in 18 HLA-A*0201 HIV type 1-infected asymptomatic patients. HLA-A*0201 molecules were complexed to HIV Gag p17 (amino acids 77-85) and reverse transcriptase (amino acids 464-472) peptides, biotinylated, and bound to streptavidin-phycoerythrin to form tetramers. We show in this study that 17 of 18 HIV-1-infected asymptomatic patients have circulating frequencies of 1/50-1/1000 CD8+ T cells that recognize both Gag and Pol CTL epitopes or either epitope alone. The functional nature of these cells is open to interpretation, as we show that despite relatively high frequencies of fresh epitope-specific CD8+ T cells, variant epitope sequences in viral plasma progeny were rare. In addition, the majority of tetramer-positive cells did not display discernible fresh CTL activity; only after restimulation with specific peptide in culture was there an expansion of epitope-specific CD8+ cells, correlating with high CTL activity. These data suggest that fresh tetramer-stained cells probably represent memory precursors; we demonstrate, with the application of highly active antiretroviral therapy, that the interruption of chronic antigenic stimulation causes significant reductions in the frequency of these cells in five of six patients. In conclusion, this study provides evidence that persistently replicating viral populations are probably required to maintain high frequencies of HIV-1 epitope-specific CD8+ T cells in asymptomatic chronically infected individuals


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/inmunología , Antígenos HLA-A/metabolismo , Proteínas Virales , Secuencia de Aminoácidos , Linfocitos T CD8-positivos/efectos de los fármacos , Epítopos/química , Epítopos/genética , Productos del Gen gag/química , Productos del Gen gag/genética , Productos del Gen gag/inmunología , Antígenos VIH/química , Antígenos VIH/genética , Antígenos VIH/inmunología , Transcriptasa Inversa del VIH/química , Transcriptasa Inversa del VIH/genética , Transcriptasa Inversa del VIH/inmunología , VIH-1/enzimología , VIH-1/genética , Antígenos HLA-A/química , Humanos , Activación de Linfocitos , Datos de Secuencia Molecular , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Fenotipo , Conformación Proteica , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana
20.
J Acquir Immune Defic Syndr ; 22(4): 341-7, 1999 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-10634195

RESUMEN

Delayed-type hypersensitivity (DTH) responses to intradermal recombinant HIV envelope glycoprotein (rgp160) may assess cell-mediated immune responses to HIV envelope. In three studies, DTH and lymphocyte proliferation responses to rgp160 were obtained in a total of 106 HIV-seropositive subjects with CD4+ counts >400 cells/mm3. Several subjects participated in more than one study. Before immunization, DTH responses were seen in 5 of 56 (9%) of HIV-infected study subjects. After immunization with an alum-adjuvanted experimental rgp160 vaccine, DTH responses were seen in 46 of 52 (89%). Using in vitro lymphocyte proliferation activity (LPA) to rgp160 as an indication of cellular immune response, skin testing has a sensitivity of 0.75 (95% confidence Interval [CI], 0.59-0.88) and a specificity of 0.84 (95% CI, 0.72-0.92). Biopsy samples of skin that had tested positive confirmed the presence of a DTH reaction with a predominance of CD4+ T cells in the perivascular, inflammatory infiltrate. Skin testing before and after immunization with candidate AIDS vaccines could provide a simple method in the field to assess new cell mediated immune responses.


Asunto(s)
Vacunas contra el SIDA/inmunología , Proteínas gp160 de Envoltorio del VIH/inmunología , Infecciones por VIH/inmunología , Hipersensibilidad Tardía/etiología , Vacunación , Vacunas Sintéticas/inmunología , Proteínas gp160 de Envoltorio del VIH/efectos adversos , Proteínas gp160 de Envoltorio del VIH/genética , Infecciones por VIH/terapia , VIH-1/inmunología , Humanos , Activación de Linfocitos , Pruebas Cutáneas , Vacunas Sintéticas/efectos adversos
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