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1.
J Alzheimers Dis ; 67(2): 515-525, 2019.
Article in English | MEDLINE | ID: mdl-30584144

ABSTRACT

The etiology and pathogenesis of Alzheimer's disease (AD) are not fully understood. Thus, there are no drugs available that can provide a cure for it. We and others found that DNA polymerase-ß (DNA pol-ß) is required for neuronal death in several neurodegenerative models. In the present study, we tested the effect of a DNA pol-ß inhibitor 2',3'- Dideoxycytidine (DDC) in AD models both in vitro and in vivo. DDC protected primary neurons from amyloid-ß (Aß)-induced toxicity by inhibiting aberrant DNA replication mediated by DNA pol- ß. Chronic oral administration of DDC alleviated Aß deposition and memory deficits in the Tg2576 mouse model of AD. Moreover, DDC reversed synaptic loss in Tg2576 mice. These results suggest that DDC represents a novel therapeutic agent for the treatment of AD.


Subject(s)
Alzheimer Disease/drug therapy , DNA Polymerase beta/antagonists & inhibitors , Enzyme Inhibitors/therapeutic use , Memory Disorders/drug therapy , Neuroprotective Agents/therapeutic use , Zalcitabine/therapeutic use , Alzheimer Disease/complications , Alzheimer Disease/psychology , Amyloid beta-Peptides/toxicity , Animals , DNA Polymerase beta/metabolism , DNA Replication/drug effects , Enzyme Inhibitors/adverse effects , Maze Learning/drug effects , Memory Disorders/etiology , Memory Disorders/psychology , Mice , Mice, Inbred C57BL , Neurons/drug effects , Neuroprotective Agents/adverse effects , Primary Cell Culture , Synapses/drug effects , Synapses/pathology , Zalcitabine/adverse effects
2.
Article in English | MEDLINE | ID: mdl-28559274

ABSTRACT

We explored if baseline CD4/CD8 T-cell ratio is associated with immunodiscordant response to antiretroviral therapy in HIV-infected subjects. Comparing immunodiscordant and immunoconcordant subjects matched by pretreatment CD4 counts, we observed a lower pretreatment CD4/CD8 T-cell ratio in immunodiscordant subjects. Furthermore, pretreatment CD4/CD8 T-cell ratio, but not CD4 counts, correlated with the main immunological alterations observed in immunodiscordants, including increased regulatory T-cell (Treg) frequency and T-cell turnover-related markers. Then, in a larger cohort, only baseline CD4/CD8 T-cell ratio was independently associated with immunodiscordance, after adjusting by the viral CXCR4-tropic HIV variants. Our results suggest that the CD4/CD8 T-cell ratio could be an accurate biomarker of the subjacent immunological damage triggering immunodiscordance.


Subject(s)
Antiretroviral Therapy, Highly Active/methods , CD4-CD8 Ratio , CD8-Positive T-Lymphocytes/immunology , HIV Infections/drug therapy , HIV Infections/immunology , T-Lymphocytes, Regulatory/immunology , Adult , Anti-HIV Agents/therapeutic use , Biomarkers/metabolism , Cell Survival/drug effects , Didanosine/therapeutic use , Female , Humans , Male , Middle Aged , Receptors, CXCR4/immunology , Stavudine/therapeutic use , Viral Load , Zalcitabine/therapeutic use , Zidovudine/therapeutic use
3.
Article in English | MEDLINE | ID: mdl-28396546

ABSTRACT

HIV-1 reverse transcriptase (RT) is targeted by multiple drugs. RT mutations that confer resistance to nucleoside RT inhibitors (NRTIs) emerge during clinical use. Q151M and four associated mutations, A62V, V75I, F77L, and F116Y, were detected in patients failing therapies with dideoxynucleosides (didanosine [ddI], zalcitabine [ddC]) and/or zidovudine (AZT). The cluster of the five mutations is referred to as the Q151M complex (Q151Mc), and an RT or virus containing Q151Mc exhibits resistance to multiple NRTIs. To understand the structural basis for Q151M and Q151Mc resistance, we systematically determined the crystal structures of the wild-type RT/double-stranded DNA (dsDNA)/dATP (complex I), wild-type RT/dsDNA/ddATP (complex II), Q151M RT/dsDNA/dATP (complex III), Q151Mc RT/dsDNA/dATP (complex IV), and Q151Mc RT/dsDNA/ddATP (complex V) ternary complexes. The structures revealed that the deoxyribose rings of dATP and ddATP have 3'-endo and 3'-exo conformations, respectively. The single mutation Q151M introduces conformational perturbation at the deoxynucleoside triphosphate (dNTP)-binding pocket, and the mutated pocket may exist in multiple conformations. The compensatory set of mutations in Q151Mc, particularly F116Y, restricts the side chain flexibility of M151 and helps restore the DNA polymerization efficiency of the enzyme. The altered dNTP-binding pocket in Q151Mc RT has the Q151-R72 hydrogen bond removed and has a switched conformation for the key conserved residue R72 compared to that in wild-type RT. On the basis of a modeled structure of hepatitis B virus (HBV) polymerase, the residues R72, Y116, M151, and M184 in Q151Mc HIV-1 RT are conserved in wild-type HBV polymerase as residues R41, Y89, M171, and M204, respectively; functionally, both Q151Mc HIV-1 and wild-type HBV are resistant to dideoxynucleoside analogs.


Subject(s)
Anti-HIV Agents/therapeutic use , Didanosine/therapeutic use , Gene Products, pol/antagonists & inhibitors , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/drug effects , Hepatitis B virus/drug effects , Reverse Transcriptase Inhibitors/therapeutic use , Zalcitabine/therapeutic use , Zidovudine/therapeutic use , Crystallography, X-Ray , DNA-Binding Proteins/genetics , Drug Resistance, Viral/genetics , HIV Reverse Transcriptase/genetics , Hepatitis B virus/genetics , Humans , Mutation/genetics , Protein Conformation , Protein Structure, Quaternary
4.
J Immunol ; 191(12): 6060-70, 2013 Dec 15.
Article in English | MEDLINE | ID: mdl-24227774

ABSTRACT

The programmed cell death-1 (PD-1)/programmed cell death ligand-1 pathway has been shown to limit cell-mediated effector functions during chronic viral infections impeding clearance of pathogens. As a strategy to reverse this exhaustion and increase T cell polyfunctionality, PD-1 ligands were blocked in vivo using a recombinant macaque PD-1 fused to a macaque Ig-Fc (rPD-1-Fc) in SIVmac239-infected rhesus macaques during the early chronic phase of infection, either alone or in combination with antiretroviral therapy. In vitro blockade showed improvement of Ag-specific CD4(+) and CD8(+) T cells from monkeys chronically infected with SIV. Of note, a prolonged 5-d blockade in culture was beneficial for both gag-specific CD4(+) and CD8(+) T cells based on proliferation and dual cytokine production. Although the in vivo administration of rPD-1-Fc induced enhanced SIV-specific CD4 and CD8 T cell proliferation both in the blood and gut, it failed to alter plasma viremia. However, rPD-1-Fc administration in the context of antiretroviral therapy interruption induced a significant delay of viral load rebound. In addition, rPD-1-Fc administration in MamuA*001(+) monkeys led to both an increase in the frequencies and Ki67 expression of GagCM9(+) CD8(+) T cells in the blood and rectal mucosa and polyfunctionality of GagCM9(+) CD8(+) T cells in blood. In conclusion, however, our data suggest that PD-1/programmed cell death ligand-1 blockade using soluble rPD-1-Fc instead of anti-PD-1 mAb, although effective in rescuing the effector function of SIV-specific CD4(+) and CD8(+) T cells during the early chronic phase of infection, has limited clinical benefit.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Immunoglobulin Fc Fragments/therapeutic use , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/therapeutic use , Simian Acquired Immunodeficiency Syndrome/drug therapy , Viremia/drug therapy , Adenine/analogs & derivatives , Adenine/therapeutic use , Animals , Anti-Retroviral Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Apoptosis , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/metabolism , Combined Modality Therapy , Drug Evaluation, Preclinical , Emtricitabine/analogs & derivatives , Histocompatibility Antigens Class I/immunology , Immunity, Cellular , Immunoglobulin Fc Fragments/pharmacology , Immunotherapy , Lymphokines/metabolism , Macaca mulatta , Organophosphonates/therapeutic use , RNA, Viral/blood , Recombinant Proteins/pharmacology , Recombinant Proteins/therapeutic use , Simian Acquired Immunodeficiency Syndrome/blood , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Immunodeficiency Virus/genetics , Solubility , Tenofovir , Viremia/blood , Viremia/immunology , Zalcitabine/analogs & derivatives , Zalcitabine/therapeutic use
5.
Article in Chinese | MEDLINE | ID: mdl-21619836

ABSTRACT

OBJECTIVE: To assess the curative effects of different drugs on liver cell damage of rats induced by acute nickel carbonyl poisoning. METHODS: In present study 220 SD rats were divided into control group (10 rats), carbonyl nickel group (10 rats), 20 mg/kg methylprednisolone group (40 rats), 100 mg/kg DDC group (40 rats), 10 µmol/kg sodium selenite group (40 rats), 0.25 ml shenfuhuiyangtang group (40 rats) and 20 mg/kg methylprednisolone with 100 mg/kg DDC group (40 rats). All rats except for control group inhaled passively 250 mg/m(3) carbonyl nickel for 30 minutes. At 4h and 30h after exposure, the drugs were given intraperitoneally to the rats. On the 3rd and 7th days after exposure, the liver samples were taken from 10 rats each group. The DNA damage of liver cells was detected using comet assay, the ultrastructure changes in liver cells were examined under an electronmicroscope. RESULTS: Compared to carbonyl nickel group, the tail lengths of liver cells in 5 groups administrated at 4 h or 30 h and tested on the 3rd or 7th day after exposure decreased significantly (P < 0.05). Compared to the control group, the tail lengths of liver cells in sodium selenite and shenfuhuiyangtang groups administrated at 4h after exposure or sodium selenite, shenfuhuiyangtang and methylprednisolone with DDC groups administrated at 30h after exposure increased significantly (P < 0.05 or P < 0.01), when tested on the 3rd day after exposure. Except from methylprednisolone sub-group administrated at 4h and tested on the 7th day after exposure, the tail lengths of liver cells in other groups administrated at 4 h or 30 h and tested on the 7th day after exposure increased significantly (P < 0.05). Compared to carbonyl nickel group, the Olive moment of liver cells in 5 groups administrated at 4 h or 30 h tested on the 3rd or 7th day after exposure decreased significantly (P < 0.05 or P < 0.01). Compared to the control group, the Olive moment of liver cells in following groups (selenite and shenfuhuiyangtang groups administrated at 4 h or 30 h and tested on the 3rd or 7th day after exposure, DDC group administrated at 4 h or 30 h and tested on the 7th day after exposure, DDC group administrated at 30h and tested on the 3rd day after exposure, and methylprednisolone with DDC group administrated at 30 h and tested on the 7th day after exposure) increased significantly (P < 0.05 or P < 0.01). As compared with carbonyl nickel group, the ultrastructure observation indicated that the nucleus and other organelles of liver cells in methylprednisolone, DDC and methylprednisolone with DDC groups administrated at 4h and tested on the 3rd day were access to normal levels. CONCLUSION: The results of present study showed that methylprednisolone, DDC and methylprednisolone with DDC could improve obviously the repair of rat liver cell damage induced by acute carbonyl nickel poisoning, and the curative effects of early treatment were better than those of later treatment.


Subject(s)
Chemical and Drug Induced Liver Injury/drug therapy , Hepatocytes/pathology , Methylprednisolone/therapeutic use , Organometallic Compounds/poisoning , Zalcitabine/therapeutic use , Animals , Chemical and Drug Induced Liver Injury/pathology , DNA Damage , Drugs, Chinese Herbal/therapeutic use , Male , Rats , Rats, Sprague-Dawley , Sodium Selenite/therapeutic use
7.
Lifetime Data Anal ; 16(4): 509-24, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20063182

ABSTRACT

The analysis of recurrent failure time data from longitudinal studies can be complicated by the presence of dependent censoring. There has been a substantive literature that has developed based on an artificial censoring device. We explore in this article the connection between this class of methods with truncated data structures. In addition, a new procedure is developed for estimation and inference in a joint model for recurrent events and dependent censoring. Estimation proceeds using a mixed U-statistic based estimating function approach. New resampling-based methods for variance estimation and model checking are also described. The methods are illustrated by application to data from an HIV clinical trial as with a limited simulation study.


Subject(s)
Data Interpretation, Statistical , Models, Statistical , AIDS-Related Opportunistic Infections/epidemiology , Computer Simulation , Didanosine/therapeutic use , HIV Infections/drug therapy , Humans , Kaplan-Meier Estimate , Recurrence , Zalcitabine/therapeutic use
9.
Antivir Ther ; 13(2): 289-95, 2008.
Article in English | MEDLINE | ID: mdl-18505180

ABSTRACT

BACKGROUND: Peripheral neuropathy (PN) in HIV-infected individuals is thought be due to a toxic effect on mitochondria induced by some nucleoside reverse transcriptase inhibitors (NRTI). METHODS: A time-to-event analysis was performed using data from the Delta trial to study the incidence of PN in HIV-infected individuals receiving zidovudine (AZT) alone or in combination with didanosine (ddl) or zalcitabine (ddC). In an on-treatment analysis, changes in the incidence of PN by duration of treatment were directly estimated using a flexible parametric survival model. RESULTS: A total of 3,195 patients (total follow-up 4,593 person-years) were included in the analysis. AZT+ddC was associated with a higher incidence of PN (6.2 cases/100 person-years) compared with AZT monotherapy (3.0 cases/100 person-years) and AZT+ddl (2.2 cases/100 person-years). The risk of PN peaked around day 90 following randomization (at 8.9 events/100 person-years in the AZT+ddC arm). PN was also associated with age at entry (hazard ratio (HR)=2.35 for those aged 35-44 years compared with <30) and current CD4+ T-cell count (HR=2.27 for CD4+ T-cell counts <150 cell/mm3 compared with >350). CONCLUSION: Our findings challenge the common supposition that PN arises from cumulative exposure to NRTIs. We found that patients who developed PN tended to do so shortly after exposure to antiretroviral therapy. Therefore, our results support the hypothesis of a susceptibility in a subgroup of patients. These results will be of direct interest to those working in resource-limited countries where potentially neurotoxic dideoxynucleosides are still widely used.


Subject(s)
Anti-HIV Agents/adverse effects , HIV Infections/drug therapy , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/epidemiology , Reverse Transcriptase Inhibitors/adverse effects , Adult , Anti-HIV Agents/therapeutic use , Didanosine/adverse effects , Didanosine/therapeutic use , Double-Blind Method , Drug Therapy, Combination , Female , HIV Infections/complications , HIV Infections/virology , Humans , Incidence , Male , Middle Aged , Reverse Transcriptase Inhibitors/therapeutic use , Risk Factors , Time Factors , Zalcitabine/adverse effects , Zalcitabine/therapeutic use , Zidovudine/adverse effects , Zidovudine/therapeutic use
10.
Drug Metab Dispos ; 36(8): 1616-23, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18490433

ABSTRACT

Carrier-mediated transport across cell membranes is an important determinant of activity, resistance, and toxicity of chemotherapeutic agents including antiretroviral (ARV) drugs (ARDs). The organic cation transporters (OCTs) 1 and 2 have been implicated in the translocation of different cationic drugs but so far were insufficiently tested for interactions with ARDs. Here, we assessed among cationic drugs commonly used in human immunodeficiency virus (HIV) therapy inhibitors and substrates of OCTs, and analyzed the tissue distribution of OCTs and their expression in lymph nodes (LNs), the primary intracellular target of HIV and ARDs. Inhibitors were identified by measuring the attenuated uptake of the radiolabeled model substrate 1-methyl-4-phenylpyridinium into OCT-transfected human embryonic kidney-293 cells in the presence of ARDs. Substrates were identified by measuring OCT-specific intracellular accumulation using liquid chromatography/tandem mass spectrometry. Inhibitory drugs were (in order of increasing potency): nelfinavir < ritonavir < saquinavir < indinavir < trimethoprim < pentamidine, with consistently lower IC(50) values determined for OCT1. Substrates with highest transport efficacy (V(max)/K(m)) were lamivudine (OCT1, 8 microl/mg protein/min; OCT2, 4.4 microl/mg protein/min) and zalcitabine (OCT1, 4.1 microl/mg protein/min; OCT2, 2.6 microl/mg protein/min). Using quantitative real-time polymerase chain reaction, a marked expression level of OCT1 was detected in human samples of liver, ovary, prostate, and testis, and of OCT2 in kidney, colon, heart, skeletal muscle, and testis. Expression of OCTs in LNs was low in HIV-negative control individuals but dramatically increased in HIV-infected persons. These data suggest that drug interactions about the OCTs may be relevant for the ARV therapy, in particular by influencing drug accession to infected tissues and hepatic or renal elimination.


Subject(s)
HIV Infections/drug therapy , Lamivudine/therapeutic use , Organic Cation Transport Proteins/physiology , Organic Cation Transporter 1/physiology , Reverse Transcriptase Inhibitors/therapeutic use , Zalcitabine/therapeutic use , Cell Line , Chromatography, High Pressure Liquid , Humans , Lymph Nodes/metabolism , Organic Cation Transport Proteins/antagonists & inhibitors , Organic Cation Transport Proteins/metabolism , Organic Cation Transporter 1/antagonists & inhibitors , Organic Cation Transporter 1/metabolism , Organic Cation Transporter 2 , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Spectrometry, Mass, Electrospray Ionization , Tandem Mass Spectrometry
11.
Hepatology ; 47(2): 613-24, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18098314

ABSTRACT

UNLABELLED: In previous studies, microarray analysis of livers from mice fed diethyl-1,4-dihydro-2,4,6-trimethyl-3,5-pyridine decarboxylate (DDC) for 10 weeks followed by 1 month of drug withdrawal (drug-primed mice) and then 7 days of drug refeeding showed an increase in the expression of numerous genes referred to here as the molecular cellular memory. This memory predisposes the liver to Mallory Denk body formation in response to drug refeeding. In the current study, drug-primed mice were refed DDC with or without a daily dose of S-adenosylmethionine (SAMe; 4 g/kg of body weight). The livers were studied for evidence of oxidative stress and changes in gene expression with microarray analysis. SAMe prevented Mallory Denk body formation in vivo. The molecular cellular memory induced by DDC refeeding lasted for 4 months after drug withdrawal and was not manifest when SAMe was added to the diet in the in vivo experiment. Liver cells from drug-primed mice spontaneously formed Mallory Denk bodies in primary tissue cultures. SAMe prevented Mallory Denk bodies when it was added to the culture medium. CONCLUSION: SAMe treatment prevented Mallory Denk body formation in vivo and in vitro by preventing the expression of a molecular cellular memory induced by prior DDC feeding. No evidence for the involvement of oxidative stress in induction of the memory was found. The molecular memory included the up-regulation of the expression of genes associated with the development of liver cell preneoplasia.


Subject(s)
Inclusion Bodies/drug effects , Liver/cytology , S-Adenosylmethionine/therapeutic use , Aldehydes/metabolism , Animals , Inclusion Bodies/pathology , Liver/drug effects , Liver/physiology , Liver/ultrastructure , Male , Malondialdehyde/metabolism , Mice , Mice, Inbred C3H , Oligonucleotide Array Sequence Analysis , RNA/genetics , RNA/isolation & purification , Rats , Reverse Transcriptase Polymerase Chain Reaction , Zalcitabine/therapeutic use
12.
Enferm Infecc Microbiol Clin ; 26 Suppl 8: 25-30, 2008 Jun.
Article in Spanish | MEDLINE | ID: mdl-19195435

ABSTRACT

As with other nucleoside analogues, tenofovir (TDF) can be affected by several mutations in the reverse transcriptase gene. Most nucleoside analogue mutations (NAMs) are not induced specifically by TDF, although they can affect the activity of this drug. The impact of thymidine analogue mutations (TAMs) on tenofovir varies and, as with the remaining nucleoside analogue reverse transcriptase inhibitors, largely depends on the type and number present. Thus, the greater the number of TAMs, and the greater the number of type 1 TAMs, the more TDF activity will be affected. The 41L and 210W mutations have the greatest effect. The incidence of the 65R mutation was slight before the clinical introduction of TDF. This mutation was selected by treatments with zalcitabine monotherapy. However, after TDF came on to the market, the 65R mutation began to be more frequently reported and is currently the signature mutation of this drug. TDF has been shown to be safe and effective in patients with prior virological failure and resistance mutations in the reverse transcriptase gene. In these patients, the presence of the 41L and 210W mutations is associated with a worse response to rescue therapy containing TDF. In contrast, the presence of type 2 TAMs (67N, 70R and 219Q/E/N) has little effect on TDF activity in these patients. Importantly, in TDF therapy, the presence of the 184V mutation is associated with a more favorable virologic response than the absence of this mutation, with any of the distinct combinations of mutations present.


Subject(s)
Adenine/analogs & derivatives , Anti-HIV Agents/therapeutic use , Drug Resistance, Multiple, Viral/genetics , HIV Infections/drug therapy , HIV Reverse Transcriptase/antagonists & inhibitors , HIV/enzymology , Organophosphonates/therapeutic use , Reverse Transcriptase Inhibitors/therapeutic use , Salvage Therapy , Adenine/administration & dosage , Adenine/pharmacology , Adenine/therapeutic use , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/classification , Anti-HIV Agents/pharmacology , Antimetabolites/pharmacology , Clinical Trials, Phase III as Topic/statistics & numerical data , Drug Therapy, Combination , HIV/genetics , HIV Reverse Transcriptase/genetics , Humans , Multicenter Studies as Topic , Mutation , Organophosphonates/administration & dosage , Organophosphonates/pharmacology , Randomized Controlled Trials as Topic/statistics & numerical data , Retrospective Studies , Reverse Transcriptase Inhibitors/administration & dosage , Reverse Transcriptase Inhibitors/pharmacology , Selection, Genetic , Tenofovir , Thymidine/analogs & derivatives , Treatment Failure , Viral Load , Zalcitabine/administration & dosage , Zalcitabine/pharmacology , Zalcitabine/therapeutic use
14.
AIDS ; 21(8): 905-9, 2007 May 11.
Article in English | MEDLINE | ID: mdl-17457083

ABSTRACT

OBJECTIVE: We previously described chimeric HIV-1, EcoHIV, which can infect mouse cells in culture and cause spreading infection in conventional immunocompetant mice. We have now applied this system as a model for preclinical evaluation of anti-retroviral drugs. DESIGN AND METHODS: We used chimeric virus EcoHIV/NDK constructed on the backbone of subtype D NDK. EcoHIV/NDK expression in mice was characterized 5-10 days after infection by testing viral DNA, RNA, and protein burdens in spleen and macrophages by real-time PCR (QPCR), RT-PCR, and p24 ELISA. For antiviral evaluation, groups of 5-7 mice were pretreated with 2',3'-dideoxycytidine (ddC), abacavir, or vehicle; mice were then infected with EcoHIV/NDK, treatment maintained for additional 48 h, and tested for viral DNA and RNA burdens in spleens and macrophages by QPCR. RESULTS: EcoHIV/NDK infected mice reproducibly showed viral burdens of up to 1.4 x 10 viral DNA copies and 200 pg p24 per 10 spleen cells and expressed spliced Vif RNA and mature p24 in macrophages 5-10 days after infection. Treatment of mice with 60 or 300 mg ddC/kg/day blocked EcoHIV/NDK infection in a dose-dependent manner with significantly lower viral DNA and RNA burdens at both drug doses (P < 0.001) in the spleens of infected mice. Abacavir tested at 100 mg/kg/day caused 96% inhibition of viral DNA synthesis in spleen and it almost completely abolished viral spliced RNA synthesis in spleens and macrophages. CONCLUSIONS: The system of chimeric HIV-1 infection of mice permits rapid, statistically powerful, and inexpensive evaluation of antiretroviral drugs in vivo.


Subject(s)
Anti-HIV Agents/therapeutic use , Disease Models, Animal , Drug Evaluation, Preclinical/methods , HIV Infections/drug therapy , HIV-1/drug effects , Animals , Chimera , DNA, Viral/analysis , Dideoxynucleosides/therapeutic use , HIV Infections/prevention & control , HIV Infections/virology , HIV-1/genetics , HIV-1/isolation & purification , Macrophages, Peritoneal/virology , Mice , Polymerase Chain Reaction/methods , Spleen/virology , Viral Load , Zalcitabine/therapeutic use
15.
Rev Med Interne ; 27(8): 625-8, 2006 Aug.
Article in French | MEDLINE | ID: mdl-16854505

ABSTRACT

INTRODUCTION: HIV-associated vasculitis is an infrequent entity, and only few data about its long-term evolution is available. EXEGESIS: We report the long-term outcome of a patient with central nervous system HIV-associated periarteritis nodosa and then discuss the therapeutic options for this class of vasculitis. CONCLUSION: This observation highlights the role of HAART in the treatment of HIV-associated vasculitis. Persistent remission can be obtained when viral replication is under control.


Subject(s)
Central Nervous System Infections , HIV Infections/complications , Polyarteritis Nodosa/complications , Adult , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/therapeutic use , Antiretroviral Therapy, Highly Active , Central Nervous System Infections/diagnosis , Central Nervous System Infections/drug therapy , Female , Follow-Up Studies , HIV Infections/drug therapy , HIV Infections/virology , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/therapeutic use , Hepatitis C/complications , Humans , Indinavir/administration & dosage , Indinavir/therapeutic use , Polyarteritis Nodosa/diagnosis , Stavudine/administration & dosage , Stavudine/therapeutic use , Time Factors , Treatment Outcome , Virus Replication , Zalcitabine/administration & dosage , Zalcitabine/therapeutic use
16.
Clin Chem ; 52(6): 979-87, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16601068

ABSTRACT

BACKGROUND: To study the clinical relevance of changes in mitochondrial DNA (mtDNA) in peripheral blood mononuclear cells (PBMCs) attributable to HIV infection and/or combination antiretroviral therapy (cART), a high-throughput molecular assay to quantify mtDNA is required. METHODS: We developed a quantitative real-time duplex nucleic acid sequence-based amplification assay in which both mtDNA and nuclear DNA are simultaneously amplified in 1 tube. The assay could accurately quantify mtDNA in a range of 15-1500 copies of mtDNA per 2 genomic copies with an intrarun variation of 11% and an interrun variation of 16%. We compared this real-time assay with the lactate/pyruvate ratios in fibroblasts incubated with glucose and exposed to zalcitabine. Additionally, we studied the effects of platelet contamination and the in vivo effects of cART on mtDNA in PBMCs from a small group of patients. RESULTS: Decreases in mtDNA preceded the increase in lactate/pyruvate ratios and vice versa when zalcitabine was eliminated from the culture. Platelets affected the mtDNA in PBMCs if >5 platelets per PBMC were present. Within 12 weeks, mtDNA increased and remained increased in PBMCs from patients on continuous treatment with zidovudine/lamivudine/indinavir therapy (P = 0.03), but increased if patients were switched to stavudine/didanosine therapy (P = 0.008). CONCLUSION: After drug exposure, the mtDNA assay can detect changes in mtDNA concentrations in cell lines and PBMCs, when properly controlled for platelet effects, earlier than traditional assays.


Subject(s)
Anti-HIV Agents/therapeutic use , DNA, Mitochondrial/analysis , HIV Infections/blood , HIV Infections/drug therapy , Base Sequence , Blood Platelets/chemistry , Cell Nucleus/chemistry , Cells, Cultured , DNA, Mitochondrial/blood , Didanosine/therapeutic use , Drug Therapy, Combination , Feasibility Studies , Fibroblasts/chemistry , Fibroblasts/drug effects , Humans , Indinavir/therapeutic use , Lactic Acid/analysis , Lamivudine/therapeutic use , Leukocytes, Mononuclear/chemistry , Nucleic Acid Amplification Techniques , Pyruvic Acid/analysis , Stavudine/therapeutic use , Zalcitabine/pharmacology , Zalcitabine/therapeutic use
17.
Biostatistics ; 7(1): 29-40, 2006 Jan.
Article in English | MEDLINE | ID: mdl-15923407

ABSTRACT

In randomized trials with missing or censored outcomes, standard maximum likelihood estimates of the effect of intervention on outcome are based on the assumption that the missing-data mechanism is ignorable. This assumption is violated if there is an unobserved baseline covariate that is informative, namely a baseline covariate associated with both outcome and the probability that the outcome is missing or censored. Incorporating informative covariates in the analysis has the desirable result of ameliorating the violation of this assumption. Although this idea of including informative covariates is recognized in the statistics literature, it is not appreciated in the literature on randomized trials. Moreover, to our knowledge, there has been no discussion on how to incorporate informative covariates into a general likelihood-based analysis with partially missing outcomes to estimate the quantities of interest. Our contribution is a simple likelihood-based approach for using informative covariates to estimate the effect of intervention on a partially missing outcome in a randomized trial. The first step is to create a propensity-to-be-missing score for each randomization group and divide the scores into a small number of strata based on quantiles. The second step is to compute stratum-specific estimates of outcome derived from a likelihood-analysis conditional on the informative covariates, so that the missing-data mechanism is ignorable. The third step is to average the stratum-specific estimates and compute the estimated effect of intervention on outcome. We discuss the computations for univariate, survival, and longitudinal outcomes, and present an application involving a randomized study of dual versus triple combinations of HIV-1 reverse transcriptase inhibitors.


Subject(s)
Models, Statistical , Randomized Controlled Trials as Topic/methods , Treatment Outcome , Acquired Immunodeficiency Syndrome/drug therapy , Anti-HIV Agents/therapeutic use , CD4 Lymphocyte Count , Didanosine/therapeutic use , Humans , Likelihood Functions , Longitudinal Studies , Nevirapine/therapeutic use , Proportional Hazards Models , Survival Analysis , Zalcitabine/therapeutic use , Zidovudine/therapeutic use
19.
Article in English | MEDLINE | ID: mdl-16124442

ABSTRACT

A randomized double blind placebo controlled trial to determine the efficacy and safety of combined-herbs (SH) given with zidovudine (ZDV) and zalcitabine (ddC) for the treatment of HIV infection in Thai adults was conducted in 3 hospitals in northern Thailand during 2002 to 2003. The eligible subjects were HIV-infected Thai adults who had never received anti-retrovirals, had a Karnofski Performance Score (KPS) of > or = 70, and had no opportunistic infections. The subjects were randomized to receive either a combination of ZDV 200 mg three times per day, ddC 0.75 mg three times per day, and SH 2.5 g three times per day or a combination of ZDV 200 mg three times per day, ddC 0.75 mg three times per day, and placebo 2.5 g three times per day for 24 weeks. The main outcome measures were HIV-RNA, CD4 cells, and blood chemistry profiles prior to the treatment and then every 4 weeks for 24 weeks. The baseline characteristics of 60 evaluable subjects, 40 in the SH group and 20 in the placebo group, were not significantly different. HIV RNA at week 4 and thereafter was significantly decreased from the baseline value in both groups (p<0.001). However, the decline in HIV RNA in the SH group was significantly more than that in the placebo group. The CD4 cells in the SH group at week 12 and thereafter were significantly increased from the baseline value. Serious adverse events in the two groups were not observed. It is concluded that an addition of SH herbs to two nucleoside reverse transcriptase inhibitors has greater antiviral activity than antiretrovirals only. The SH herbs may be an alternative for the third anti-retroviral agent in the triple drug regimen for the treatment of HIV infected patients in countries with limited resources.


Subject(s)
Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , Phytotherapy , Plant Preparations/therapeutic use , Zalcitabine/therapeutic use , Zidovudine/therapeutic use , Adult , Anti-HIV Agents/administration & dosage , Astragalus propinquus/adverse effects , Carthamus tinctorius/adverse effects , Double-Blind Method , Drug Therapy, Combination , Female , Glycyrrhiza/adverse effects , Humans , Male , Middle Aged , Phytotherapy/adverse effects , Plant Preparations/adverse effects , Thailand , Treatment Outcome , Zalcitabine/administration & dosage , Zidovudine/administration & dosage
20.
J Neurovirol ; 11(2): 180-9, 2005 Apr.
Article in English | MEDLINE | ID: mdl-16036796

ABSTRACT

This study used a simian immunodeficiency virus (SIV)-macaque model to determine whether virus persists in the central nervous system (CNS) of human immunodeficiency virus (HIV)-infected individuals in which plasma viral load has been suppressed by highly active antiretroviral therapy. SIV-infected macaques were treated with two reverse transcriptase inhibitors: PMPA (q- R-(2-phosphonomethoxypropyl)adenine)which does not cross the blood-brain barrier, and FTC (beta-2('),3(')-dideoxy-3 thia-5-fluorocytidine), which does. Viral DNA and RNA were quantitated in the brain after 6 months of suppression of virus replication in blood and cerebrospinal fluid (CSF). Viral DNA was detected in brain from all macaques, including those in which peripheral viral replication had been suppressed either by antiretroviral therapy or host immune responses. Significant neurological lesions were observed only in one untreated macaque that had active virus replication in the CNS. Expression of the inflammatory markers, major histocmopatibility complex (MHC) II and CD68 was significantly lower in macaques treated with PMPA/FTC. Thus, although antiretroviral treatment may suppress virus replication in the periphery and the brain and reduce CNS inflammation, viral DNA persists in the brain despite treatment. This suggests that the brain may serve as a long-term viral reservoir in HIV-infected individuals treated with antiretroviral drugs that suppress virus replication.


Subject(s)
Adenine/analogs & derivatives , Anti-HIV Agents/therapeutic use , Organophosphonates/therapeutic use , Simian Acquired Immunodeficiency Syndrome/drug therapy , Simian Immunodeficiency Virus , Zalcitabine/therapeutic use , Adenine/administration & dosage , Adenine/therapeutic use , Animals , Anti-HIV Agents/administration & dosage , Antigens, CD/biosynthesis , Antigens, Differentiation, Myelomonocytic/biosynthesis , Brain/immunology , Brain/pathology , Brain/virology , DNA, Viral/analysis , DNA, Viral/genetics , Disease Models, Animal , Drug Therapy, Combination , Histocompatibility Antigens Class II/biosynthesis , Injections, Subcutaneous , Macaca nemestrina , Organophosphonates/administration & dosage , Polymerase Chain Reaction , RNA, Viral/cerebrospinal fluid , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/virology , Simian Immunodeficiency Virus/genetics , Simian Immunodeficiency Virus/isolation & purification , Tenofovir , Time Factors , Zalcitabine/administration & dosage
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