- Can we prevent pediatric HIV? An experience at a tertiary care hospital. [Journal Article]
- MJMed J Armed Forces India 2013; 69(3):218-21
- CONCLUSIONS: A comprehensive PPTCT programme with administration of antiretroviral therapy to the mother and infant, safe delivery practices, avoidance of breastfeeding, and close follow up, the incidence of PTCT can be reduced to negligible rates as seen in our study.
- Morphological and metabolic components of lipodystrophy in various nevirapine-based highly active antiretroviral therapy (HAART) regimens: a cross-sectional, observational study. [Journal Article]
- CDClin Drug Investig 2011 Nov 1; 31(11):759-67
- CONCLUSIONS: HAART including nevirapine has a limited impact on components of lipodystrophy in patients with HIV infection. Further studies are needed to verify if nevirapine overcomes the expected distinct lipodystrophy risk profile associated with different nucleoside backbone therapies.
- Structural basis of HIV-1 resistance to AZT by excision. [Journal Article]
- NSNat Struct Mol Biol 2010; 17(10):1202-9
- Human immunodeficiency virus (HIV-1) develops resistance to 3'-azido-2',3'-deoxythymidine (AZT, zidovudine) by acquiring mutations in reverse transcriptase that enhance the ATP-mediated excision of A...
Human immunodeficiency virus (HIV-1) develops resistance to 3'-azido-2',3'-deoxythymidine (AZT, zidovudine) by acquiring mutations in reverse transcriptase that enhance the ATP-mediated excision of AZT monophosphate from the 3' end of the primer. The excision reaction occurs at the dNTP-binding site, uses ATP as a pyrophosphate donor, unblocks the primer terminus and allows reverse transcriptase to continue viral DNA synthesis. The excision product is AZT adenosine dinucleoside tetraphosphate (AZTppppA). We determined five crystal structures: wild-type reverse transcriptase-double-stranded DNA (RT-dsDNA)-AZTppppA; AZT-resistant (AZTr; M41L D67N K70R T215Y K219Q) RT-dsDNA-AZTppppA; AZTr RT-dsDNA terminated with AZT at dNTP- and primer-binding sites; and AZTr apo reverse transcriptase. The AMP part of AZTppppA bound differently to wild-type and AZTr reverse transcriptases, whereas the AZT triphosphate part bound the two enzymes similarly. Thus, the resistance mutations create a high-affinity ATP-binding site. The structure of the site provides an opportunity to design inhibitors of AZT-monophosphate excision.
- Perinatal AZT exposure alters the acoustic and tactile startle response to 8-OH-DPAT and apomorphine in adult rats. [Journal Article]
- NTNeurotoxicol Teratol 2005 Jul-Aug; 27(4):599-608
- The present study was designed to assess the dopaminergic and serotonergic contributions of the acoustic startle response (ASR) and the tactile startle response (TSR) in adult rats that had been peri...
The present study was designed to assess the dopaminergic and serotonergic contributions of the acoustic startle response (ASR) and the tactile startle response (TSR) in adult rats that had been perinatally exposed to AZT (azidothymidine, zidovudine; an antiretroviral agent). Each dam was randomly assigned to a treatment group: non-treated, AZT0, 100 or 150 mg/kg. Once daily gastric intubation began prenatally on gestational day (G) 19 and continued to G22 and then the pups were intubated between postnatal day (PND) 2-20. On PND60, animals were tested for responses to both acoustic and tactile stimuli following a challenge of vehicle, 0.25 or 0.5 mg/kg 8-OH-DPAT, a 5-HT(1A) agonist, or 0.75 or 2.0 mg/kg apomorphine (APO, a dopaminergic agonist) IP. Both DPAT and APO increased startle magnitude as expected. Additionally, perinatal AZT exposure enhanced startle responses following both DPAT and APO, an effect not due to perinatal handling or intubation. Similarly, perinatal AZT increased tactile responses following drug challenge in a gender-specific manner. Perinatal AZT also prolonged startle latencies, a change which may indicate that perinatal AZT alters conduction velocity. Therefore, the administration of AZT during the perinatal period results in long-term functional alterations within the startle reflex pathways.
- Monitoring the intracellular metabolism of nucleoside phosphoramidate pronucleotides by 31P NMR. [Journal Article]
- NNNucleosides Nucleotides Nucleic Acids 2004; 23(1-2):483-93
- The intracellular metabolism of 3'-azido-3'-deoxythymidine (AZT)-(L)-tryptophan methyl ester phosphoramidate (L-ATO) and AZT-(L)-phenylalanine methyl ester phosphoramidate (L-APO) by the human T-lymp...
The intracellular metabolism of 3'-azido-3'-deoxythymidine (AZT)-(L)-tryptophan methyl ester phosphoramidate (L-ATO) and AZT-(L)-phenylalanine methyl ester phosphoramidate (L-APO) by the human T-lymphoblastoid cell line CCRF-CEM (CEM-1.3) and peripheral blood mononuclear cell line (PBMC) was investigated with high field 31P NMR spectroscopy. The AZT amino acid phosphoramidates were shown to accumulate intracellularly and to be readily converted into AZT-MP by both tissues types. Thus, the efficient delivery of nucleoside monophosphates to cells can be facilitated by nucleoside phosphoramidate pronucleotides.
- Risk factors for preterm birth, low birth weight, and intrauterine growth retardation in infants born to HIV-infected pregnant women receiving zidovudine. Pediatric AIDS Clinical Trials Group 185 Team. [Randomized Controlled Trial]
- AIDSAIDS 2000 Jul 07; 14(10):1389-99
- CONCLUSIONS: Risk factors for APO in antiretroviral treated HIV-infected women are similar to those reported for uninfected women. These data suggest that provision of prenatal care and ART may reduce APO.
- Protection by protein A of apoptotic cell death caused by anti-AIDS drug zidovudine. [Journal Article]
- BBBiochem Biophys Res Commun 1999 Oct 22; 264(2):601-4
- Zidovudine, the anti-AIDS drug, caused inhibition of mitogen-induced proliferation and perturbation of cell-cycle progression of cultured bone marrow cells of mice. There was significant hypoploidy o...
Zidovudine, the anti-AIDS drug, caused inhibition of mitogen-induced proliferation and perturbation of cell-cycle progression of cultured bone marrow cells of mice. There was significant hypoploidy observed in flow cytometric analysis of AZT-treated bone marrow cells. In apo-direct analysis, cells showed apoptosis in G0/G1 phase. In DNA gel analysis, characteristic laddering of apoptosis was observed in AZT-treated bone marrow cells. We demonstrated that, when the animals were pretreated with protein A (PA) of Staphylococcus aureus, the apoptotic changes could be prevented in bone marrow cells of AZT-treated animals. There is a significant (p < 0.05) increase in proliferation of bone marrow cells subjected to mitogen treatment in PA+AZT-treated animals, compared to only AZT-treated animals. However, cell-cycle phase distribution was not hampered and no laddering in DNA gel analysis was also observed in this group. In apo-direct analysis, PA treatment showed significant (p < 0.001) inhibition of AZT-induced apoptosis. These observations indicate that by using a suitable agent such as protein A the toxic side effects of AZT could be minimized.
- Tumor necrosis factor beta and soluble APO-1/Fas independently predict progression to AIDS in HIV-seropositive patients. [Journal Article]
- ARAIDS Res Hum Retroviruses 1998 Jul 1; 14(10):835-43
- The relationship between serum concentration of different components of the nerve growth factor/tumor necrosis factor (TNF) receptor family, including soluble APO-1/Fas (sAPO-1/Fas) and progression o...
The relationship between serum concentration of different components of the nerve growth factor/tumor necrosis factor (TNF) receptor family, including soluble APO-1/Fas (sAPO-1/Fas) and progression of HIV infection, was analyzed in a case-control study of individuals selected from a cohort of HIV-seropositive patients who were progressing or not progressing to AIDS while being treated with nucleoside analogs. HIV-seronegative healthy controls were also analyzed. The results showed that, despite close matching for immunologic (CD4 cell count, beta2-microglobulin concentration) and virologic (p24 antigen, detection of HIV syncytium-inducing phenotype, plasma HIV viremia) parameters, the baseline serum concentrations of TNF-beta and sAPO-1/Fas were statistically different between progressing and nonprogressing patients. In addition, serum concentrations of TNF-beta and sAPO-1/Fas showed the strongest independent predictive power for progression to AIDS in a multivariate conditional logistic regression model. Because TNF-beta and Fas were suggested to be mediators of antigen-induced cell death (AICD) in HIV infection and sAPO-1/Fas was hypothesized to protect lymphocyte against AICD, these data suggest an important pathogenetic role for AICD in the progression of HIV infection.
- Mutation of CD95 (Fas/Apo-1) gene in adult T-cell leukemia cells. [Case Reports]
- BloodBlood 1998 May 15; 91(10):3935-42
- CD95 antigen (also known as Fas or Apo-1) and Fas ligand play key roles in apoptosis of cells of the immune system, function as effector molecules of cytotoxic T lymphocytes, and function in the elim...
CD95 antigen (also known as Fas or Apo-1) and Fas ligand play key roles in apoptosis of cells of the immune system, function as effector molecules of cytotoxic T lymphocytes, and function in the elimination of activated lymphocytes during the downregulation of the immune response. The critical roles of the Fas-Fas ligand system in apoptosis suggest that its inactivation may be involved in malignant transformation. We analyzed the expression of Fas antigen on adult T-cell leukemia (ATL) cells by flow cytometry and found that Fas antigen expression was absent in a case of ATL and markedly decreased in another case among 47 cases examined. Apoptosis could not be induced in the Fas-negative ATL cells by antibody against Fas antigen. Sequencing of reverse transcription-polymerase chain reaction products of the Fas genes in the Fas negative cells showed two types of aberrant transcripts: one had a 5-bp deletion and a 1-bp insertion in exon 2, and the other transcript lacked exon 4. These mutations caused the premature termination of both alleles, resulting in the loss of expression of surface Fas antigen. These aberrant transcripts were not detected in a nonleukemic B-cell line from the same patient. An RNase protection assay of the Fas gene showed mutations in 2 additional cases with Fas-positive ATL cells of 35 cases examined: 1 case lacked exon 4 and the other was a silent mutation. In the Fas antigen-negative case, leukemic cells were resistant to anticancer drugs in vivo, indicating that the loss of expression of Fas antigen may be associated with a poor response to anticancer drugs. Indeed, Fas-negative ATL cells were resistant to adriamycin-induced apoptosis in vitro, which is consistent with the finding that ATL in this case was resistant to chemotherapy. These findings indicate that mutation of the Fas gene may be associated with the progression of ATL and with resistance to anticancer drugs.
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- Downregulation of increased CD95 (APO-1/Fas) ligand in T cells from human immunodeficiency virus-type 1-infected children after antiretroviral therapy. [Letter]
- BloodBlood 1997 Jul 15; 90(2):886-8