scholarly journals In vitro bone marrow toxicity of nucleoside analogs against human immunodeficiency virus.

1989 ◽  
Vol 33 (4) ◽  
pp. 576-579 ◽  
Author(s):  
T Inoue ◽  
K Tsushita ◽  
T Itoh ◽  
M Ogura ◽  
T Hotta ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Human Immunodeficiency Virus ◽  
Nucleoside Analogs ◽  
Bone Marrow Toxicity ◽  
Immunodeficiency Virus

scholarly journals Human Immunodeficiency Virus Types 1 and 2 Exhibit Comparable Sensitivities to Zidovudine and Other Nucleoside Analog Inhibitors In Vitro

2007 ◽  
Vol 52 (1) ◽  
pp. 329-332 ◽  
Author(s):  
Robert A. Smith ◽  
Geoffrey S. Gottlieb ◽  
Donovan J. Anderson ◽  
Crystal L. Pyrak ◽  
Bradley D. Preston
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Replication ◽  
Reverse Transcriptase ◽  
Antiviral Therapy ◽  
Nucleoside Analogs ◽  
Nucleoside Analog ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Indicator Cell

ABSTRACT Using an indicator cell assay that directly quantifies viral replication, we show that human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2, respectively) exhibit similar sensitivities to 3′-azido-3′-deoxythymidine (zidovudine) as well as other nucleoside analog inhibitors of reverse transcriptase. These data support the use of nucleoside analogs for antiviral therapy of HIV-2 infection.

scholarly journals Highly potent oxathiin carboxanilide derivatives with efficacy against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus isolates.

1997 ◽  
Vol 41 (4) ◽  
pp. 831-837 ◽  
Author(s):  
R W Buckheit ◽  
M J Snow ◽  
V Fliakas-Boltz ◽  
T L Kinjerski ◽  
J D Russell ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
In Vitro Selection ◽  
Nucleoside Analogs ◽  
Side Chain ◽  
Resistant Virus ◽  
Immunodeficiency Virus ◽  
Virus Isolates ◽  
Hiv 1

The structure-activity relationships of a series of compounds related to the nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) oxathiin carboxanilide have been described (R. W. Buckheit, Jr., T. L. Kinjerski, V. Fliakas-Boltz, J. D. Russell, T. L. Stup, L. A. Pallansch, W. G. Brouwer, D. C. Dao, W. A. Harrison, R. J. Schultz, J. P. Bader, and S. S. Yang, Antimicrob. Agents Chemother. 39:2718-2727, 1996). From these studies, the furanyl-containing analog UC10 was identified as the most potent inhibitor of human immunodeficiency virus type 1 (HIV-1) replication and a promising candidate for further development. Three new UC analogs (UC040, UC82, and UC781) have been determined to inhibit laboratory-derived and low-passage-number, primary virus isolates at low nanomolar concentrations in both established and fresh human cells. Each of the compounds synergistically interacted with the nucleoside analogs zidovudine, dideoxyinosine, dideoxycytosine, and lamivudine to inhibit HIV-1 replication. As a group, the UC compounds were found to be less active against viruses with the L100I, K103N, and Y181C amino acid changes in the RT and, upon in vitro selection, yielded resistant virus with the Y181C mutation in the RT. The most potent of the three new compounds, UC781, contains a furanyl side chain, similar to UC10, but differs in having an extended ether side chain instead of an oxime chain. The broad therapeutic index of UC781 (>62,000) resulted in effective inhibition of NNRTI-resistant virus isolates at high nanomolar concentrations. Furthermore, UC781 and the NNRTI costatolide were able to synergistically inhibit HIV-1 replication when used in combination, suggesting that UC781 may interact with the RT differently than the other UC analogs. The favorable anti-HIV properties of the UC compounds suggest they should be considered for further clinical development.

scholarly journals Human immunodeficiency virus infection of eosinophils in human bone marrow cultures.

1991 ◽  
Vol 174 (6) ◽  
pp. 1661-1664 ◽  
Author(s):  
A R Freedman ◽  
F M Gibson ◽  
S C Fleming ◽  
C J Spry ◽  
G E Griffin
Keyword(s):  
Bone Marrow ◽  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase Activity ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Rapid Decline ◽  
Immunodeficiency Virus ◽  
Hiv 1

Normal human bone marrow, cultured in vitro with interleukin 5 to promote eosinophil production and maturation, was inoculated with cell-free isolates of human immunodeficiency virus type 1 (HIV-1). CD4 expression by eosinophil precursors, determined by immunocytochemistry, was found to be greatest early in their maturation with a rapid decline after 28 d in culture. Productive HIV infection of eosinophil precursors was detected 14 d after inoculation, by a combination of immunostaining for HIV-1 p24 and gp41/160 and in situ hybridization for viral RNA, together with assay of culture supernatants for p24 antigen and reverse transcriptase activity. Thus, eosinophils are susceptible to productive HIV-1 infection in vitro and may be an important reservoir for the virus in vivo.

scholarly journals Replication of the human immunodeficiency virus 1 and impaired differentiation of T cells after in vitro infection of bone marrow immature T cells.

1989 ◽  
Vol 83 (2) ◽  
pp. 610-615 ◽  
Author(s):  
Y Lunardi-Iskandar ◽  
M T Nugeyre ◽  
V Georgoulias ◽  
F Barré-Sinoussi ◽  
C Jasmin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Immunodeficiency Virus ◽  
Human Immunodeficiency Virus 1

scholarly journals In vitro potency of inhibition by antiviral drugs of hematopoietic progenitor colony formation correlates with exposure at hemotoxic levels in human immunodeficiency virus-positive humans.

1996 ◽  
Vol 40 (2) ◽  
pp. 514-519 ◽  
Author(s):  
R E Dornsife ◽  
D R Averett
Keyword(s):  
Human Immunodeficiency Virus ◽  
Colony Formation ◽  
Rank Order ◽  
Bone Marrow Toxicity ◽  
Time Curve ◽  
Concentration Time ◽  
Immunodeficiency Virus ◽  
Nucleoside Drugs ◽  
Antiviral Nucleoside

Inhibition of in vitro colony formation of human hematopoietic progenitors (CFU-granulocyte-macrophage, burst-forming unit-erythroid) by the antiviral nucleoside drugs alovudine, zalcitabine, zidovudine, ganciclovir, stavudine, didanosine, lamivudine, and acyclovir was measured. Significant correlations between in vitro 50% inhibitory concentrations and the daily human exposures (area under the concentration-time curve from 0 to 24 h; in micromolar.hour) of these chronically administered drugs in human immunodeficiency virus-positive patients that induced neutropenia or anemia were demonstrated by both linear regression and Spearman rank-order analyses. These quantitative correlations allow estimation of the exposure at which bone marrow toxicity may occur with candidate compounds.

scholarly journals Human immunodeficiency virus infection of human bone marrow stromal fibroblasts

Blood ◽  
1990 ◽  
Vol 76 (2) ◽  
pp. 317-322 ◽  
Author(s):  
DT Scadden ◽  
M Zeira ◽  
A Woon ◽  
Z Wang ◽  
L Schieve ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Human Immunodeficiency Virus ◽  
Cell Types ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Stromal Fibroblast ◽  
Stromal Fibroblasts ◽  
Fibroblast Line ◽  
Immunodeficiency Virus

Abstract The human immunodeficiency virus (HIV) preferentially infects CD4 positive T cells and monocytes. Other human cell types have been reported to be infectable with HIV, including cells of mesenchymal origin. In this report, we show that both primary human bone marrow stromal fibroblasts and an immortalized human stromal fibroblast line are susceptible to HIV infection. These cells are capable of passing HIV to cells of lymphoid or myeloid lineage, and may thereby act as a reservoir of virus. This in vitro system may be a useful model for assessing the pathophysiology of hematopoietic dysfunction in AIDS patients.

scholarly journals Oral versus Intravenous Flucytosine in Patients with Human Immunodeficiency Virus-Associated Cryptococcal Meningitis

2006 ◽  
Vol 51 (3) ◽  
pp. 1038-1042 ◽  
Author(s):  
Annemarie E. Brouwer ◽  
Hendrikus J. M. van Kan ◽  
Elizabeth Johnson ◽  
Adul Rajanuwong ◽  
Prapit Teparrukkul ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Human Immunodeficiency Virus ◽  
Cryptococcal Meningitis ◽  
Fungicidal Activity ◽  
Controlled Trial ◽  
Oral Formulation ◽  
Bone Marrow Toxicity ◽  
Time Curve ◽  
Immunodeficiency Virus ◽  
Early Fungicidal Activity

ABSTRACT In a randomized controlled trial of amphotericin B-based therapy for human immunodeficiency virus (HIV)-associated cryptococcal meningitis in Thailand, we also compared the mycological efficacy, toxicity, and pharmacokinetics of oral versus intravenous flucytosine at 100 mg/kg of body weight/day for the initial 2 weeks. Half of 32 patients assigned to the two arms containing flucytosine were randomized to oral and half to intravenous flucytosine. Early fungicidal activity was determined from serial quantitative cultures of cerebrospinal fluid (CSF), and toxicity was assessed by clinical and laboratory monitoring. Flucytosine and fluorouracil concentrations in plasma and CSF were measured by high-performance liquid chromatography. No significant bone marrow or hepatotoxicity was seen, there was no detectable difference in bone marrow toxicity between patients on intravenous and those on oral formulation, and no patients discontinued treatment. In patients receiving intravenous flucytosine, the median 24-h area under the concentration-time curve was significantly higher than in the oral group. Despite this difference, there was no difference in early fungicidal activity between patients on intravenous compared with patients on oral flucytosine. The results suggest that either formulation can be used safely at this dosage in a developing country setting, without drug concentration monitoring. The bioavailability of the oral formulation may be reduced in late-stage HIV-infected patients in Thailand. Concentrations of flucytosine with intravenous formulation at 100 mg/kg/day may be in excess of those required for maximal fungicidal activity.

scholarly journals 3′-Azido-3′-Deoxythymidine (AZT) Mediates Cross-Resistance to Nucleoside Analogs in the Case of AZT-Resistant Human Immunodeficiency Virus Type 1 Variants

1998 ◽  
Vol 72 (6) ◽  
pp. 4858-4865 ◽  
Author(s):  
Eric J. Arts ◽  
Miguel E. Quiñones-Mateu ◽  
Jamie L. Albright ◽  
James-Paul Marois ◽  
Charles Hough ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Nucleoside Analogs ◽  
Cross Resistance ◽  
Treatment Regimens ◽  
Immunodeficiency Virus ◽  
Azt Resistance

ABSTRACT Difficulties in deciphering the mechanisms of 3′-azido-3′-deoxythymidine (AZT)-resistance by human immunodeficiency virus type 1 (HIV-1) variants are due in part to an inability to reconstitute resistance in vitro using AZT-resistant reverse transcriptases. We decided to characterize mechanisms of AZT resistance in tissue culture infections by studying the ability of drug-resistant viruses to synthesize viral DNA in the presence or absence of drug. Through use of PCR amplifications, we discovered an AZT-mediated stimulation of reverse transcription by AZT-resistant viruses carrying the M41L and T215Y mutations that can apparently override the inhibitory effects of AZT-5′-triphosphate. In addition, the presence of AZT also causes viruses containing the M41L and T215Y substitutions to have diminished sensitivity to other nucleoside analogs (i.e., ddC, ddI, and d4T). This AZT-mediated cross-resistance may help to explain the virological failure of treatment regimens that included ddI plus AZT or ddC plus AZT in situations in which the T215Y and/or M41L mutations were present (F. Brun-Vézinet, C. Boucher, C. Loveday, D. Descamps, V. Fauveau, J. Izopet, D. Jeffries, S. Kaye, C. Krzyanowski, A. Nunn, R. Schuurman, J. M. Seigneurin, C. Tamalet, R. Tedder, J. Weber, and G. J. Weverling, Lancet 350:983–990, 1997). Our results suggest that the use of AZT may be contraindicated in those patients for whom resistance to this compound (M41L and/or T215Y) has been demonstrated.

Lack of evidence for infection of or effect on growth of hematopoietic progenitor cells after in vivo or in vitro exposure to human immunodeficiency virus

Blood ◽  
1990 ◽  
Vol 76 (12) ◽  
pp. 2476-2482 ◽  
Author(s):  
JM Molina ◽  
DT Scadden ◽  
M Sakaguchi ◽  
B Fuller ◽  
A Woon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Human Immunodeficiency Virus ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Marrow Cells

The pathogenesis of the hematologic abnormalities commonly observed in patients with acquired immunodeficiency syndrome (AIDS) is incompletely understood. We report here that in vitro growth of myeloid (CFU-GM) and erythroid (BFU-E) progenitor cells from six patients with AIDS was not significantly different from that of normal human immunodeficiency virus (HIV) seronegative donors: 25.3 +/- 5 CFU-GM per 5 x 10(4) low density marrow cells and 33.5 +/- 5 BFU-E were observed in AIDS patients versus 32.7 +/- 5 CFU-GM and 42.1 +/- 5 BFU-E in controls. Furthermore, no HIV-DNA in individual colonies (CFU-GM and BFU-E) could be detected using the polymerase chain reaction (PCR) technique, although HIV-1 DNA was detected in peripheral blood mononuclear cells from the same patients. Similarly, normal bone marrow cells exposed in vitro to different isolates of HIV or recombinant purified HIV-1 envelope glycoprotein (gp) 120 did not exhibit any difference in growth of CFU-GM or BFU-E as compared with mock exposed bone marrow cells. HIV- 1 DNA could not be detected by the PCR technique in individual colonies derived from HIV exposed marrow. This study suggests that committed myeloid and erythroid progenitors from AIDS patients are responsive to hematopoietic growth factors in vitro and do not appear to contain HIV- 1 DNA. Also, HIV or its envelope gp did not alter the growth of hematopoietic progenitor cells in vitro. No evidence of HIV infection of progenitor cells could be demonstrated. Impaired hematopoiesis in patients with AIDS may not be related to direct effects of HIV on committed progenitor cells.

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