Search PubMed⌕ Search

Biomedical subjects

C S Crumpacker

Publications and source records attributed to C S Crumpacker.

At least 37 records · Page 2Linked to original sources
PubMed1996

Association of plasma human immunodeficiency virus type 1 RNA level with risk of clinical progression in patients with advanced infection. AIDS Clinical Trials Group (ACTG) 116B/117 Study Team. ACTG Virology Committee Resistance and HIV-1 RNA Working Groups.

Human immunodeficiency virus (HIV)-1 RNA level in plasma was evaluated as a surrogate marker for disease progression in a clinical trial of advanced HIV-1 infection. Baseline HIV-1 RNA level was an independent predictor of disease progression (relative hazard [RH] for each doubling of HIV-1 RNA level, 1.26; 95% confidence interval [CI], 1.03-1.54; P = .02), after adjusting for the week 4 change in HIV-1 RNA level, baseline CD4 cell count, syncytium-inducing phenotype, clinical status at study entry, and therapy randomization. A 50% reduction in HIV-1 RNA level was associated with a 27% decrease in the adjusted risk of disease progression during the study (RH, 0.73; 95% CI, 0.52-1.02; P = .07). The partial validation of HIV-1 RNA as a predictor for clinical end points has implications for the use of HIV-1 RNA in clinical trials and practice.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Effect of foscarnet on quantities of cytomegalovirus and human immunodeficiency virus in blood of persons with AIDS.

Four intravenous dosages of foscarnet given for 10 days were compared with no therapy in persons with AIDS who had asymptomatic cytomegalovirus (CMV) viremia. CMV viremia was quantitated by endpoint cell dilution microcultures, pp65 antigenemia assay, and measurement of CMV DNA in peripheral blood leukocytes by a quantitative-competitive PCR. Human immunodeficiency virus type 1 (HIV-1) viremia was quantitated by endpoint cell dilution microculture, serum p24 antigen assay, and PCR for HIV-1 RNA in plasma. Twenty-seven subjects who had received a median of 22 months of nucleoside antiretroviral therapy were enrolled. Twenty-two subjects received foscarnet, which was well tolerated and decreased the CMV burden, as reflected by all three indicator assays. During the 10 days of dosing, the level of CMV viremia, as measured by 50 percent tissue culture infective doses, decreased from 117.5 to 12.7 (P = 0.001), the amount of CMV DNA decreased from 20,328 copies to 622 copies per 150,000 leukocytes (P = 0.02), and the level of CMV pp65 antigenemia decreased from 14.9 to 1.6 positive peripheral blood mononuclear cells per 50,000 leukocytes (P = 0.008). A significant pharmacodynamic relationship was found between the peak foscarnet concentration and a decrease in the level of CMV antigenemia (P < 0.05). Foscarnet had no effect on quantitative HIV-1 microcultures during the 10 days of treatment, but the HIV-1 p24 antigen level in serum decreased significantly, from 454 to 305 pg/ml (P = 0.01). Also, a significant pharmacodynamic relationship was seen between plasma HIV-1 RNA concentrations and both peak foscarnet concentration (P < 0.01) and the area under the foscarnet time-concentration curve (P < 0.05). Reductions in the levels of CMV and HIV-1 viremia correlated quantitatively with systemic exposure to foscarnet, whereas control subjects actually experienced an increase in CMV and HIV-1 burdens. The dual antiviral activity of foscarnet shown in this trial encourages investigation of its use in combination with other antiretroviral therapies for persons with AIDS.

AIDS-Related Opportunistic Infections↗
PubMed1995

Zidovudine resistance and HIV-1 disease progression during antiretroviral therapy. AIDS Clinical Trials Group Protocol 116B/117 Team and the Virology Committee Resistance Working Group.

OBJECTIVE: To evaluate the association between resistance of human immunodeficiency virus type 1 (HIV-1) to zidovudine and clinical progression. DESIGN: Retrospective analysis of specimens from patients in the AIDS Clinical Trials Group (ACTG) protocol 116B/117, a randomized comparison of didanosine with continued zidovudine therapy in patients with advanced HIV-1 disease who had received 16 weeks or more of previous zidovudine therapy. SETTING: Participating ACTG virology laboratories. PATIENTS: 187 patients with baseline HIV-1 isolates. MEASUREMENTS: Zidovudine susceptibility testing and assays for syncytium-inducing phenotype were done on baseline HIV-1 isolates. Relative hazards for clinical progression or death associated with baseline clinical, virologic, and immunologic factors were determined from Cox proportional hazards regression models. RESULTS: Compared with other patients, 15% (26 of 170) with isolates showing high-level zidovudine resistance (50% inhibitory zidovudine concentration > or = 1.0 microM) had 1.74 times the risk for progressing to a new AIDS-defining event or death (95% CI, 1.00 to 3.03) and 2.78 times the risk for death (CI, 1.21 to 6.39) in analyses that controlled for baseline CD4+ T-lymphocyte count, syncytium-inducing HIV-1 phenotype, disease stage, and randomized treatment assignment. The clinical benefit of didanosine was not limited to patients with highly zidovudine-resistant baseline HIV-1 isolates. CONCLUSIONS: High-level resistance of HIV-1 to zidovudine predicted more rapid clinical progression and death when adjusted for other factors. However, patients with advanced HIV-1 disease may benefit from a change in monotherapy from zidovudine to didanosine whether high-level HIV-1 resistance to zidovudine is present or absent, and laboratory assessment of zidovudine resistance is not necessary for deciding when to switch monotherapy from zidovudine to didanosine.

Acquired Immunodeficiency Syndrome↗
PubMed1995

A rapid, direct test for zidovudine susceptibility in clinical isolates of human immunodeficiency virus type 1 (HIV-1) from infected children.

BACKGROUND: Existing phenotypic tests of antiretroviral susceptibility in clinical isolates of human immunodeficiency virus (HIV) are expensive and slow, and require passage of virus in cell culture with the possible consequence of selecting variants. OBJECTIVES: We sought to develop a rapid 14-day assay for zidovudine susceptibility of cell-associated HIV performed directly in patient blood samples. STUDY DESIGN: Twenty-three tests were performed prospectively in 21 children, and the results were compared with those of the AIDS Clinical Trials Group/Department of Defense consensus drug susceptibility assay (DSA) as well as certain clinical parameters. RESULTS: Five strains from ZDV-naive children were sensitive by the rapid test. Three were tested by DSA, and all were sensitive. Six strains from children who had received >/=24 months of ZDV were resistant by the rapid assay. Four of these strains were tested by the DSA, and all were shown resistant. The viral strains from children who received <24 months of therapy or who had switched from ZDV to other antiviral therapy exhibited variable sensitivity by both tests. Changes in CD4 cells in the subsequent 6 months, as well as weight gain during this time were both correlated to the results of the rapid test. The syncytium-inducing capacity of the virus strains was analyzed similarly. CONCLUSIONS: The rapid intracellular virus susceptibility assay is a test of drug sensitivity performed on HIV growing in cells obtained directly from an infected patient. The test has a two-week turn-around time and, in this preliminary report, gives results which correlate with both time on zidovudine and also subsequent CD4 cell changes.

Journal Article↗
PubMed1995

Detection of human cytomegalovirus DNA, RNA, and antibody in normal donor blood.

Peripheral blood samples from 313 normal donors were tested for prior human cytomegalovirus (HCMV) infection: 37%, 0.9%, and 43% of the samples were positive by antibody detection, DNA hybridization, and RNA hybridization assays, respectively. An early mRNA, which is transcribed from a HindIII-b fragment of the CMV genome and detected with an antisense RNA probe, can be detected more frequently than antibody and CMV DNA. The early CMV mRNA transcripts can be detected in the peripheral white blood cells in 44% of HCMV-seronegative blood donors. Blood samples that were CMV RNA positive but antibody negative comprised 27% of the tested samples. Whether CMV RNA in donor blood indicates that CMV can be transmitted via blood transfusion must be determined by further studies.

Antibodies, Viral↗
PubMed1995

Prevalence and clinical significance of zidovudine resistance mutations in human immunodeficiency virus isolated from patients after long-term zidovudine treatment. AIDS Clinical Trials Group 116B/117 Study Team and the Virology Committee Resistance Working Group.

Zidovudine resistance mutations at reverse transcriptase codons 215 or 41 were found in two-thirds of human immunodeficiency virus type 1 (HIV-1) isolates obtained at baseline from patients enrolled in an AIDS Clinical Trials Group (ACTG) protocol that compared didanosine with continued zidovudine in patients with > or = 16 weeks of previous zidovudine therapy (ACTG 116B/117). The combined presence of mutations at both codons 215 and 41 conferred an increased risk for progression (relative hazard, 1.82; 95% confidence interval [CI], 1.02-3.26) and an increased risk for death (RH, 5.42; 95% CI, 1.92-15.30) in analyses that controlled for other factors predictive of progression. However, the benefit of switching to didanosine compared with continued zidovudine therapy was independent of the presence of these mutations. Although this information is not helpful in determining when to alter therapy, detection of zidovudine resistance mutations provides prognostic information in patients with advanced HIV disease.

Adult↗
PubMed1994

Recurrence and resistance patterns of herpes simplex virus following cessation of > or = 6 years of chronic suppression with acyclovir. Acyclovir Study Group.

Questions have arisen regarding the clinical outcome and the possible selection of resistant virus when patients with genital herpes discontinue prolonged chronic acyclovir; 239 immunocompetent patients with a history of frequently recurring genital herpes who stopped successful suppressive therapy after 6 years were studied. Of the patients, 85.8% had at least one recurrence and 75% had at least two recurrences in the subsequent year (median time to first and second recurrence, 68 and 180 days, respectively). Herpes simplex virus isolates recovered from these patients had a median acyclovir sensitivity of 0.79 micrograms/mL and 4 (3.5%) were resistant (> or = 3 micrograms/mL). These values are comparable to those of pretherapy isolates and to reported values of isolates from acyclovir-naive patients. Also, paired pre- and posttherapy isolates from 13 patients showed no trend toward development of resistance. Thus, even after 6 years of acyclovir suppression, most patients continue to have recurrences, but the selection of resistant virus has not been observed.

Acyclovir↗
PubMed1994

Dideoxynucleoside resistance emerges with prolonged zidovudine monotherapy. The RV43 Study Group.

Human immunodeficiency virus type 1 (HIV-1) isolates resistant to zidovudine (ZDV) have previously been demonstrated to exhibit in vitro cross-resistance to other similar dideoxynucleoside agents which contain a 3'-azido group. However, cross-resistance to didanosine (ddI) or dideoxycytidine (ddC) has been less well documented. ZDV, ddI, and ddC susceptibility data have been collected from clinical HIV-1 isolates obtained by five clinical centers and their respective retrovirology laboratories. All subjects were treated only with ZDV. Clinical HIV-1 isolates were isolated, amplified, and assayed for drug susceptibility in standardized cultures of phytohemagglutinin-stimulated donor peripheral blood mononuclear cells obtained from healthy seronegative donors. All five cohorts showed a correlation between decreased in vitro susceptibility to ZDV and decreased susceptibility to ddI and ddC. For each 10-fold decrease in ZDV susceptibility, an average corresponding decrease of 2.2-fold in ddI susceptibility was observed (129 isolates studied; P < 0.001, Fisher's test of combined significance). Similarly, susceptibility to ddC decreased 2.0-fold for each 10-fold decrease in ZDV susceptibility (82 isolates studied; P < 0.001, Fisher's test of combined significance). These data indicate that a correlation exists between HIV-1 susceptibilities to ZDV and ddI or ddC for clinical HIV-1 isolates.

AIDS-Related Complex↗
PubMed1993

Three inhibitors of type 1 human immunodeficiency virus long terminal repeat-directed gene expression and virus replication.

Transcription of type 1 human immunodeficiency virus (HIV-1) provirus is governed by the viral long terminal repeat (LTR). Drugs can block HIV-1 replication by inhibiting activity of its LTR. We report that topotecan, beta-lapachone, and curcumin are potent and selective inhibitors of HIV-1 LTR-directed gene expression, at concentrations that have minor effects on cells. At these concentrations, each drug inhibited p24 antigen production in cells either acutely or chronically infected with HIV-1. Their target is transcriptional function of the LTR.

Acute Disease↗
PubMed1993

HIV infection of the BS-1 human stroma cell line: effect on murine hematopoiesis.

BS-1, a stroma cell line derived from normal human bone marrow, can support the growth of murine erythroid (BFU-E), granulocyte-macrophage (CFU-GM), and megakaryocyte (CFU-Meg) progenitor cells in a short-term in vitro coculture system. Exposure of BS-1 cell to the human immunodeficiency virus (HIV) prior to coculture results in a marked reduction in the stroma cell's ability to support murine BFU-E and CFU-GM. The effect of HIV on the BS-1 cell's hematopoietic support function (HSF) is dependent on the multiplicity of infection (m.o.i.). BS-1 stimulation of CFU-GM is significantly impaired at m.o.i. values ranging from 10 to 0.1, whereas its support of BFU-E colony formation is inhibited at m.o.i. values of 10 and 1. No effect of HIV on the BS-1 cell's HSF is observed with further log dilutions of virus. The HIV-mediated suppression of the BS-1 cell's ability to support hematopoiesis is neutralized by a monoclonal antibody (titers ranging from 1:10 to 1:50) to the Gp160 surface antigen of the virus. Suppression of BS-1 cell's HSF is again observed with log dilution (> 1:100) of the antibody. HIV suppression of the BS-1 cell's HSF correlates with replication of the virus. P24 antigen levels of 150 pG/ml are measured as early as Day 6 postinfection and rise to 360 pG/ml by Day 16 of culture. The results suggest that HIV may impair normal hematopoiesis by infecting the stroma cells of the bone marrow microenvironment and compromising their role as accessory cells in supporting the proliferation and differentiation of hematopoietic progenitor cells.

Animals↗
PubMed1993

Two regions of the herpes simplex virus type 1 UL42 protein are required for its functional interaction with the viral DNA polymerase.

Two essential gene products of herpes simplex virus type 1, the viral DNA polymerase (pol) and UL42, its accessory protein, physically and functionally interact to form the core of the viral DNA replication complex. Understanding this essential interaction would provide a basis from which to develop novel anti-herpesvirus agents. We previously have shown that when coexpressed in an in vitro transcription-translation system, UL42 stimulates pol activity (M. L. Gallo, D. I. Dorsky, C. S. Crumpacker, and D. S. Parris, J. Virol. 63:5023-5029, 1989). By analyzing various insertion, deletion, and frameshift mutations of UL42 in this system, we found the C-terminal 149 amino acids to be dispensable for the ability of the protein to stimulate pol activity. In addition, two distinct internal regions of UL42 were found to be required for pol stimulation. Regions I and II were defined to lie between amino acid residues 129 and 163 and between residues 202 and 337, respectively. When physical association was examined with antibody to UL42, pol was found to coimmunoprecipitate to the same level when expressed with a UL42 mutant protein lacking region I as that with wild-type UL42. Thus, mere physical association is insufficient for stimulation of pol activity. Deletion of region II reduced or eliminated coimmunoprecipitation with pol. Interestingly, an antibody to pol specific for residues 1216 to 1224 coimmunoprecipitated UL42 when both proteins were synthesized in a baculovirus expression system but not in rabbit reticulocyte lysates. These results indicate that (i) at least a portion of the region recognized by the pol antiserum may be accessible in the pol-UL42 heterodimer and (ii) immunoprecipitation results for products made in different expression systems may vary. Thus, at least two distinct regions of UL42 are essential for functional interaction with pol. Moreover, these results point to a UL42 region I function other than physical association with pol.

Binding Sites↗
PubMed1993

Resistance of herpes simplex virus type 2 to neomycin maps to the N-terminal portion of glycoprotein C.

Entry of herpes simplex virus (HSV) into cells is believed to be mediated by specific binding of envelope proteins to a cellular receptor. Neomycin specifically blocks this initial step in infection by HSV-1 but not HSV-2. Resistance of HSV-2 to this compound maps to a region of the genome encoding glycoprotein C (gC-2). We have studied the function of gC-2 in the initial interaction of the virus with the host cell, using HSV-2 mutants deleted for gC-2 and gC-2-rescued recombinants. Resistance to neomycin was directly linked to the presence of gC-2 within the viral genome. In addition, deletion of the gC-2 gene caused a marked delay in adsorption to cells relative to the wild-type virus. HSV-1 recombinants containing chimeric gC genes composed of HSV-1 and HSV-2 sequences were used to localize neomycin resistance within the N-terminal 223 amino acids of gC-2. This region of the glycoprotein comprises an important domain responsible for binding of HSV-2 to cell receptors in the presence of neomycin. A gC-2-negative mutant is still infectious, indicating that HSV-2 also has an alternative pathway of adsorption.

Animals↗
PubMed1992

A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. The NIAID AIDS Clinical Trials Group.

BACKGROUND: Although zidovudine is effective in patients with human immunodeficiency virus (HIV) infection, its efficacy may decline with prolonged use. Didanosine is another inhibitor of HIV reverse transcriptase. We evaluated the effectiveness of changing anti-HIV treatment from zidovudine to didanosine. METHODS: This multicenter, double-blind study involved 913 patients who had tolerated zidovudine for at least 16 weeks. The patients had the acquired immunodeficiency syndrome (AIDS), AIDS-related complex with less than or equal to 300 CD4 cells per cubic milliliter, or asymptomatic HIV infection with less than or equal to 200 CD4 cells per cubic milliliter. They were randomly assigned to receive 600 mg per day of zidovudine, 750 mg per day of didanosine, or 500 mg per day of didanosine. RESULTS: There were significantly fewer new AIDS-defining events and deaths among the 298 subjects assigned to 500 mg per day of didanosine than among the subjects who continued to receive zidovudine (relative risk, 1.39; 95 percent confidence interval, 1.06 to 1.82; P = 0.015). With 750 mg of didanosine, there was no clear benefit over zidovudine (relative risk, 1.10; 95 percent confidence interval, 0.86 to 1.42). The efficacy of didanosine was unrelated to the duration of previous zidovudine treatment. In the two didanosine groups, there were improvements in the number of CD4 cells (P less than 0.001 for both groups) and in p24 antigen levels (P = 0.03 in the 500-mg group; P = 0.005 in the 750-mg group), as compared with the zidovudine group. CONCLUSIONS: Changing treatment from zidovudine to 500 mg per day of didanosine appears to slow the progression of HIV disease.

AIDS-Related Complex↗
PubMed1992

Mechanism of action of foscarnet against viral polymerases.

Foscarnet is a pyrophosphate analogue with activity against herpesviruses, human immunodeficiency virus (HIV), and other RNA and DNA viruses. Foscarnet and its analogues achieve their antiviral effects via inhibition of viral polymerases, with such inhibition not being dependent on activation or phosphorylation of the compounds by viral or cellular proteins. Current evidence indicates that foscarnet interferes with exchange of pyrophosphate from deoxynucleoside triphosphate during viral replication by binding to a site on the herpesvirus DNA polymerase or HIV reverse transcriptase. Reviewed herein are basic findings regarding the mechanism of action and antiviral activity of foscarnet and the related compound phosphonoacetic acid (PAA), as well as findings regarding potential mechanisms of viral resistance and interactions with other antiviral agents.

Antiviral Agents↗
PubMed1992

Cytokine dysregulation in AIDS: in vivo overexpression of mRNA of tumor necrosis factor-alpha and its correlation with that of the inflammatory cytokine GRO.

The human immunodeficiency virus establishes an intimate interaction with the immune system. The virus can use cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (Il-1), to regulate its own expression by modifying the normal immunoregulatory network. We demonstrate that mRNA of the cytokine TNF-alpha from peripheral blood mononuclear cells is overexpressed in virtually all patients with AIDS who do not have active opportunistic infections compared with uninfected volunteers (p < 0.0001). This overexpression correlates with elevated mRNA levels of the recently discovered GRO (p < 0.05), a cytokine involved in the inflammatory response.

Acquired Immunodeficiency Syndrome↗