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Biomedical subjects

S A Spector

Publications and source records attributed to S A Spector.

At least 55 records · Page 3Linked to original sources
PubMed1998

Use of changes in plasma levels of human immunodeficiency virus type 1 RNA to assess the clinical benefit of antiretroviral therapy.

Data from 1330 human immunodeficiency virus type 1 (HIV-1)-infected patients enrolled in seven antiretroviral treatment trials were analyzed to characterize the clinical benefit of treatment-mediated reductions in plasma HIV-1 RNA levels. The risk of a new AIDS-defining event or death was reduced proportionally to the magnitude of the reduction of the HIV-1 RNA level during the first 6 months of therapy. Pretherapy HIV-1 RNA levels were prognostic independently of on-therapy levels. In addition, the reduction in risk associated with any given reduction of the level of HIV-1 RNA did not vary by pretherapy level. Having either a reduction in HIV-1 RNA level or an increase in CD4+ lymphocyte count, or both, was associated with a delay in clinical disease progression. This indicates that patient prognosis should be assessed using both HIV-1 RNA and CD4+ lymphocyte responses to therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Human immunodeficiency virus type 1 phenotypes in children with advanced disease treated with long-term zalcitabine.

Baseline and posttreatment human immunodeficiency virus type 1 (HIV-1) isolates from 38 symptomatic, zidovudine-experienced HIV-1-infected children enrolled in a prospective trial of zalcitabine (dideoxycytidine) monotherapy (Pediatric AIDS Clinical Trials Group 138) were studied for the presence of syncytium-inducing (SI) phenotype and zalcitabine resistance. Twenty of the isolates were SI and 18 were non-SI (NSI) at baseline. After >44 weeks of zalcitabine treatment, the SI and NSI phenotypes were maintained in 16 and 17 patients, respectively. One patient had an NSI-to-SI phenotypic switch, while SI-to-NSI reversion occurred in 4 children (20%). Isolates from 30 of these patients were analyzed by in vitro drug susceptibility assay: Mean IC50 values were 0.14 microM at baseline and 0.18 microM following zalcitabine treatment. Only 1 child (3%) developed zalcitabine resistance. Knowledge of the low incidence of zalcitabine resistance and the switch from SI to NSI phenotype in some children may prove useful when selecting antiretroviral drugs to be used in combination.

Adolescent↗
PubMed1998

Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Pediatric AIDS Clinical Trials Group Protocol 250 Team.

The safety, toxicity, and pharmacokinetics of intrapartum and early newborn nevirapine were evaluated in 17 human immunodeficiency virus type 1-infected women in labor and their newborns. No adverse effects of nevirapine were noted in any study mothers or infants. Following maternal dosing with 200 mg during labor, concentrations exceeding 100 ng/mL (10 times the in vitro IC50) were achieved in the newborns. Nevirapine elimination was prolonged in both mothers and infants, with median half-lives ranging from 36.8 to 65.7 h. Administration of 200 mg orally to the mothers in labor and of a single 2-mg/kg oral dose to the infants at 48-72 h after birth maintained serum concentrations in the infants > 100 ng/mL through 7 days of life.

Adult↗
PubMed1998

Zidovudine pharmacokinetics in premature infants exposed to human immunodeficiency virus.

We used population analysis techniques to determine zidovudine (ZDV) pharmacokinetic parameters in 15 preterm neonates (mean gestational age, 29.4 weeks; mean birth weight, 1,230 g) at a mean age of 5.5 days. The values of the pharmacokinetic parameters were as follows: clearance, 2.53 +/- 0.44 ml/min/kg; volume of distribution, 1.59 +/- 0.51 liters/kg; and half-life, 7.2 +/- 1.5 h. For seven infants studied a second time, at a mean age of 17.7 days, an increase in the mean clearance (2.33 versus 4.35 ml/min/kg; P = 0.024) and a decrease in the half-life (7.3 versus 4.4 h; P = 0.003) were found. The ZDV clearance is low and the half-life is prolonged in premature neonates, but the clearance increases and the half-life decreases with postnatal age. Potentially toxic concentrations may accumulate in serum if the standard dosage for full-term infants is used. We suggest that initial ZDV dosing should be reduced to 1.5 mg every 12 h for preterm neonates.

Aging↗
PubMed1998

Human immunodeficiency virus type 1 induction mediated by genistein is linked to cell cycle arrest in G2.

Protein tyrosine kinase (PTK) phosphorylation is involved in cellular proliferation and differentiation processes that are key factors for human immunodeficiency virus type 1 (HIV-1) regulation in infected monocytic cells. Short-term exposure of the chronically infected promyelocytic OM10 cell line with the PTK inhibitor genistein induced a dose-dependent increase in p24 antigen production in culture supernatants. This induction persisted in the presence of the reverse transcriptase inhibitor, zidovudine, and was associated with an increased transcription of HIV-1 multiply spliced and unspliced RNAs, suggesting a transcriptional mechanism targeting the integrated provirus. Genistein induced cell differentiation, apoptosis, and a G2 arrest in the OM10 cells. Cell differentiation and apoptosis were not directly involved in the observed increase in HIV-1 replication that was closely linked to genistein-induced G2 arrest. Alleviation of the G2 arrest by pentoxyfylline resulted in a concomitant reduction of HIV-1 to baseline replication. Additionally, by flow cytometry, a significant increase in the number of p24 antigen-expressing cells was observed in cells arrested in G2 compared to those located in G1 or S. Tyrosine kinase inhibition was found not to be essential for enhanced viral replication, which seemed to be related to two other properties of genistein, inhibition of topoisomerase II activity and inhibition of phosphotidylinositol turnover. These findings are consistent with the recent observation that HIV-1 Vpr induces viral replication through preventing proliferation of cells by arresting them in G2 of the cell cycle and strongly suggest that manipulation of the cell cycle plays an important role in HIV-1 pathogenesis.

Cell Division↗
PubMed1997

HIV-induced apoptosis of activated primary CD4+ T lymphocytes is not mediated by Fas-Fas ligand.

OBJECTIVE: To investigate the role of the Fas-Fas ligand (FasL) interaction in HIV-1-induced apoptosis of primary CD4+ T lymphocytes. DESIGN: Activated CD4+ T lymphocytes are the main target of HIV, and T-cell activation leads to the expression of Fas-FasL and enhances HIV-mediated apoptosis. Phytohemagglutinin-activated primary CD4+ T cells were infected with HIV; the process of cell death was examined, and whether the dying and dead cells were the productively infected cells. The modulation of Fas and FasL expression and its role in HIV-induced cell death was also investigated. METHODS: The number of viable and dead cells was determined by trypan blue exclusion. Apoptosis was quantified using an enzyme-linked immunosorbent assay measuring the release of cytoplasmic histone-associated DNA fragments. The percentage of HIV-infected cells was determined by FACS analysis, and viral production was assessed by a p24 core antigen assay. The following three markers, HIV-gp-120, annexin-V and 7-AAD, were used to monitor the apoptotic process in HIV-negative and positive cells. Fas and FasL expression was analyzed at the RNA level by reverse transcription polymerase chain reaction and at the protein level by flow cytometry. The contribution of Fas-FasL interactions to apoptosis was examined by blocking experiments using the antagonist ZB4 anti-Fas antibody. RESULTS: HIV-induced apoptosis in activated purified CD4+ T lymphocytes required infectious virus and was dose-dependent. Apoptosis in HIV-infected cultures was mostly confined to productively infected cells. The expression of Fas and FasL was not significantly modulated by infection and blocking Fas-FasL interactions did not reduce the extent of apoptosis. CONCLUSIONS: HIV-induced apoptosis of activated CD4+ T cells in vitro is confined to productively infected cells and is not mediated by a Fas-FasL interaction.

Apoptosis↗
PubMed1997

Monitoring plasma HIV-1 RNA levels in addition to CD4+ lymphocyte count improves assessment of antiretroviral therapeutic response. ACTG 241 Protocol Virology Substudy Team.

BACKGROUND: CD4+ lymphocyte counts and plasma HIV-1 RNA levels predict progression of HIV-related disease, but the relative importance of these and other virological factors in defining response to antiretroviral therapy is not yet clear. OBJECTIVE: To determine the short-term variability of plasma HIV-1 RNA level during stable therapy; the relative importance of pretreatment values and early changes in CD4+ count, HIV-1 RNA levels, and infectious HIV-1 titers in mononuclear cells of peripheral blood and pretreatment syncytium-inducing phenotype of an HIV-1 isolate for prediction of disease progression and decline in CD4+ counts during therapy. DESIGN: Data were collected prospectively in a randomized, clinical trial comparing two combination regimens (ACTG [AIDS Clinical Trials Group] Protocol 241) and pooled across treatments. SETTING: 8 AIDS Clinical Trials Units. PATIENTS: 198 adults with HIV-1 infection and no more than 350 CD4+ lymphocytes/mm3 who had received at least 6 months of nucleoside therapy. INTERVENTIONS: All patients received zidovudine and didanosine; 100 received nevirapine and 98 received placebo. MEASUREMENTS: CD4+ lymphocyte counts, plasma HIV-1 RNA levels, and infectious HIV-1 titers in cells were measured before and 8 and 48 weeks after study treatment. Assay for the syncytium-inducing viral phenotype was done at baseline. Progression was defined as occurrence of opportunistic infection, malignancy, or death during the 48 weeks after treatment began. RESULTS: The difference between two measurements of HIV-1 RNA levels at baseline was within +/-0.39 log10 copies/mL (2.5-fold) for 90% of 167 patients receiving stable therapy. In a multivariate model, risk for disease progression was reduced by 56% (95% CI, 8% to 79% [P = 0.028]) for every 10-fold lower HIV-1 RNA level at baseline, by 52% (CI, 6% increase to 79% reduction [P = 0.071]) for every 10-fold reduction in HIV-1 RNA level at 8 weeks after treatment initiation, and by 67% (CI, 42% to 81% [P < 0.001]) for every 2-fold higher CD4+ count at baseline. These risk factors and syncytium-inducing viral phenotype at baseline, but not infectious HIV-1 titers in circulating cells, were associated with change in CD4+ counts over 48 weeks. CONCLUSIONS: For an individual patient, a change in plasma HIV-1 RNA level of 2.5-fold or more probably indicates a true biological change. Monitoring HIV-1 RNA levels and CD4+ lymphocytes before a change in antiretroviral treatment and monitoring HIV-1 RNA levels shortly thereafter improves prediction of disease progression and decline in CD4+ counts for 1 year compared with monitoring CD4+ counts of HIV-1 RNA levels alone. Additional monitoring of infectious HIV-1 titers in mononuclear cells of peripheral blood is not useful.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Human cytomegalovirus-associated immunosuppression is mediated through interferon-alpha.

Human cytomegalovirus (HCMV) infections are commonly associated with a generalized immunologic hyporesponsiveness. The present study was designed to evaluate the potential mechanisms of HCMV-associated immunosuppression. In our initial experiments, monocytes in peripheral blood mononuclear cells (PBMCs) exposed to cell-free HCMV appeared morphologically less differentiated than monocytes in PBMCs exposed to a mock preparation. These morphologic changes were closely correlated with a decrease in monocyte oxidative activity and occurred under noncytopathic conditions. HCMV-associated suppression of monocyte differentiation did not require virus replication, occurred in PBMCs from either HCMV seropositive or seronegative donors, and required HCMV interaction with the nonadherent cells. An HCMV-induced soluble factor was found to not only reproduce the identical changes in purified monocytes but to inhibit the phagocytic activity of these cells. Additionally, the HCMV-induced factor accounted for a generalized defect in the ability of PBMCs to proliferate in response to mitogens and recall antigens. In subsequent experiments, interferon-alpha (IFN-alpha) was identified as the soluble factor involved in these immunosuppressive effects. Thus, PBMCs, when exposed to HCMV, produce a soluble factor, identified as IFN-alpha, that appears to be an important mediator of immunosuppression associated with HCMV infection.

Cell Differentiation↗
PubMed1997

Safety and efficacy of strength training in patients with sporadic inclusion body myositis.

We studied the effects of a 12-week progressive resistance strength training program in weakened muscles of 5 patients with sporadic inclusion body myositis (IBM). Strength was evaluated with Medical Research Council (MRC) scale ratings and quantitative isometric and dynamic tests. Changes in serum creatine kinase (CK), lymphocyte subpopulations, muscle size (determined by magnetic resonance imaging), and histology in repeated muscle biopsies were examined before and after training. After 12 weeks, the values of repetition maximum improved in the least weakened muscles, 25-120% from baseline. This dynamic effect was not captured by MRC or isometric muscle strength measurements. Serum CK, B cells, T-cell subsets, and NK cells remained unchanged. Repeat muscle biopsies did not reveal changes in the number and degree of degenerating fibers or inflammation. The size of the trained muscles did not change. We conclude that a supervised progressive resistance training program in IBM patients can lead to gains in dynamic strength of the least weak muscles without causing muscle fatigue and muscle injury or serological, histological, and immunological abnormalities. Even though the functional significance of these gains is unclear, this treatment modality is a safe and perhaps overlooked means of rehabilitation of IBM patients.

Activities of Daily Living↗
PubMed1997

Cerebrospinal fluid human immunodeficiency virus type 1 RNA levels are elevated in neurocognitively impaired individuals with acquired immunodeficiency syndrome. HIV Neurobehavioral Research Center Group.

To determine whether cerebrospinal fluid (CSF) viral burden measurements can assist in the evaluation of human immunodeficiency virus (HIV)-associated neurocognitive disorders, we quantified HIV type 1 (HIV-1) RNA in CSF. Because previous findings suggested that disease stage, lymphocytic pleocytosis, and HIV-1 RNA levels in plasma may influence CSF viral burden, these variables were examined as potential modifying factors. HIV-1 RNA levels were quantified by using a reverse transcriptase-polymerase chain reaction assay. Performance on a comprehensive neuropsychological (NP) battery was noted in 97 prospectively enrolled, HIV-infected subjects. Among subjects with acquired immunodeficiency syndrome (AIDS) (<200 CD4+ lymphocytes), NP impairment was associated with significantly higher CSF RNA levels (3.1 vs 1.8 log10 copies/ml; p = 0.02); most impaired subjects met criteria for HIV-associated dementia or minor cognitive-motor disorder. In subjects without AIDS, CSF RNA and NP impairment were unrelated. Before AIDS, CSF RNA was strongly correlated to plasma RNA and to pleocytosis, but in AIDS, CSF and plasma RNA were independent. In conclusion, we found elevated CSF HIV-1 RNA levels in NP impaired subjects with AIDS. Before AIDS, systemic viral replication, possibly through CD4+ mononuclear cell trafficking, may govern virus levels in CSF, whereas in AIDS, CD4 cell depletion may unmask a correlation between increased productive central nervous system HIV infection and clinical neurocognitive disorders.

Acquired Immunodeficiency Syndrome↗
PubMed1997

High-level resistance of cytomegalovirus to ganciclovir is associated with alterations in both the UL97 and DNA polymerase genes.

Mutations in both the viral phosphotransferase gene, UL97, and the DNA polymerase gene, UL54, have been shown to confer ganciclovir resistance to cytomegalovirus (CMV). Moreover, UL54 alterations have been associated with in vitro cross-resistance of CMV to cidofovir. To investigate the relative significance of UL97 versus UL54 alterations in conferring antiviral resistance, phenotypic and genotypic characterization of 28 ganciclovir-resistant clinical CMV isolates was undertaken. Isolates were either low-level ganciclovir-resistant, which have ganciclovir ID50 values > or =8 microM and <30 microM and sensitivity to cidofovir, or high-level ganciclovir-resistant, which have ganciclovir ID50 values > or =30 microM and cross-resistance to cidofovir. Low-level ganciclovir-resistant isolates were associated with UL97 alterations and short periods of ganciclovir treatment, while high-level ganciclovir-resistant isolates were associated with both UL97 and polymerase alterations and were cultured after extended ganciclovir therapy.

Antiviral Agents↗
PubMed1997

Ganciclovir treatment of symptomatic congenital cytomegalovirus infection: results of a phase II study. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.

Congenital cytomegalovirus (CMV) infection occurs in approximately 1% of newborns in the United States. A phase II evaluation was done of ganciclovir for the treatment of symptomatic congenital CMV infection. Daily doses of 8 or 12 mg/kg were administered in divided doses at 12-h intervals for 6 weeks. Clinical and laboratory evaluations sought evidence of toxicity, quantitative virologic responses in urine, plasma drug concentrations, and clinical outcome. A total of 14 and 28 babies received 8 and 12 mg/kg/day, respectively. Five additional babies received ganciclovir on a compassionate plea basis. Significant laboratory abnormalities included thrombocytopenia (< or = 50,000/mm3) in 37 babies and absolute neutropenia (< or = 500 mm3) in 29 babies. Quantitative excretion of CMV in the urine decreased; however, after cessation of therapy, viruria returned to near pretreatment levels. Hearing improvement or stabilization occurred in 5 (16%) of 30 babies at 6 months or later, indicating efficacy.

Alanine Transaminase↗
PubMed1997

Utility of urine and leukocyte cultures and plasma DNA polymerase chain reaction for identification of AIDS patients at risk for developing human cytomegalovirus disease.

Urine and blood leukocyte cultures and qualitative plasma polymerase chain reaction (PCR) and quantitative competitive (QC) PCR were evaluated for their ability to identify AIDS patients at risk for human cytomegalovirus (HCMV) disease. AIDS patients were followed with urine and blood specimens every 3 months. During a mean follow-up of 12 months, 26 (28%) developed HCMV disease. The sensitivity, specificity, positive predictive value, and negative predictive value for urine culture were 85%, 29%, 31%, and 83%; for leukocyte culture were 38%, 74%, 69%, and 81%; for qualitative plasma PCR were 89%, 75%, 58%, and 94%; for QC-PCR (>1000 copies/microL) were 35%, 100%, 100%, and 80%; and for QC-PCR (>100 copies/microL) were 73%, 90%, 73%, and 90%, respectively. Of 41 patients identified by qualitative PCR to have HCMV DNA in plasma, the 24 who developed HCMV disease had 1510 +/- 448 (mean +/- SE) peak copies of HCMV DNA/microL by QC-PCR, versus 161 +/- 52 for the 17 patients who did not develop disease (P = .0007). Thus, plasma PCR is superior to culture for identification of AIDS patients at risk for HCMV disease, and quantitation of plasma DNA further identifies high-risk persons.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Current therapeutic challenges in the treatment of cytomegalovirus retinitis.

Cytomegalovirus (CMV) retinitis has become one of the most common manifestations of active CMV infection in patients with acquired immunodeficiency syndrome (AIDS). If left untreated, it results in complete loss of vision. At present, three systemic antiviral agents-ganciclovir, foscarnet, and cidofovir-are available for treatment of CMV retinitis. Unfortunately, reactivation of retinitis will occur with all three agents, and almost all patients eventually experience disease progression while receiving treatment. Therefore, our primary therapeutic challenge is to develop a means of preventing reactivation of CMV retinitis. Another challenge is to develop drugs that can be easily administered. Thus far, oral formulations have not succeeded in effectively meeting this challenge. Direct delivery of an antiviral agent into the vitreous of an infected eye, although easily performed and more effective in delaying time to progression, is unable to prevent or delay the progression of extraocular CMV disease. The ideal antiviral agent would have high central nervous system and tissue penetration, would suppress viral replication and mutation, would be administered orally, and would be inexpensive.

AIDS-Related Opportunistic Infections↗
PubMed1997

Molecular analysis of the differential restriction of human immunodeficiency virus type 1 replication in neuronal cell lines.

Human immunodeficiency virus type 1 (HIV-1) replication is restricted partially in SK-N-MC and completely in SK-N-SH neuronal cells. To investigate the molecular mechanism of this differential restriction of HIV-1 replication, cells infected with HIV-1 were analysed for their steady-state levels of: total and unintegrated HIV-1 DNA by DNA PCR, different species of HIV-1 RNA by RT-PCR, and HIV-1 p24 protein production by an ELISA procedure. We found that the kinetics of the infection were slower and there was a lower level of accumulation of HIV-1 macromolecules (total and unintegrated circular DNA, unspliced and spliced RNAs and viral proteins) in the SK-N-MC cells than in the permissive CEM cells. In SK-N-SH cells, HIV-1 DNA was only transiently detected during the first 24 h post-infection, and the unspliced RNA was detected up to 1 week post-infection. However, the HIV-1 spliced RNAs and the 2-LTR circular DNA were not detected at all during the course of infection. Both SK-N-MC and SK-N-SH cells showed higher levels of HIV-1 DNA, RNA and p24 protein when infected with an HIV-1 (amphotropic retrovirus) pseudotype, HIV-1B. However, the level of HIV-1 replication was still lower in SK-N-SH than in SK-N-MC cells. Moreover, although the kinetics of viral protein production were comparable in SK-N-MC cells infected with HIV-1B and CEM cells infected with HIV-1, the overall level of virus replication was still much lower in HIV-1B-infected SK-N-MC cells. These data suggest that the restriction of HIV-1 replication in neuronal cell lines takes place at both virus-entry and post-entry levels, and cellular factors may be involved in the differential restriction of HIV-1 replication in these cells.

Cell Line↗