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Biomedical subjects

K S Slobod

Publications and source records attributed to K S Slobod.

At least 19 recordsLinked to original sources
PubMed2001

Structural features of HIV envelope defined by antibody escape mutant analysis.

Two neutralizing antibodies specific for the V3 sequence of HIV envelope were used to generate escape variants from the HTLV(IIIB) founder virus. The full gp120 sequence of each variant was then analyzed to identify mutations responsible for immune escape. As predicted, most escape variants harbored amino acid changes in the V3 crown sequence. However, one variant differed from its founder only within the conserved C2 region. These findings, when analyzed in conjunction with crystallographic data, suggest a new three-dimensional model for HIV envelope folding, in which the V3 loop extends across the CD4-binding face of gp120 to associate with discontinuous C2 residues. This envelope configuration may provide an effective immune defense mechanism for HIV, as the highly variable residues of the V3 loop may shield conserved amino acids pertinent to viral infection.

Amino Acid Sequence↗
PubMed2001

Localization of CD4+ T cell epitope hotspots to exposed strands of HIV envelope glycoprotein suggests structural influences on antigen processing.

The spectrum of immunogenic epitopes presented by the H2-IA(b) MHC class II molecule to CD4(+) T cells has been defined for two different (clade B and clade D) HIV envelope (gp140) glycoproteins. Hybridoma T cell lines were generated from mice immunized by a sequential prime and boost regime with DNA, recombinant vaccinia viruses, and protein. The epitopes recognized by reactive T cell hybridomas then were characterized with overlapping peptides synthesized to span the entire gp140 sequence. Evidence of clonality also was assessed with antibodies to T cell receptor Valpha and Vbeta chains. A total of 80 unique clonotypes were characterized from six individual mice. Immunogenic peptides were identified within only four regions of the HIV envelope. These epitope hotspots comprised relatively short sequences ( approximately 20-80 aa in length) that were generally bordered by regions of heavy glycosylation. Analysis in the context of the gp120 crystal structure showed a pattern of uniform distribution to exposed, nonhelical strands of the protein. A likely explanation is that the physical location of the peptide within the native protein leads to differential antigen processing and consequent epitope selection.

Amino Acid Sequence↗
PubMed2001

Effect of extended immunosuppressive drug treatment on B cell vs T cell reconstitution in pediatric bone marrow transplant recipients.

Allogeneic bone marrow transplantation (BMT) is an effective therapy for a variety of malignancies and blood disorders, but rarely serves as a frontline treatment because of numerous, potential complications. Important and frequent complications relate to the profound immunosuppression that inevitably occurs during the first several months following treatment. To better elucidate and subsequently improve immune reconstitution, we examined T and B cell subsets among 43 pediatric BMT recipients in a retrospective study. We found that the relative numbers of T cells and B cells (T:B ratios) were discordant and highly variable among patients at day approximately 100 after BMT. Further investigation of BMT parameters identified a strong correlation between T:B ratios and immunosuppressive drug treatments, providing an explanation for variable lymphocyte reconstitution profiles. Results suggest that: (1) immunosuppressive therapy inhibits B cell expansion more strongly than T cell expansion following BMT; (2) WBC and absolute lymphocyte counts fail to reveal profound B cell immunodeficiencies in some BMT patients; and (3) routine analyses of T:B ratios serve to identify patients warranting close follow-up and extended supportive immunotherapy.

Adrenal Cortex Hormones↗
PubMed2001

T cell immunotherapeutic populations control viral infections in bone marrow transplant recipients.

Immunotherapies designed to prevent infection serve as an increasingly important adjunct to bone marrow transplantation (BMT). T cell immunotherapies are particularly useful for the control of virus infections, provided that T cell populations are free of graft-vs-host (GVH) activity. In this review, we describe positive and negative selection methods with which donor T cell populations devoid of GVH activity can be prepared for transfer to the immunodeficient BMT recipient. The support of patients with T cell immunotherapies may ultimately revolutionize BMT, elevating the procedure from a salvage to a front-line treatment strategy for otherwise fatal disorders.

Animals↗
PubMed2000

Oral cefixime is similar to continued intravenous antibiotics in the empirical treatment of febrile neutropenic children with cancer.

Empiric oral antibiotic therapy for febrile neutropenic cancer patients has been suggested as a means to decrease hospitalization, but the safety of this approach has not been adequately studied in children. We compared continued iv antibiotic therapy with switching treatment to orally administered cefixime in a group of selected febrile neutropenic children for whom blood cultures were sterile after 48 h of incubation. Two hundred episodes of febrile neutropenia were studied (156 patients), and 100 episodes were randomized to receive each treatment. Failure to respond to therapy was defined by documented or suspected bacterial infection, recurrent fever, or discontinuation of assigned therapy for any reason before neutropenia resolved. Rates of treatment failure were similar in the oral cefixime group (28%) and in the iv antibiotic group (27%; P=1.0). Results support the safety of oral cefixime therapy for low-risk febrile neutropenic children, a therapeutic approach that would facilitate earlier outpatient management and decrease the costs of treatment.

Administration, Oral↗
PubMed2000

Epstein-Barr virus-targeted therapy for AIDS-related primary lymphoma of the central nervous system.

Epstein-Barr virus (EBV) targeted therapeutic strategies for viral associated malignant diseases have received only perfunctory consideration, first, because latent herpesviruses have been intractable to antiviral chemotherapy and, second, because the role EBV has in maintenance of the malignant cell phenotype has been uncertain. Two patients with EBV related primary central nervous system lymphoma (PCNSL) in the setting of advanced AIDS, were treated with low dose hydroxyurea based on in vitro anti-EBV activity. The responses obtained here suggest the promise of antiviral approaches in select cancers.

Adolescent↗
PubMed2000

Molecular evidence of ocular Epstein-Barr virus infection.

Ocular manifestations have been attributed to the Epstein-Barr virus (EBV), largely on the basis of seroepidemiologic data. Two patients who developed conjunctival disease as the presenting feature of EBV infection are reported, each confirmed by in situ hybridization of EBV genome in affected tissue biopsy specimens. Recognition of EBV-induced ocular disease as an initial presentation of clinical EBV infection is important to the practitioner because of the ubiquitous nature of this herpesvirus.

Child↗
PubMed2000

Multi-envelope HIV vaccine safety and immunogenicity in small animals and chimpanzees.

A significant obstacle to HIV vaccine development lies in the remarkable diversity of envelope proteins, the major targets of neutralizing antibody. That envelope diversity must be targeted is demonstrated by results from nonhuman primate studies in which single-envelope vaccines have protected against homologous, but rarely against heterologous virus challenges. Similarly, in clinical trials, single-envelope vaccines have failed to prevent break-through infections when challenge viruses were inevitably mismatched with the vaccine. To protect humans from infection by any isolate of HIV, we have prepared vaccine cocktails combining multiple envelopes from distinct viral isolates. We have tested several vehicles for vaccine delivery in small animals and have shown that successive immunizations with envelope, presented first as a DNA recombinant, then as a vaccinia virus (VV) recombinant, and finally as purified protein elicited strong neutralizing antibody responses. We have also tested the VV recombinant vaccine in chimpanzees. Pairs of animals received either single- or multi-envelope VV recombinant vaccines administered by the subcutaneous route. Results showed that the multi-envelope vaccine was safe, immunogenic, and superior to the single-envelope vaccine in eliciting HIV-specific antibody measurable in a standard clinical, immune assay. The promise of this system has led to the initiation of clinical trials, with which the hypothesis that cocktail vaccines will prevent human HIV infections may ultimately be tested.

AIDS Vaccines↗
PubMed1998

Expression of the human immunodeficiency virus type 1 primer binding sequence inhibits HIV-1 replication.

Optimal targets for anti-human immunodeficiency virus (HIV) moieties are those regions of the viral genome that are greatly conserved. The primer binding site (PBS) of HIV is an 18-nucleotide sequence complementary to the 3' end of tRNA(Lys3) that serves as the primer for HIV-1 reverse transcription. All HIV-1 isolates analyzed to date contain a PBS complementary to tRNA(Lys3) illustrating the conservation of this sequence. We investigated the activity of a hammerhead ribozyme targeting the PBS of HIV-1. CEMss cells transduced with retroviral vectors containing either the PBS hammerhead ribozyme or its complementary sequence (as a control) in the R region of the vector long terminal repeat (LTR) were challenged with HIV-1NL4-3. Surprisingly >80% inhibition of HIV-1 production was observed with the vector containing the (control) sequence complementary to the PBS ribozyme. We propose that the LTR-driven vector transcript containing 18 nucleotides identical to the HIV-1 PBS may act like an RNA decoy to titrate viral proteins such as reverse transcriptase and nucleocapsid away from genuine viral transcripts, thus compromising virus replication.

Base Sequence↗
PubMed1998

Profound abnormality of the B/T lymphocyte ratio during chemotherapy for pediatric acute lymphoblastic leukemia.

The fluorescence-activated cell sorter (FACS) was utilized to phenotype lymphocyte compartments in children receiving intensive chemotherapy for acute lymphoblastic leukemia (ALL). Sixteen patients (eight males and eight females) of diverse ages, risks of relapse, and within weeks 7-53 of maintenance/continuation chemotherapy treatment were arbitrarily selected for study. All 16 patients had profound B cell lymphopenia. In contrast, T cell numbers were often normal or marginally low, and accounted for up to 98% of the lymphocyte populations. No abnormality in T cell phenotypes could be demonstrated. Due to the highly skewed B/T lymphocyte ratios in these ALL patients, the absolute white blood cell counts and lymphocyte percentages were not predictive of the underlying B cell lymphopenia. Patients were also tested for serum immunoglobulin levels and most had abnormally low IgG and IgM. None of four patients immunized with the 1996-1997 influenza virus vaccine seroconverted to at least two vaccine antigens as compared to 10 of 10 healthy, age-matched controls. In total, these data highlight for the first time the profound abnormality of the B/T lymphocyte ratio in patients during treatment for ALL, and argue for consideration of B cell-targeted immunotherapy.

Adolescent↗
PubMed1998

Primary central nervous system lymphoma in a child with acute B-cell lymphoblastic leukaemia: consecutive Epstein-Barr virus-related malignancies.

Primary central nervous system lymphoma (PCNSL), observed among immunocompromised AIDS patients, has not been reported during chemotherapy for acute lymphoblastic leukaemia (ALL). We report a case of PCNSL occurring in a child receiving intensive multiagent chemotherapy for B-cell ALL. In situ hybridization studies demonstrated Epstein-Barr virus genome in both tumours, suggesting a possible link between the two diseases. The clinical response of the PCNSL to conservative therapy highlights the importance of accurately diagnosing such EBV-related disorders, especially in patients where immune compromise can be reversed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Pulmonary complications in children with hematologic malignancies: accuracy of diagnosis with chest radiography and CT.

PURPOSE: To determine the diagnostic accuracy of chest radiography and computed tomography (CT) in patients with complications during treatment for hematologic malignancies. MATERIALS AND METHODS: CT scans were obtained 1 week or less before bronchoscopic sampling or biopsy in 48 pediatric patients (age range, 8 months to 18 years at diagnosis) undergoing treatment for leukemia, lymphoma, or myeloproliferative disease. Radiographs were obtained less than 1 week before CT. Pulmonary complications comprised fungal (n = 11), viral (n = 4), and bacterial (n = 5) pneumonias; cryptogenic organizing pneumonia ([COP] n = 4); and pulmonary tumor (n = 4). Chest radiographs and CT scans were rated independently by three radiologists who were unaware of these diagnoses. RESULTS: Satisfactory diagnostic accuracy, defined by the area under the receiver operating characteristic (ROC) curve, was noted for fungal pneumonia (radiography, ROC area = 0.82; CT, ROC area = 0.78), COP (radiography, ROC area = 0.75; CT, ROC area = 0.75), and pulmonary tumor (radiography, ROC area = 0.73; CT, ROC area = 0.83). Generalizability was good for fungal pneumonia (radiography, generalizability coefficient [GC] = 0.84; CT, GC = 0.84) and COP (radiography, GC = 0.75; CT, GC = 0.99). There was no statistically significant difference in diagnostic accuracy between radiography and CT for any of the diagnoses. CONCLUSION: Radiography and CT have satisfactory accuracies for fungal pneumonia and COP. For these conditions, CT identified more true-positive cases than did radiography.

Adolescent↗
PubMed1996

Mobilization of CD34+ progenitor cells by granulocyte colony-stimulating factor in human immunodeficiency virus type 1-infected adults.

We conducted a clinical trial to determine the feasibility of growth factor mobilization of CD34+ progenitor cells in human immunodeficiency virus type 1 (HIV-1)-infected individuals. Eight asymptomatic, HIV-1-infected adults (median CD4+ T-cell count, 415 cells/microL), received 480 micrograms/d of granulocyte colony-stimulating factor (G-CSF) for 6 days without evidence of viral activation. Despite concerns that HIV-1 might inhibit hematopoiesis, CD34+ cells were successfully mobilized to the periphery of all donors, independent of the baseline CD4+ T-cell count, and the status of antiretroviral therapy. Leukapheresis was performed on day 6, and yielded a median of 194 x 10(6) CD34+ cells per leukapheresis (n = 7). CD34-enriched cells from the leukapheresis were predominantly myeloid-committed, but between 0.2% and 1.7% were primitive CD34+/CD38- progenitors. A median of 21.7% of the mobilized CD34+ cells were dimly positive for CD4. Consequently, CD34(+)-enriched cells were purified on the cell sorter (mean purity, 97.7% +/- 2.4%; n = 7), and examined for HIV-1 DNA. Purified CD34+ cells from two of seven donors were polymerase chain reaction (PCR)-positive for HIV-1, but only from one of three samples from each donor. We conclude that G-CSF can safely mobilize CD34+ progenitor cells in HIV-1-infected subjects, and that these cells are suitable for consideration in gene-transfer strategies.

Adult↗