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C Buckner

Publications and source records attributed to C Buckner.

12 recordsLinked to original sources
PubMed2006

Shedding of PECAM-1 during HIV infection: a potential role for soluble PECAM-1 in the pathogenesis of NeuroAIDS.

Human immunodeficiency virus (HIV) infection is characterized by viral entry into the central nervous system (CNS), which is mediated, in part, by the transmigration of HIV-infected monocytes into the brain. The elaboration of chemokines and other factors by these infected cells contributes to CNS inflammation and cognitive impairment in a significant number of HIV-infected individuals. Recently, we demonstrated that HIV-infected monocyte transmigration into the CNS is enhanced greatly by the chemokine CC chemokine ligand 2 (CCL2)/monocyte chemoattractant protein-1. Platelet endothelial cell adhesion molecule-1 (PECAM-1) plays an important role in leukocyte transmigration across the endothelium of the systemic vasculature by mediating homophilic interactions between endothelial cells (EC)-EC and EC-leukocytes, thus preserving vessel integrity. The role of PECAM-1 in HIV-infected leukocyte transmigration across the blood brain barrier (BBB) and NeuroAIDS has not been characterized. We demonstrate that in brain tissue from individuals with HIV encephalitis, there is an accumulation of cleaved, soluble forms of the extracellular region of PECAM-1 (sPECAM-1). In addition, HIV-infected individuals have elevated levels of sPECAM-1 in their sera. Our in vitro data demonstrate that HIV-infected leukocytes, when treated with CCL2, shed sPECAM-1, suggesting a mechanism of extracellular PECAM-1 cleavage and release dependent on HIV infection and CCL2. We hypothesize that sPECAM-1 production by HIV-infected leukocytes, resulting in the accumulation of sPECAM-1 within the CNS vasculature and the generation of truncated, intracellular forms of PECAM-1 within leukocytes, alters PECAM-1 interactions between EC-EC and EC-leukocytes, thus contributing to enhanced transmigration of HIV-infected leukocytes into the CNS and changes in BBB permeability during the pathogenesis of NeuroAIDS.

AIDS Dementia Complex↗
PubMed2003

Antigenic variations in the CD4 induced sites of the CCR5-tropic, pathogenic SHIVsf162p3 gp120 variants.

In vivo passage of non-pathogenic, CCR5-tropic simian/human immunodeficiency virus (SHIV) - SHIVsf162 resulted in a pathogenic isolate, SHIVsf162p3. In an attempt to characterize envelope (Env)-mediated properties that may contribute to its pathogenicity, major (P3 major) and minor (P3 minor) Env gp120 variants were cloned from the plasma of a SHIVsf162p3-infected animal, and expressed in the context of luciferase reporter viruses. Entry mediated by these envelopes and susceptibility to neutralization by CD4 induced-site (CD4i) antibodies (MAbs) was analyzed in comparison to parental SF162. Sequence analysis revealed that the P3 major and minor variant Envs contained 14 and 17 amino acid changes, respectively, compared with SF162. The rank order of entry mediated by the three envelopes was P3 major > SF162 > P3 minor, whereas the reverse order was observed for susceptibility to neutralization by CD4i MAbs. Since CD4i epitopes overlap the coreceptor (CoR) binding site, these findings suggest that the amino acid changes accumulated upon in vivo passage of SHIVsf162 result in Env gp120 structural rearrangements that modulate the exposure and/or conformation of the CoR binding site. This, in turn, led to increased entry and infectivity of the P3 major variant and may be responsible, in part, for the enhanced pathogenicity of SHIVsf162p3.

Amino Acid Sequence↗
PubMed2001

The ability of an oligomeric human immunodeficiency virus type 1 (HIV-1) envelope antigen to elicit neutralizing antibodies against primary HIV-1 isolates is improved following partial deletion of the second hypervariable region.

Partial deletion of the second hypervariable region from the envelope of the primary-like SF162 virus increases the exposure of certain neutralization epitopes and renders the virus, SF162DeltaV2, highly susceptible to neutralization by clade B and non-clade B human immunodeficiency virus (HIV-positive) sera (L. Stamatatos and C. Cheng-Mayer, J. Virol. 78:7840-7845, 1998). This observation led us to propose that the modified, SF162DeltaV2-derived envelope may elicit higher titers of cross-reactive neutralizing antibodies than the unmodified SF162-derived envelope. To test this hypothesis, we immunized rabbits and rhesus macaques with the gp140 form of these two envelopes. In rabbits, both immunogens elicited similar titers of binding antibodies but the modified immunogen was more effective in eliciting neutralizing antibodies, not only against the SF162DeltaV2 and SF162 viruses but also against several heterologous primary HIV type 1 (HIV-1) isolates. In rhesus macaques both immunogens elicited potent binding antibodies, but again the modified immunogen was more effective in eliciting the generation of neutralizing antibodies against the SF162DeltaV2 and SF162 viruses. Antibodies capable of neutralizing several, but not all, heterologous primary HIV-1 isolates tested were elicited only in macaques immunized with the modified immunogen. The efficiency of neutralization of these heterologous isolates was lower than that recorded against the SF162 isolate. Our results strongly suggest that although soluble oligomeric envelope subunit vaccines may elicit neutralizing antibody responses against heterologous primary HIV-1 isolates, these responses will not be broad and potent unless specific modifications are introduced to increase the exposure of conserved neutralization epitopes.

AIDS Vaccines↗
PubMed1999

High-dose chemotherapy with peripheral blood stem cell support for stage IIIB inflammatory carcinoma of the breast.

The purpose of this study was to determine outcomes for 56 patients with inflammatory breast cancer (IBC) receiving high-dose chemotherapy (HDC) with cyclophosphamide, thiotepa and carboplatin (CTCb) with peripheral blood stem cell (PBSC) support. All patients received the same total amount of chemotherapy but there were differences in the sequence of therapy: 15 received induction chemotherapy, chemotherapy mobilization of PBSC and CTCb after surgery (adjuvant group) while 41 received induction chemotherapy with (n = 17) or without (n = 24) chemotherapy for mobilization of PBSC prior to surgery and CTCb after surgery (neoadjuvant group). Median time from diagnosis to HDC was 5.5 months (range 3.5-12.5). Fifty-one patients (91%) required admission to the hospital following HDC for a median of 11 days (range 5-25). There were two (4%) infectious deaths after HDC. Twenty-four patients (43%) have relapsed at a median of 18 months (range 8-50) from diagnosis resulting in death in 34%. The probabilities of overall (OS) and event-free survival (EFS) at 3 years for all 56 patients were 0.72 and 0.53, respectively, with a median follow-up of 44 months (range 15-76) from diagnosis. There were no differences in OS, EFS or patterns of relapse between patients in the adjuvant or neoadjuvant groups. These sequences of combined modality therapy incorporating HDC are comparable or superior to other intensive approaches for the treatment of IBC. Further improvements will be necessary to decrease systemic recurrences.

Adenocarcinoma↗
PubMed1998

Construction of attenuated HIV-1 accessory gene immunization cassettes.

Delivery of genetic expression cassettes into animals can effectively induce both humoral and cellular immunity to the expressed gene product. Previously, we used this strategy to immunize against HIV-1 structural and enzymatic proteins in mice, non-human primates and in humans. In contrast, the use of the accessory genes including vif, vpr, vpu and nef as immunotherapeutic vaccine targets has not been well characterized. Our goal is to design an effective genetic HIV vaccine, which includes the accessory genes as part of a multi-component immunogen. In order to develop accessory genes as genetic vaccines, we have molecularly cloned and analysed the sequence variation and immunogenic potential present in these genes derived from viral isolates obtained from HIV-1 infected patients and laboratory isolates. Prototype genetic variants were selected and their ability to induce humoral and cellular immune responses was studied in animal models. We observed that attenuated accessory genes can effectively induce both humoral and cellular responses in mice and the resulting immune response is directly correlated with DNA concentrations delivered and the number of boosts. This strategy can be used generally to develop an effective, safe DNA vaccine for any pathogen.

AIDS Vaccines↗
PubMed1995

Neurologic abnormalities in murderers.

Thirty-one individuals awaiting trial or sentencing for murder or undergoing an appeal process requested a neurologic examination through legal counsel. We attempted in each instance to obtain EEG, MRI or CT, and neuropsychological testing. Neurologic examination revealed evidence of "frontal" dysfunction in 20 (64.5%). There were symptoms or some other evidence of temporal lobe abnormality in nine (29%). We made a specific neurologic diagnosis in 20 individuals (64.5%), including borderline or full mental retardation (9) and cerebral palsy (2), among others. Neuropsychological testing revealed abnormalities in all subjects tested. There were EEG abnormalities in eight of the 20 subjects tested, consisting mainly of bilateral sharp waves with slowing. There were MRI or CT abnormalities in nine of the 19 subjects tested, consisting primarily of atrophy and white matter changes. Psychiatric diagnoses included paranoid schizophrenia (8), dissociative disorder (4), and depression (9). Virtually all subjects had paranoid ideas and misunderstood social situations. There was a documented history of profound, protracted physical abuse in 26 (83.8%) and of sexual abuse in 10 (32.3%). It is likely that prolonged, severe physical abuse, paranoia, and neurologic brain dysfunction interact to form the matrix of violent behavior.

Adolescent↗
PubMed1993

Infection with human T-lymphotropic viruses leads to constitutive expression of leukemia inhibitory factor and interleukin-6.

Leukemia inhibitory factor (LIF), similar to interleukin-6 (IL-6), is a glycoprotein growth factor and differentiation regulator that has pleiotropic activity in several cellular systems. Recent reports of constitutive IL-6 production from spontaneously proliferating cells from human T-cell leukemia virus (HTLV)-infected individuals led us to examine the expression of IL-6 and LIF during HTLV infection. In vitro infection of peripheral blood lymphocytes with HTLV-I was associated with production of both soluble LIF and IL-6 in conjunction with the increasing HTLV antigen concentration. Northern blot analysis of T-cell lines generated from individuals infected with HTLV-I (MT-2, HuT-102, FS, EG, SP) and HTLV-II (Mo-T, H2A, H2E) demonstrated a marked increase in constitutive expression of LIF and IL-6 transcripts, as compared with uninfected cell lines (HuT-78, Jurkat). The constitutive expression of LIF and IL-6 was independent of presence of IL-2 in the culture medium, as both IL-2-independent (MT-2, HuT-102, SP, Mo-T) and IL-2-dependent (FS, EG, H2A, H2E) cell lines expressed LIF and IL-6 transcripts. Furthermore, LIF and IL-6 RNA expression in an HTLV-I-infected cell line (MT-2) was enhanced by phorbol ester stimulation via mechanisms that appear to be dependent on the posttranscriptional regulatory controls. These results show that both LIF and IL-6 are produced by HTLV-I- and HTLV-II-infected cells, which could potentially alter the transcriptional regulation of HTLV gene expression by inducing certain early response genes.

Cell Line↗
PubMed1993

Isotypic and IgG subclass restriction of the humoral immune responses to human T-lymphotropic virus type-I.

We have investigated the isotypic and IgG subclass profile of the antibody response to HTLV-I structural proteins (gag and env) in patients with HTLV-I-associated myelopathy (HAM; n = 20), adult T-cell leukemia (ATL; n = 15), and HTLV-I-positive asymptomatic carriers (ASY; n = 21). IgG, IgM, and IgA were the predominant antibody responses in all HTLV-I-infected individuals; minimal IgE response was detectable in the HAM and ATL groups. Among the IgG subclasses, IgG1 was the most predominant antibody detected in responses to HTLV-I antigens, followed by IgG3 and IgG2; IgG4 could not be detected in any patient group. Levels of both IgG1 and IgG3 were significantly higher in patients with HAM, when compared to ATL and ASY (P < 0.01 for both comparisons). In addition, Ig isotypes and IgG subclass antibody in patient sera reactive with purified viral proteins and several immunodominant epitopes, represented by synthetic peptides, Gag-1a102-117, Env-1(191-214), Env-5(242-257), and recombinant proteins, MTA-1(162-209) and r21e303-440, were examined to delineate specific epitopes responsible for inducing the host immune responses of each isotype and subclass to the structural proteins of HTLV-I. IgG, IgM, and IgA responses were directed against both the gag and env gene products. Among IgG subclasses, the IgG1 and IgG3 responses were directed against both the gag (p53, p24, p19, and Gag-1a) and env (recombinant MTA-1, r21e, and synthetic Env-1, Env-5) proteins; IgG2 responses were mainly restricted to gag proteins. The frequency profile of HTLV-I-specific antigen recognition in all four IgG subclasses were similar in all of the clinical groups. These results further define the fine specificity of anti-HTLV-I immune reaction for understanding the mechanism of pathogenesis in these individuals and suggest that factors other than the humoral immune responses may be associated with the clinical manifestation of the disease.

Amino Acid Sequence↗
PubMed1992

Immune responsiveness to the immunodominant recombinant envelope epitopes of human T lymphotropic virus types I and II in diverse geographic populations.

The heterogeneity of immune responsiveness to the immunodominant epitopes of human T lymphotropic virus (HTLV) types I (MTA-1(162-209)) and II (K-55(162-205)) were determined in natural infections with HTLV-I and -II from diverse geographic areas (n = 285). Of the HTLV-I specimens confirmed by polymerase chain reaction (PCR), all North American (n = 37) and Peruvian (n = 19) specimens reacted with MTA-1. Of HTLV-II specimens confirmed by PCR, 44 (96%) of 46 from North American blood donors, 28 (97%) of 29 from native Americans, and all from intravenous drug users (n = 29) reacted with K-55. Specimens from other geographic areas (Peru, 30; Brazil, 4; Mexico, 10; Italy, 5; Somalia, 13; Ethiopia, 17; Japan, 32; and Jamaica, 15) all reacted either with MTA-1 or K-55. By synthetic peptide-based serologic typing, all of these specimens could be typed as HTLV-I or -II. In addition to the direct implications of these findings for diagnostic purposes, these data provide indirect evidence for the conservation of immunodominant HTLVenv epitopes in diverse geographic populations.

Africa↗
PubMedDate not supplied

The effects of infection prevention regimens on early infectious complications in marrow transplant patients: a four arm randomized study.

Three hundred and forty-two patients with hematological malignancies underwent allogeneic marrow transplantation from family donors and were allocated to receive 1) no specific infection prophylaxis in a conventional hospital room (control, 100 patients), 2) prophylactic systemic antibiotics (PSA) in a conventional hospital room (PSA group, 101 patients), 3) decontamination and isolation in a laminar air flow (LAF) room (LAF group, 65 patients) and 4) PSA in an LAF room (LAF+PSA group, 76 patients). Patients were studied for bacterial and fungal complications from the day of admission and until engraftment. LAF isolation was discontinued before engraftment in 27% (LAF+PSA group) to 32% (LAF group) of isolated in 26% (LAF+PSA group) to 27% (PSA group) of patients on prophylactic antibiotics. Septicemia occurred in 41%, 22%, 25% and 10% of patients in the control, PSA, LAF and LAF+PSA group, respectively. The incidence of septicemia was significantly less in the LAF+PSA group than in the control and LAF group with the incidence of septicemia significantly higher in the control group than in any of the other three groups. No other risk factors analyzed in proportional hazards regression tests were associated with septicemia acquisition. It is concluded that effective infection prevention modalities significantly reduce infection morbidity in transplant patients. Since most granulocytopenic transplant patients not receiving PSA will receive empiric or therapeutic broad spectrum antibiotics. The use of PSA in or out of LAF isolation is recommended as an effective modality to reduce septicemia acquisition.

Adolescent↗