41 results on '"Johnston MN"'
Search Results
2. Korean Vivax Malaria
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Jackson Ls, Marx Rl, Johnston Mn, Gilbert M, Di Lorenzo A, Kenny Ec, Richard B. Jones, Levy Bl, and Alf S. Alving
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Curative effect ,medicine.medical_specialty ,Primaquine ,business.industry ,medicine.disease ,Infectious Diseases ,Virology ,Internal medicine ,Toxicity ,Vivax malaria ,medicine ,Parasitology ,business ,Malaria ,medicine.drug - Published
- 1953
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Catalog
3. Exploring How the Surface-Area-to-Volume Ratio Influences the Partitioning of Surfactants to the Air-Water Interface in Levitated Microdroplets.
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Jacobs MI, Johnston MN, and Mahmud S
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Quantitative characterization of the surface of microdroplets is important to understanding and predicting numerous chemical and physical processes, such as cloud droplet formation and accelerated chemistry in microdroplets. However, it is increasingly appreciated that the surface compositions of microdroplets do not necessarily match those of macroscale solution due to their large surface-area-to-volume (SA-V) ratios and confined volumes. In this work, we explore how both droplet size and composition affect the surface composition of microdroplets by measuring the equilibrium surface tensions of levitated microdroplets containing a single surfactant. We measure the critical micelle concentrations (CMCs) for surfactants of various strengths (macroscale CMC values ranging from 0.02 to 10 mM) in microdroplets with radii ranging from 5 to 25 μm. We accurately model the surface tensions of microdroplets using an equilibrium partitioning model that only requires droplet size and adsorption parameters from macroscale measurements as inputs. Our model predicts that surfactants have an "effective CMC" in microdroplets that is always larger in value than the corresponding macroscale CMC. In some instances, the effective CMC of a surfactant in microdroplets is several orders of magnitude larger than both its macroscale CMC and its macroscale solubility limit. We present a simple expression for the effective CMC in microdroplets that depends on both the macroscale CMC of a surfactant and the SA-V ratio of the microdroplet. Ultimately, our experimental results and model can be used broadly to predict microdroplet surface compositions when investigating surface-driven accelerated chemistry in microdroplets or estimating cloud droplet activation. more...
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- 2024
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4. Executive Summary: Topical Management of Malignant Cutaneous Wounds: Canadian Best Practice Recommendations for Health Care Professionals Developed by Nurses Specialized in Wound, Ostomy and Continence Canada (in collaboration with the Canadian Palliative Care Nursing Association).
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Johnston D, Chaplain V, Kerr M, Malley J, Popov V, Ross D, and Smart J
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- Humans, Canada, Ostomy nursing, Ostomy methods, Health Personnel statistics & numerical data, Health Personnel psychology, Wound Healing, Hospice and Palliative Care Nursing methods, Hospice and Palliative Care Nursing standards, Practice Guidelines as Topic, Wounds and Injuries
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Malignant cutaneous wounds pose unique challenges in patient care, requiring specialized attention to alleviate local symptoms and enhance health-related quality of life. As the prevalence of these wounds continues to rise with improving cancer survival rates, it is essential to establish comprehensive best practice recommendations for their topical management. To address this need, a task force was assembled from across Canada, consisting of members from Nurses Specialized in Wound, Ostomy, and Continence Canada and the Canadian Palliative Care Nursing Association. The purpose of these recommendations is to provide a framework for the topical management of malignant cutaneous wounds for health care professionals, emphasizing the substantial role of their support persons. Recognizing the impact of cultural humility and the need to deliver care that respects individual beliefs and practices is crucial in providing effective and equitable care. The 23 presented recommendations aim to guide nurses, the interdisciplinary team, and the health system to enhance the overall quality of malignant cutaneous wound care management., Competing Interests: The authors report no conflicts of interests., (Copyright © 2024 by the Wound, Ostomy, and Continence Nurses Society.) more...
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- 2024
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5. Filling the Gap: Establishing the Standard for the Topical Management of Malignant Cutaneous Wounds.
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Johnston D, Kerr M, Smart J, Chaplain V, Malley J, and Ross D
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Competing Interests: Conflicts of interest: This work was funded by an unrestricted educational grant from Molnlycke.
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- 2024
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6. Safe Searches: The Scale and Spread of a Quality Improvement Project.
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Abela-Dimech F and Johnston K
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- Humans, Leadership, Psychiatric Department, Hospital standards, Staff Development, Visitors to Patients, Health Plan Implementation methods, Quality Improvement, Safety standards, Security Measures standards
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To ensure the safety of staff, patients, and visitors to psychiatric inpatient units, a standardized safe search protocol was developed and implemented across a psychiatric facility. This article provides an overview of the methods used in the planning, implementation, and spread of this quality improvement initiative, focusing on the concepts of change management, leadership, and team involvement. The professional development of point-of-care staff is enhanced by active engagement in quality improvement initiatives. more...
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- 2017
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7. Executive Summary: Enhanced Recovery After Surgery: Best Practice Guideline for Care of Patients With a Fecal Diversion.
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Miller D, Pearsall E, Johnston D, Frecea M, and McKenzie M
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- Colostomy psychology, Colostomy rehabilitation, Colostomy standards, Humans, Ileostomy psychology, Ileostomy rehabilitation, Ileostomy standards, Length of Stay trends, Ontario, Ostomy psychology, Ostomy standards, Patient Education as Topic methods, Patient Education as Topic standards, Postoperative Care rehabilitation, Postoperative Complications prevention & control, Guidelines as Topic standards, Ostomy rehabilitation, Postoperative Care standards, Practice Guidelines as Topic, Societies trends
- Abstract
Enhanced Recovery After Surgery (ERAS) is a multimodal program developed to decrease postoperative complications, improve patient safety and satisfaction, and promote early discharge. In the province of Ontario, Canada, a standardized approach to the care of adult patients undergoing elective colorectal surgery (including benign and malignant diseases) was adopted by 15 hospitals in March 2013. All colorectal surgery patients with or without an ostomy were included in the ERAS program targeting a length of stay of 3 days for colon surgery and 4 days for rectal surgery. To ensure the individual needs of patients requiring an ostomy in an ERAS program were being met, a Provincial ERAS Enterostomal Therapy Nurse Network was established. Our goal was to develop and implement an evidence-based, ostomy-specific best practice guideline addressing the preoperative, postoperative, and discharge phases of care. The guideline was developed over a 3-year period. It is based on existing literature, guidelines, and expert opinion. This article serves as an executive summary for this clinical resource; the full guideline is available as Supplemental Digital Content 1 (available at: http://links.lww.com/JWOCN/A36) to this executive summary. more...
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- 2017
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8. Enhanced Recovery After Surgery and Fecal Diversions: Development of a Best Practice Guideline.
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Johnston D, Miller D, Frecea M, and McKenzie M
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- Humans, Ostomy nursing, Abdomen surgery, Guidelines as Topic, Ostomy rehabilitation, Quality of Health Care standards, Time Factors
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- 2016
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9. An incidental finding? Pneumatosis intestinalis after minor trauma.
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Hoot NR, Pfennig CL, Johnston MN, and Jones I
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- Accidents, Traffic, Arthritis, Rheumatoid drug therapy, Emergency Service, Hospital, Female, Humans, Immunocompromised Host, Immunosuppressive Agents therapeutic use, Lupus Erythematosus, Systemic drug therapy, Middle Aged, Tomography, X-Ray Computed, Incidental Findings, Pneumatosis Cystoides Intestinalis diagnostic imaging
- Abstract
Background: Pneumatosis intestinalis (PI) refers to the identification of air within the wall of the gastrointestinal tract. This finding often marks serious underlying pathology, which can be potentially surgical in nature. However, this process may also occur within a benign context, for example, in patients who are chronically immunosuppressed. The prevalence of benign PI may be greater than previously anticipated, because its discovery is facilitated by the increasingly widespread use of computed tomography (CT) scanning., Objectives: We will illustrate how widespread use of CT scanning after trauma leads to incidental findings, some of which are difficult to distinguish from acute pathologic findings. We will also discuss the differential diagnosis for PI and the associated clinical significance., Case Report: A female patient with two autoimmune disorders requiring immunosuppression presented after minor trauma. Her clinical stability and benign examination led us to refrain from ordering a full radiographic evaluation, including an abdominal CT scan. She was safely discharged; however, per CT several days later, the incidental finding was made of PI with free intraperitoneal air. These findings after trauma commonly prompt an exploratory laparotomy. However, given her persistent stability, we attributed this to immunosuppression rather than to recent trauma., Conclusion: The indications for ordering CT scans after minor trauma must be carefully considered, and incidental findings must be interpreted in the context of the overall clinical scenario., (Copyright © 2013 Elsevier Inc. All rights reserved.) more...
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- 2013
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10. Uvular trauma from a laryngeal mask.
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Emmett SR, Lloyd SD, and Johnston MN
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- Adult, Female, Humans, Necrosis, Laryngeal Masks adverse effects, Uvula pathology
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- 2012
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11. The role of barium swallow in the management of the globus pharyngeus.
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Alaani A, Vengala S, and Johnston MN
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- Aged, Deglutition, Diagnosis, Differential, Esophageal Neoplasms diagnosis, Female, Humans, Male, Middle Aged, Pharyngeal Neoplasms diagnosis, Sensitivity and Specificity, Treatment Outcome, Barium Sulfate, Otolaryngology methods, Pharyngeal Diseases diagnosis, Pharyngeal Diseases therapy
- Abstract
Globus pharyngeus is a common benign condition with controversial management. Patients with globus pharyngeus are usually investigated to exclude the possibility of upper aerodiagestive malignancies. There is a great debate about the role of barium swallow in the management of this condition. Review of 1,145 barium swallow repourts of patients presented with globus pharyngeus between 1999 and 2004 has failed to diagnose any patient with pharyngeal or oesophageal cancer. We conclude that barium swallow should not be requested systematically as part of management of globus pharyngeus patients. This approach will reduce the cost and radiation effect of unnecessary investigations. more...
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- 2007
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12. Selective depletion of high-avidity human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells after early HIV-1 infection.
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Lichterfeld M, Yu XG, Mui SK, Williams KL, Trocha A, Brockman MA, Allgaier RL, Waring MT, Koibuchi T, Johnston MN, Cohen D, Allen TM, Rosenberg ES, Walker BD, and Altfeld M
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- Adult, Cell Degranulation, Cells, Cultured, Cytokines biosynthesis, Female, Flow Cytometry, HIV Infections virology, HIV-1 physiology, Humans, Leukocytes, Mononuclear immunology, Male, Middle Aged, Receptors, Antigen, T-Cell immunology, T-Lymphocyte Subsets immunology, Viremia, CD8-Positive T-Lymphocytes immunology, HIV Infections immunology, HIV-1 immunology
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Human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells in early infection are associated with the dramatic decline of peak viremia, whereas their antiviral activity in chronic infection is less apparent. The functional properties accounting for the antiviral activity of HIV-1-specific CD8+ T cells during early infection are unclear. Using cytokine secretion and tetramer decay assays, we demonstrated in intraindividual comparisons that the functional avidity of HIV-1-specific CD8+ T cells was consistently higher in early infection than in chronic infection in the presence of high-level viral replication. This change of HIV-1-specific CD8+ T-cell avidity between early and chronic infections was linked to a substantial switch in the clonotypic composition of epitope-specific CD8+ T cells, resulting from the preferential loss of high-avidity CD8+ T-cell clones. In contrast, the maintenance of the initially recruited clonotypic pattern of HIV-1-specific CD8+ T cells was associated with low-level set point HIV-1 viremia. These data suggest that high-avidity HIV-1-specific CD8+ T-cell clones are recruited during early infection but are subsequently lost in the presence of persistent high-level viral replication. more...
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- 2007
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13. Fully differentiated HIV-1 specific CD8+ T effector cells are more frequently detectable in controlled than in progressive HIV-1 infection.
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Addo MM, Draenert R, Rathod A, Verrill CL, Davis BT, Gandhi RT, Robbins GK, Basgoz NO, Stone DR, Cohen DE, Johnston MN, Flynn T, Wurcel AG, Rosenberg ES, Altfeld M, and Walker BD
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- Acquired Immunodeficiency Syndrome pathology, Adolescent, Boston, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes pathology, Cell Differentiation, Child, Child, Preschool, Disease Progression, Epitopes analysis, HIV Infections pathology, Humans, Kinetics, RNA, Viral blood, T-Lymphocytes immunology, T-Lymphocytes virology, Viral Load, Viremia drug therapy, Young Adult, Acquired Immunodeficiency Syndrome immunology, CD8-Positive T-Lymphocytes virology, HIV Infections immunology, HIV-1 immunology
- Abstract
Background: CD8+ T cells impact control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. In HIV-1 infection, persistent HIV-1 specific IFN-gamma+ CD8+ T cell responses are detected in the setting of disease progression, consistent with functional impairment in vivo. Recent data suggest that impaired maturation, as defined by the lineage markers CD45RA and CCR7, may contribute to a lack of immune control by these responses., Methodology/principal Findings: We investigated the maturation phenotype of epitope-specific CD8+ T cell responses directed against HIV-1 in 42 chronically infected, untreated individuals, 22 of whom were "Controllers" (median 1140 RNA copies/ml plasma, range<50 to 2520), and 20 "progressors" of whom had advanced disease and high viral loads (median 135,500 RNA copies/ml plasma, range 12100 to >750000). Evaluation of a mean of 5 epitopes per person revealed that terminally differentiated CD8+ T cells directed against HIV-1 are more often seen in HIV-1 Controllers (16/22; 73%) compared to HIV-1 progressors (7/20; 35%)(p = 0.015), but the maturation state of epitope-specific responses within a given individual was quite variable. Maturation phenotype was independent of the HLA restriction or the specificity of a given CD8+ T cell response and individual epitopes associated with slow disease progression were not more likely to be terminally differentiated., Conclusions/significance: These data indicate that although full maturation of epitope-specific CD8+ T cell responses is associated with viral control, the maturation status of HIV-1 specific CD8+ T cell responses within a given individual are quite heterogeneous, suggesting epitope-specific influences on CD8+ T cell function. more...
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- 2007
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14. Prospective randomised single-blind controlled trial of glacial acetic acid versus glacial acetic acid, neomycin sulphate and dexamethasone spray in otitis externa and infected mastoid cavities.
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Johnston MN, Flook EP, Mehta D, and Mortimore S
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- Acetic Acid administration & dosage, Acute Disease, Administration, Topical, Aerosols, Anti-Bacterial Agents administration & dosage, Anti-Inflammatory Agents administration & dosage, Dexamethasone administration & dosage, Drug Therapy, Combination, Humans, Mastoiditis epidemiology, Neomycin administration & dosage, Otitis Externa epidemiology, Prospective Studies, Severity of Illness Index, Single-Blind Method, Acetic Acid therapeutic use, Anti-Bacterial Agents therapeutic use, Anti-Inflammatory Agents therapeutic use, Dexamethasone therapeutic use, Mastoiditis drug therapy, Neomycin therapeutic use, Otitis Externa drug therapy
- Abstract
Objectives: The literature reports the merits of antibacterial, antibiotic and steroid agents in treating otological infections but no controlled clinical trial has directly compared 2% glacial acetic acid (EarCalm; Stafford-Miller Ltd, Brentford, UK) against 2% glacial acetic acid, 0.1% dexamethasone and 3250 U/ml of neomycin sulphate (Otomize; Stafford-Miller Ltd) in the treatment of otitis externa and infected mastoid cavities., Design: Prospective, single-blind randomised controlled trial., Setting: Outpatients, Derby Royal Infirmary, Derby, UK., Patients: Emergency and GP referrals with acute otitis externa (n = 53) and infected mastoid cavities (n = 56)., Main Outcome Measures: Otoscopy was performed at initial randomisation and then at 2 and 4 weeks, the ear assessed for active and inactive disease., Results: Patients with active otitis externa, 71% (15/21) resolved with glacial acetic acid, dexamethasone and of neomycin sulphate after 2 weeks, increasing to 86% (18/21) after 4 weeks treatment. Patients on glacial acetic acid had only 38% (12/32) resolution after 4 weeks (P < 0.0005). Two per cent glacial acetic acid, dexamethasone and neomycin sulphate resolved only 30% (8/27) of infected mastoid cavities compared to only 10% (3/29) on glacial acetic acid (P < 0.07). A further 2 weeks treatment this increased to 67%, (18/27) with glacial acetic acid, dexamethasone and neomycin sulphate and 48% (14/29) with glacial acetic acid. These results are not statistically significant., Conclusion: Glacial acetic acid, dexamethasone and neomycin sulphate is significantly more effective in treating otitis externa when compared with glacial acetic acid. This effect failed to be significant in the infected mastoid cavities group. We therefore recommend that in conjunction with aural toilet, antibiotic/steroid combination is more effective than an antibacterial agent for otitis externa. Larger numbers of infected mastoid cavities are required to be studied. more...
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- 2006
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15. HLA Alleles Associated with Delayed Progression to AIDS Contribute Strongly to the Initial CD8(+) T Cell Response against HIV-1.
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Altfeld M, Kalife ET, Qi Y, Streeck H, Lichterfeld M, Johnston MN, Burgett N, Swartz ME, Yang A, Alter G, Yu XG, Meier A, Rockstroh JK, Allen TM, Jessen H, Rosenberg ES, Carrington M, and Walker BD
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- Alleles, Antigenic Variation, Cohort Studies, Disease Progression, Epitopes, T-Lymphocyte immunology, Female, Genes, MHC Class I immunology, HIV Infections immunology, Humans, Immunodominant Epitopes immunology, Male, Proportional Hazards Models, Acquired Immunodeficiency Syndrome genetics, Acquired Immunodeficiency Syndrome immunology, CD8-Positive T-Lymphocytes immunology, HIV-1 immunology, HLA Antigens genetics
- Abstract
Background: Very little is known about the immunodominance patterns of HIV-1-specific T cell responses during primary HIV-1 infection and the reasons for human lymphocyte antigen (HLA) modulation of disease progression., Methods and Findings: In a cohort of 104 individuals with primary HIV-1 infection, we demonstrate that a subset of CD8(+) T cell epitopes within HIV-1 are consistently targeted early after infection, while other epitopes subsequently targeted through the same HLA class I alleles are rarely recognized. Certain HLA alleles consistently contributed more than others to the total virus-specific CD8(+) T cell response during primary infection, and also reduced the absolute magnitude of responses restricted by other alleles if coexpressed in the same individual, consistent with immunodomination. Furthermore, individual HLA class I alleles that have been associated with slower HIV-1 disease progression contributed strongly to the total HIV-1-specific CD8(+) T cell response during primary infection., Conclusions: These data demonstrate consistent immunodominance patterns of HIV-1-specific CD8(+) T cell responses during primary infection and provide a mechanistic explanation for the protective effect of specific HLA class I alleles on HIV-1 disease progression. more...
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- 2006
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16. T cell receptor cross-recognition of an HIV-1 CD8+ T cell epitope presented by closely related alleles from the HLA-A3 superfamily.
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Lichterfeld M, Williams KL, Mui SK, Shah SS, Mothe BR, Sette A, Kim A, Johnston MN, Burgett N, Frahm N, Cohen D, Brander C, Rosenberg ES, Walker BD, Altfeld M, and Yu XG
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- Alleles, Cross Reactions, Gene Products, nef immunology, HLA-A Antigens immunology, HLA-A11 Antigen, Humans, nef Gene Products, Human Immunodeficiency Virus, Antigen Presentation immunology, CD8-Positive T-Lymphocytes immunology, Epitopes, T-Lymphocyte immunology, Genes, T-Cell Receptor beta immunology, HIV Infections immunology, HIV-1 immunology, HLA-A3 Antigen immunology
- Abstract
HLA-A3 and -A11 share similar peptide-binding motifs, however, it is unclear if promiscuous epitope presentation by HLA-A3 or HLA-A11 is associated with promiscuous TCR recognition. Here, we show that despite widespread cross-presentation of identical HIV-1 peptides in HIV-1-infected individuals expressing HLA-A3 or HLA-A11, peptides presented by HLA-A3 or HLA-A11 commonly exhibited clear immune distinctiveness with exclusive TCR recognition. Yet, using HLA-A3 and HLA-A11 tetramers for testing T cell cross-recognition of the HIV-1 Nef QK10 epitope, we observed in two study persons that specific CD8+ T cell populations were able to cross-recognize this peptide in the context of both HLA-A3 and HLA-A11. This cross-recognition was mediated by single cross-reactive TCRs, as shown by TCR sequencing in conjunction with TCR Vbeta chain immunostaining. In each cross-reactive cell population, multiple TCR beta chain variants were detected in the presence of only one TCR alpha chain variant. Thus, despite distinct TCR recognition of HLA-A3 or HLA-A11 presented HIV-1 peptides in the vast majority of cases, specific TCRs can cross-recognize their antigen in the context of both HLA-A3 and HLA-A11. more...
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- 2006
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17. The need to include BIPP reactions in routine consent.
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Flook EP, Uddin FJ, and Johnston MN
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- Anti-Infective Agents, Local administration & dosage, Bismuth administration & dosage, Drug Combinations, Humans, Hydrocarbons, Iodinated administration & dosage, Anti-Infective Agents, Local adverse effects, Bismuth adverse effects, Hydrocarbons, Iodinated adverse effects, Informed Consent standards
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- 2006
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18. Longitudinal analysis of clinical markers following antiretroviral therapy initiated during acute or early HIV type 1 infection.
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Kassutto S, Maghsoudi K, Johnston MN, Robbins GK, Burgett NC, Sax PE, Cohen D, Pae E, Davis B, Zachary K, Basgoz N, D'agata EM, DeGruttola V, Walker BD, and Rosenberg ES
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- Acquired Immunodeficiency Syndrome immunology, Acquired Immunodeficiency Syndrome virology, Acute Disease, Adult, CD4 Lymphocyte Count, Female, Humans, Longitudinal Studies, Male, Proportional Hazards Models, Prospective Studies, Viral Load, Acquired Immunodeficiency Syndrome drug therapy, Anti-HIV Agents therapeutic use, HIV-1
- Abstract
Background: Treatment of acute human immunodeficiency virus type 1 (HIV-1) infection may have unique immunologic, virological, and clinical benefits. However, the timing of treatment, optimal starting regimens, and expected response to therapy have not been defined.Methods. One hundred two subjects treated during acute and early HIV-1 infection were observed prospectively to determine the effect of time elapsed before initiation of therapy on time to virological suppression and absolute CD4+ cell count. Subjects were divided into pre- and postseroconversion groups on the basis of HIV-1 antibody status at the time of initiation of treatment. Absolute CD4+ cell counts were compared between these groups and with those of historical untreated persons who had experienced seroconversion. Potential predictors of time to virological suppression and CD4+ cell count at > or =12 months were assessed., Results: Ninety-nine (97%) of 102 subjects achieved virological suppression. The median time to suppression was 11.1 weeks (95% confidence interval, 9.4-14.9) and was independent of initial regimen. The mean CD4+ cell count at 12 months was 702 cells/mm3 (95% confidence interval, 654-750 cells/mm3) and showed an increasing trend over 60 months. Treated subjects demonstrated a statistically significant gain in the CD4+ cell count, compared with untreated historical control subjects, at > or =12 months. Comparable virological and immunologic outcomes were seen in the pre- and postseroconversion groups. Baseline virus load and nadir CD4+ cell count predicted time to virological suppression and CD4+ cell count at > or =12 months, respectively., Conclusions: Early treatment of HIV-1 infection is well tolerated and results in rapid and sustained virological suppression. Preservation of CD4+ cell counts may be achieved with early therapy, independent of seroconversion status. Protease inhibitor-based and nonnucleoside reverse-transcriptase inhibitor-based regimens show comparable performance in tolerability, time to virological suppression, and CD4+ cell count when used as a first regimen. more...
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- 2006
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19. Expansion of HIV-specific CD4+ and CD8+ T cells by dendritic cells transfected with mRNA encoding cytoplasm- or lysosome-targeted Nef.
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Kavanagh DG, Kaufmann DE, Sunderji S, Frahm N, Le Gall S, Boczkowski D, Rosenberg ES, Stone DR, Johnston MN, Wagner BS, Zaman MT, Brander C, Gilboa E, Walker BD, and Bhardwaj N
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- Cell Line, Cytoplasm immunology, Epitopes, T-Lymphocyte genetics, Epitopes, T-Lymphocyte immunology, Gene Products, nef genetics, HIV genetics, HIV Infections genetics, HIV Infections therapy, Humans, Immunotherapy, Adoptive methods, Lysosomes immunology, Protein Transport genetics, Protein Transport immunology, RNA, Messenger genetics, RNA, Messenger immunology, Transfection methods, nef Gene Products, Human Immunodeficiency Virus, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Dendritic Cells immunology, Gene Products, nef immunology, HIV immunology, HIV Infections immunology
- Abstract
Transfection with synthetic mRNA is a safe and efficient method of delivering antigens to dendritic cells for immunotherapy. Targeting antigens to the lysosome can sometimes enhance the CD4+ T-cell response. We transfected antigen-presenting cells (APCs) with mRNA encoding Gag-p24 and cytoplasmic, lysosomal, and secreted forms of Nef. Antigen-specific cytotoxic T cells were able to lyse the majority of transfected targets, indicating that transfection was efficient. Transfection of APCs with a Nef construct bearing lysosomal targeting signals produced rapid and prolonged antigen presentation to CD4+ and CD8+ T cells. Polyclonal CD4+ and CD8+ T-cell lines recognizing multiple distinct epitopes were expanded by coculture of transfected dendritic cells with peripheral blood mononuclear cells from viremic and aviremic HIV-infected subjects. Importantly, lysosome-targeted antigen drove a significantly greater expansion of Nef-specific CD4+ T cells than cytoplasmic antigen. The frequency of recognition of CD8 but not CD4 epitopes by mRNA-expanded T cells was inversely proportional to sequence entropy and was similar to ex vivo responses from a large chronic cohort. Thus human dendritic cells transfected with mRNA encoding lysosome-targeted HIV antigen can expand a broad, polyclonal repertoire of antiviral T cells, offering a promising approach to HIV immunotherapy. more...
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- 2006
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20. Sequential deregulation of NK cell subset distribution and function starting in acute HIV-1 infection.
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Alter G, Teigen N, Davis BT, Addo MM, Suscovich TJ, Waring MT, Streeck H, Johnston MN, Staller KD, Zaman MT, Yu XG, Lichterfeld M, Basgoz N, Rosenberg ES, and Altfeld M
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- Acute Disease, Antigens, CD immunology, Case-Control Studies, Female, HIV Infections immunology, HIV Infections pathology, Humans, Lymphocyte Count methods, Male, Virus Replication immunology, Antigens, CD blood, HIV Infections blood, HIV-1 immunology, Killer Cells, Natural immunology, Killer Cells, Natural pathology, Killer Cells, Natural virology, Lymphocyte Subsets immunology, Lymphocyte Subsets pathology, Lymphocyte Subsets virology
- Abstract
Natural killer (NK) cells are critical in the first-line defense against viral infections. Chronic HIV-1 infection leads to a perturbation in the NK cell compartment, yet the kinetics of this deregulation and the functional consequences are unclear. Here, we characterized changes in the NK cell compartment longitudinally by multiparameter flow cytometry, starting in acute HIV-1 infection. Acute HIV-1 infection was associated with elevated NK cell numbers, with an expansion of CD3(neg)CD56(dim)CD16(pos) NK cells and an early depletion of CD3(neg)CD56(bright)CD16(neg) NK cells. Ongoing viral replication resulted in a depletion of CD3(neg)CD56(dim)CD16(pos) NK cells with a paralleled increase in functionally anergic CD3(neg)CD56(neg)CD16(pos) NK cells, accompanied by reduced functional activity, as measured by CD107a expression and cytokine secretion. Taken together, these studies demonstrate a sequential impairment of NK cell function with persistent viral replication resulting from a progressive deregulation of NK cell subsets with distinct functional properties. more...
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- 2005
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21. Selective escape from CD8+ T-cell responses represents a major driving force of human immunodeficiency virus type 1 (HIV-1) sequence diversity and reveals constraints on HIV-1 evolution.
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Allen TM, Altfeld M, Geer SC, Kalife ET, Moore C, O'sullivan KM, Desouza I, Feeney ME, Eldridge RL, Maier EL, Kaufmann DE, Lahaie MP, Reyor L, Tanzi G, Johnston MN, Brander C, Draenert R, Rockstroh JK, Jessen H, Rosenberg ES, Mallal SA, and Walker BD more...
- Subjects
- Acute Disease, Alleles, Amino Acid Sequence, Amino Acid Substitution, Chronic Disease, Cohort Studies, Epitopes, T-Lymphocyte genetics, Genes, MHC Class I genetics, Germany, HIV Infections virology, Humans, Lymphocyte Count, Molecular Sequence Data, Sequence Alignment, United States, CD8-Positive T-Lymphocytes immunology, Evolution, Molecular, HIV Infections immunology, HIV-1 genetics, HIV-1 immunology, Mutation immunology, Polymorphism, Genetic, Selection, Genetic
- Abstract
The sequence diversity of human immunodeficiency virus type 1 (HIV-1) represents a major obstacle to the development of an effective vaccine, yet the forces impacting the evolution of this pathogen remain unclear. To address this issue we assessed the relationship between genome-wide viral evolution and adaptive CD8+ T-cell responses in four clade B virus-infected patients studied longitudinally for as long as 5 years after acute infection. Of the 98 amino acid mutations identified in nonenvelope antigens, 53% were associated with detectable CD8+ T-cell responses, indicative of positive selective immune pressures. An additional 18% of amino acid mutations represented substitutions toward common clade B consensus sequence residues, nine of which were strongly associated with HLA class I alleles not expressed by the subjects and thus indicative of reversions of transmitted CD8 escape mutations. Thus, nearly two-thirds of all mutations were attributable to CD8+ T-cell selective pressures. A closer examination of CD8 escape mutations in additional persons with chronic disease indicated that not only did immune pressures frequently result in selection of identical amino acid substitutions in mutating epitopes, but mutating residues also correlated with highly polymorphic sites in both clade B and C viruses. These data indicate a dominant role for cellular immune selective pressures in driving both individual and global HIV-1 evolution. The stereotypic nature of acquired mutations provides support for biochemical constraints limiting HIV-1 evolution and for the impact of CD8 escape mutations on viral fitness. more...
- Published
- 2005
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22. De novo generation of escape variant-specific CD8+ T-cell responses following cytotoxic T-lymphocyte escape in chronic human immunodeficiency virus type 1 infection.
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Allen TM, Yu XG, Kalife ET, Reyor LL, Lichterfeld M, John M, Cheng M, Allgaier RL, Mui S, Frahm N, Alter G, Brown NV, Johnston MN, Rosenberg ES, Mallal SA, Brander C, Walker BD, and Altfeld M
- Subjects
- Chronic Disease, Epitopes, T-Lymphocyte genetics, Epitopes, T-Lymphocyte immunology, HIV Core Protein p24 genetics, HIV Core Protein p24 immunology, HIV-1 genetics, HLA-A Antigens metabolism, HLA-A11 Antigen, Humans, Molecular Sequence Data, Mutation, Receptors, Antigen, T-Cell, alpha-beta immunology, Species Specificity, CD8-Positive T-Lymphocytes immunology, HIV Infections immunology, HIV-1 immunology, T-Lymphocytes, Cytotoxic immunology
- Abstract
Human immunodeficiency virus type 1 (HIV-1) evades CD8(+) T-cell responses through mutations within targeted epitopes, but little is known regarding its ability to generate de novo CD8(+) T-cell responses to such mutants. Here we examined gamma interferon-positive, HIV-1-specific CD8(+) T-cell responses and autologous viral sequences in an HIV-1-infected individual for more than 6 years following acute infection. Fourteen optimal HIV-1 T-cell epitopes were targeted by CD8(+) T cells, four of which underwent mutation associated with dramatic loss of the original CD8(+) response. However, following the G(357)S escape in the HLA-A11-restricted Gag(349-359) epitope and the decline of wild-type-specific CD8(+) T-cell responses, a novel CD8(+) T-cell response equal in magnitude to the original response was generated against the variant epitope. CD8(+) T cells targeting the variant epitope did not exhibit cross-reactivity against the wild-type epitope but rather utilized a distinct T-cell receptor Vbeta repertoire. Additional studies of chronically HIV-1-infected individuals expressing HLA-A11 demonstrated that the majority of the subjects targeted the G(357)S escape variant of the Gag(349-359) epitope, while the wild-type consensus sequence was significantly less frequently recognized. These data demonstrate that de novo responses against escape variants of CD8(+) T-cell epitopes can be generated in chronic HIV-1 infection and provide the rationale for developing vaccines to induce CD8(+) T-cell responses directed against both the wild-type and variant forms of CD8 epitopes to prevent the emergence of cytotoxic T-lymphocyte escape variants. more...
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- 2005
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23. Incomplete HIV type 1 antibody evolution and seroreversion in acutely infected individuals treated with early antiretroviral therapy.
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Kassutto S, Johnston MN, and Rosenberg ES
- Subjects
- Adult, Drug Administration Schedule, Humans, Male, Middle Aged, RNA, Viral blood, Viral Load, Anti-HIV Agents therapeutic use, HIV Antibodies metabolism, HIV Infections drug therapy, HIV Infections immunology
- Abstract
Background: The diagnosis of human immunodeficiency virus type 1 (HIV-1) infection by standard tests relies on the formation of HIV-1-specific antibodies. Early treatment of acute HIV-1 infection may have unique immunologic effects on host cellular and humoral responses. Rare cases of HIV-1 seroreversion have been reported for patients with advanced or rapidly progressive disease. Here, we report seroreversion that occurred in subjects with acute HIV-1 infection who initiated early antiretroviral therapy., Methods: A total of 150 patients with symptomatic acute or early onset HIV-1 infection that was treated with antiretroviral therapy were observed prospectively by means of monthly clinical and laboratory evaluation, which included serial HIV enzyme-linked immunosorbent assay and Western blots, until a fully evolved HIV-1 antibody response was documented., Results: Three patients who initiated antiretroviral therapy a mean interval of 8 days (range, 1-16 days) after presentation and were observed for a mean duration of 50.2 months (range, 40.2-55.7 months) did not develop a fully evolved HIV-1 antibody response or demonstrated complete or partial HIV-1 seroreversion, despite maintenance of cytomegalovirus-specific humoral responses. Virologic suppression and seroreversion (complete or partial) occurred a mean duration of 4.1 months (range, 2.3-5.7 months) and 15.5 months (range, 6.7-26.3 months), respectively, after the initiation of therapy. All patients maintained complete virologic suppression while receiving therapy and had an undetectable HIV-1 RNA load at the time of seroreversion., Conclusions: Early antiretroviral therapy associated with durable virologic suppression in acute HIV-1 infection may abrogate the formation or detection of HIV-1-specific antibodies. Ongoing antigenic stimulation may be required to maintain HIV-1-specific humoral responses. Incomplete evolution of the HIV-1 antibody response and/or presence of seroreversion (although infrequently observed) underscore the potential unique immunologic effect of early antiretroviral therapy in patients with primary HIV-1 infection. more...
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- 2005
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24. Limited durability of viral control following treated acute HIV infection.
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Kaufmann DE, Lichterfeld M, Altfeld M, Addo MM, Johnston MN, Lee PK, Wagner BS, Kalife ET, Strick D, Rosenberg ES, and Walker BD
- Subjects
- Acute Disease, Adult, Drug Administration Schedule, Female, HIV-1 pathogenicity, Humans, Longitudinal Studies, Male, Middle Aged, Treatment Outcome, Viremia, Antiretroviral Therapy, Highly Active, HIV Infections drug therapy, HIV Infections virology
- Abstract
Background: Early treatment of acute HIV infection with highly active antiretroviral therapy, followed by supervised treatment interruption (STI), has been associated with at least transient control of viremia. However, the durability of such control remains unclear. Here we present longitudinal follow-up of a single-arm, open-label study assessing the impact of STI in the setting of acute HIV-1 infection., Methods and Findings: Fourteen patients were treated during acute HIV-1 infection and subsequently subjected to an STI protocol that required retreatment if viral load exceeded 50,000 RNA copies/ml plasma or remained above 5,000 copies/ml for more than three consecutive weeks. Eleven of 14 (79%) patients were able to achieve viral loads of less than 5,000 RNA copies/ml for at least 90 d following one, two, or three interruptions of treatment. However, a gradual increase in viremia and decline in CD4+ T cell counts was observed in most individuals. By an intention-to-treat analysis, eight (57%), six (43%), and three (21%) of 14 patients achieved a maximal period of control of 180, 360, and 720 d, respectively, despite augmentation of HIV-specific CD4+ and CD8+ T cell responses. The magnitude of HIV-1-specific cellular immune responses before treatment interruption did not predict duration of viremia control. The small sample size and lack of concurrent untreated controls preclude assessment of possible clinical benefit despite failure to control viremia by study criteria., Conclusions: These data indicate that despite initial control of viremia, durable viral control to less than 5,000 RNA copies/ml plasma in patients following treated acute HIV-1 infection occurs infrequently. Determination of whether early treatment leads to overall clinical benefit will require a larger and randomized clinical trial. These data may be relevant to current efforts to develop an HIV-1 vaccine designed to retard disease progression rather than prevent infection since they indicate that durable maintenance of low-level viremia may be difficult to achieve. more...
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- 2004
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25. Loss of HIV-1-specific CD8+ T cell proliferation after acute HIV-1 infection and restoration by vaccine-induced HIV-1-specific CD4+ T cells.
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Lichterfeld M, Kaufmann DE, Yu XG, Mui SK, Addo MM, Johnston MN, Cohen D, Robbins GK, Pae E, Alter G, Wurcel A, Stone D, Rosenberg ES, Walker BD, and Altfeld M
- Subjects
- Acute Disease, Adult, Amino Acid Sequence, Cells, Cultured, Female, Humans, Interferon-gamma biosynthesis, Interleukin-2 physiology, Male, Middle Aged, Molecular Sequence Data, AIDS Vaccines immunology, Acquired Immunodeficiency Syndrome immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, HIV-1 immunology, Lymphocyte Activation
- Abstract
Virus-specific CD8(+) T cells are associated with declining viremia in acute human immunodeficiency virus (HIV)1 infection, but do not correlate with control of viremia in chronic infection, suggesting a progressive functional defect not measured by interferon gamma assays presently used. Here, we demonstrate that HIV-1-specific CD8(+) T cells proliferate rapidly upon encounter with cognate antigen in acute infection, but lose this capacity with ongoing viral replication. This functional defect can be induced in vitro by depletion of CD4(+) T cells or addition of interleukin 2-neutralizing antibodies, and can be corrected in chronic infection in vitro by addition of autologous CD4(+) T cells isolated during acute infection and in vivo by vaccine-mediated induction of HIV-1-specific CD4(+) T helper cell responses. These data demonstrate a loss of HIV-1-specific CD8(+) T cell function that not only correlates with progressive infection, but also can be restored in chronic infection by augmentation of HIV-1-specific T helper cell function. This identification of a reversible defect in cell-mediated immunity in chronic HIV-1 infection has important implications for immunotherapeutic interventions. more...
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- 2004
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26. HIV-1-specific cytotoxicity is preferentially mediated by a subset of CD8(+) T cells producing both interferon-gamma and tumor necrosis factor-alpha.
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Lichterfeld M, Yu XG, Waring MT, Mui SK, Johnston MN, Cohen D, Addo MM, Zaunders J, Alter G, Pae E, Strick D, Allen TM, Rosenberg ES, Walker BD, and Altfeld M
- Subjects
- Adult, CD8-Positive T-Lymphocytes immunology, Caspase 3, Caspases metabolism, Female, Humans, Immunophenotyping, Male, Middle Aged, Substrate Specificity, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes virology, HIV Infections immunology, HIV-1, Interferon-gamma metabolism, Tumor Necrosis Factor-alpha metabolism
- Abstract
CD8(+) T cells play a crucial role in the control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. Recent data suggest that HIV-1-specific CD8(+) T cell subsets may differ in their ability to exert these effector functions. Here, we directly compared the cytokine secretion patterns and cytotoxic capacity of HIV-1-specific CD8(+) T cells, using a flow-cytometric cytotoxicity assay based on caspase-3 activation in dying target cells. These experiments revealed considerable intraindividual and interindividual differences among epitope-specific T-cell effector functions: while the frequency of HIV-1-specific CD8(+) T cells secreting interferon-gamma but no tumor necrosis factor-alpha (TNF-alpha) following antigenic stimulation was only weakly correlated to their cytotoxic activity (R = 0.05, P =.57), a subset of CD8(+) T cells secreting both inter-feron-gamma and TNF-alpha was substantially more strongly associated with cytotoxicity (R = 0.67, P <.001). This subset of CD8(+) T cells also exhibited stronger intracellular perforin expression and more pronounced direct ex vivo HIV-1-specific cytoxicity than CD8(+) T cells secreting solely interferon-gamma following sorting of these subpopulations according to their cytokine profile. These results suggest that HIV-1-specific cytotoxicity of CD8(+) T cells is preferentially mediated by a subset of CD8(+) T cells secreting both interferon-gamma and TNF-alpha. more...
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- 2004
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27. HIV-1 Nef is preferentially recognized by CD8 T cells in primary HIV-1 infection despite a relatively high degree of genetic diversity.
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Lichterfeld M, Yu XG, Cohen D, Addo MM, Malenfant J, Perkins B, Pae E, Johnston MN, Strick D, Allen TM, Rosenberg ES, Korber B, Walker BD, and Altfeld M
- Subjects
- Adult, Aged, Female, Genes, Viral immunology, Genes, nef immunology, Genetic Variation immunology, HIV Infections immunology, HIV-1 immunology, Humans, Immunity, Cellular, Male, Middle Aged, Viral Structural Proteins genetics, Virus Replication, CD8-Positive T-Lymphocytes immunology, Genes, nef genetics, HIV Infections genetics, HIV-1 genetics
- Abstract
Objective: To compare the magnitude, breadth and protein specificity of HIV-1-specific CD8 T-cell responses against the clade B consensus sequence during primary and chronic HIV-1 infection and to analyze the impact of viral diversity on the localization of detected responses., Methods: HIV-1-specific CD8 T-cell responses against the clade B consensus sequence in individuals with acute (n = 10), early (n = 19) and chronic (n = 10) infection were longitudinally assessed using an interferon-gamma EliSpot assay., Results: CD8 T-cell responses against clade B consensus sequences were preferentially directed against central regions of Nef during primary HIV-1 infection, despite a relatively higher degree of genetic diversity compared with other subsequently targeted regions. In subjects with acute and early infection, Nef-specific CD8 T-cell responses against the consensus Nef sequence represented 94 and 46% of the total magnitude of HIV-1-specific CD8 T-cell responses, respectively. Subjects with untreated chronic infection exhibited broadly diversified CD8 T-cell responses against more conserved viral regions, with only 17% of virus-specific T-cell responses targeting Nef. The initial immunodominance of Nef persisted in individuals with treated acute infection, but shifted rapidly to Gag, Env and Pol in subjects with continuous antigen exposure., Conclusion: These data show that despite relatively high sequence variability, viral regions within the clade B consensus sequence of Nef are preferentially recognized during primary HIV-1 infection. Later diversification of responses to other proteins during prolonged antigen exposure provides evidence of the initial preferential immunogenicity of Nef epitopes compared to similarly conserved regions within other viral proteins. more...
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- 2004
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28. Selection, transmission, and reversion of an antigen-processing cytotoxic T-lymphocyte escape mutation in human immunodeficiency virus type 1 infection.
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Allen TM, Altfeld M, Yu XG, O'Sullivan KM, Lichterfeld M, Le Gall S, John M, Mothe BR, Lee PK, Kalife ET, Cohen DE, Freedberg KA, Strick DA, Johnston MN, Sette A, Rosenberg ES, Mallal SA, Goulder PJ, Brander C, and Walker BD more...
- Subjects
- Amino Acid Sequence, Epitopes, T-Lymphocyte immunology, HIV Infections immunology, HIV Infections virology, HIV-1 genetics, HLA-A3 Antigen metabolism, Humans, Immunodominant Epitopes immunology, Molecular Sequence Data, Selection, Genetic, gag Gene Products, Human Immunodeficiency Virus, Amino Acid Substitution, Antigen Presentation, Evolution, Molecular, Gene Products, gag genetics, HIV Antigens genetics, HIV-1 immunology, T-Lymphocytes, Cytotoxic immunology, Viral Proteins genetics
- Abstract
Numerous studies now support that human immunodeficiency virus type 1 (HIV-1) evolution is influenced by immune selection pressure, with population studies showing an association between specific HLA alleles and mutations within defined cytotoxic T-lymphocyte epitopes. Here we combine sequence data and functional studies of CD8 T-cell responses to demonstrate that allele-specific immune pressures also select for mutations flanking CD8 epitopes that impair antigen processing. In persons expressing HLA-A3, we demonstrate consistent selection for a mutation in a C-terminal flanking residue of the normally immunodominant Gag KK9 epitope that prevents its processing and presentation, resulting in a rapid decline in the CD8 T-cell response. This single amino acid substitution also lies within a second HLA-A3-restricted epitope, with the mutation directly impairing recognition by CD8 T cells. Transmission of the mutation to subjects expressing HLA-A3 was shown to prevent the induction of normally immunodominant acute-phase responses to both epitopes. However, subsequent in vivo reversion of the mutation was coincident with delayed induction of new CD8 T-cell responses to both epitopes. These data demonstrate that mutations within the flanking region of an HIV-1 epitope can impair recognition by an established CD8 T-cell response and that transmission of these mutations alters the acute-phase CD8(+) T-cell response. Moreover, reversion of these mutations in the absence of the original immune pressure reveals the potential plasticity of immunologically selected evolutionary changes. more...
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- 2004
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29. Comprehensive analysis of human immunodeficiency virus type 1-specific CD4 responses reveals marked immunodominance of gag and nef and the presence of broadly recognized peptides.
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Kaufmann DE, Bailey PM, Sidney J, Wagner B, Norris PJ, Johnston MN, Cosimi LA, Addo MM, Lichterfeld M, Altfeld M, Frahm N, Brander C, Sette A, Walker BD, and Rosenberg ES
- Subjects
- Adult, Amino Acid Sequence, Child, Preschool, Epitope Mapping, Epitopes, T-Lymphocyte, HIV Infections immunology, HIV Infections virology, HLA-DR Antigens metabolism, Humans, Interferon-gamma metabolism, Middle Aged, Molecular Sequence Data, Peptides chemistry, nef Gene Products, Human Immunodeficiency Virus, CD4-Positive T-Lymphocytes immunology, Gene Products, gag immunology, Gene Products, nef immunology, HIV-1 immunology, Immunodominant Epitopes immunology, Peptides immunology
- Abstract
Increasing evidence suggests that human immunodeficiency virus type 1 (HIV-1)-specific CD4 T-cell responses contribute to effective immune control of HIV-1 infection. However, the breadths and specificities of these responses have not been defined. We screened fresh CD8-depleted peripheral blood mononuclear cells (PBMC) from 36 subjects at different stages of HIV-1 infection for virus-specific CD4 responses by gamma interferon enzyme-linked immunospot assay, using 410 overlapping peptides spanning all HIV-1 proteins (based on the clade B consensus sequence). HIV-1-specific CD4 responses were identified in 30 of the 36 individuals studied, with the strongest and broadest responses detected in persons treated in acute infection who underwent treatment interruption. In individuals with identified responses, the total number of recognized HIV-1 peptides ranged from 1 to 36 (median, 7) and the total magnitude of responses ranged from 80 to >14,600 (median, 990) spot-forming cells/10(6) CD8-depleted PBMC. Neither the total magnitude nor the number of responses correlated with viremia. The most frequent and robust responses were directed against epitopes within the Gag and Nef proteins. Peptides targeted by >/=25% of individuals were then tested for binding to a panel of common HLA-DR molecules. All bound broadly to at least four of the eight alleles tested, and two bound to all of the HLA-DR molecules studied. Fine mapping and HLA restriction of the responses against four of these peptides showed a combination of clustering of epitopes and promiscuous presentation of the same epitopes by different HLA class II alleles. These findings have implications for the design of immunotherapeutic strategies and for testing candidate HIV vaccines. more...
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- 2004
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30. Evidence of subtle auditory deficit in a group of patients recovered from bacterial meningitis.
- Author
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Mulheran M, Wiselka M, and Johnston MN
- Subjects
- Acoustic Impedance Tests, Adolescent, Adult, Audiometry, Pure-Tone, Case-Control Studies, Cochlea physiopathology, Female, Humans, Male, Otoacoustic Emissions, Spontaneous, Prospective Studies, Surveys and Questionnaires, Auditory Threshold, Hearing Loss, Sensorineural etiology, Meningitis, Bacterial complications
- Abstract
Objectives: Sensorineural hearing loss of greater than 30 dB hearing loss occurs in up to 30% of patients after acute bacterial meningitis. This study investigated whether postbacterial meningitic patients with no apparent clinical sensorineural hearing loss had any evidence of more subtle subclinical cochlear deficit., Design: Prospective case-controlled clinical trial., Setting: Departments of Otolaryngology in Leicester and Nottingham, England, UK., Patients: Fifty-eight controls and 20 postbacterial meningitic patients aged between 18 and 38 years were screened by a questionnaire and tympanometry to exclude hearing loss attributable to other causes. All participants fell below the 90th percentile pure-tone audiometry threshold of the Lutman and Davis UK data sets., Main Outcome Measures: In both ears, standard (0.25-8 kHz) pure-tone audiometry, high-frequency pure-tone audiometry (10-16 kHz), and distortion product otoacoustic emissions at 2, 4, and 6 kHz were measured., Results: Mean thresholds over the range of standard pure-tone audiometry (analyzed independently) for the postbacterial meningitic patients were significantly elevated at most frequencies (p < 0.05-p < 0.001) between 4 and 7 dB in both ears above control group values. There was no evidence of significant high-frequency threshold elevation (10-16 kHz). The mean iso-distortion product values at 2, 4, and 6 kHz were elevated in both ears in the meningitis group; significantly so (p < 0.05-p < 0.01) at all three frequencies in the right ear and at 4 kHz in the left., Conclusions: Postbacterial meningitic patients with hearing below the 90th percentile range had a slight but significant subclinical threshold elevation over the standard pure-tone audiometry. This may reflect a real effect of the infection at the level of the cochlea, or it may be attributable to a mild residual cognitive defect. The moderate increases in iso-distortion product values are more likely to be real and reflect an effect on outer hair cell function in response to lower stimulus intensities. more...
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- 2004
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31. Principles of septal correction.
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Marshall AH, Johnston MN, and Jones NS
- Subjects
- Cartilage surgery, Fractures, Bone surgery, Fractures, Cartilage, Humans, Nasal Septum abnormalities, Nasal Septum injuries, Nose Deformities, Acquired surgery, Rhinoplasty, Turbinates surgery, Nasal Septum surgery
- Abstract
The operation of septoplasty is often given to junior surgeons to perform and dismissed as a simple procedure. This can lead to unsatisfactory results with unnecessary morbidity for the patient and disillusionment for the surgeon. Trainee surgeons feel that the operation of septoplasty is poorly taught. Some common problems encountered during septal surgery are described and a variety of surgical solutions are offered. more...
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- 2004
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32. Progressive reversion of human immunodeficiency virus type 1 resistance mutations in vivo after transmission of a multiply drug-resistant virus.
- Author
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Gandhi RT, Wurcel A, Rosenberg ES, Johnston MN, Hellmann N, Bates M, Hirsch MS, and Walker BD
- Subjects
- Adult, Biological Evolution, Drug Resistance, Viral, Genotype, HIV-1 genetics, Humans, Longitudinal Studies, Male, Mutation, Anti-HIV Agents pharmacology, Drug Resistance, Multiple, Viral genetics, HIV-1 drug effects
- Abstract
Evolution and transmission of multiply drug-resistant human immunodeficiency virus type 1 (HIV-1) may limit therapeutic options as global treatment efforts expand. However, the stability of these mutants in the absence of drug selection pressure is not known. We performed a longitudinal analysis of plasma virus from a person who acquired HIV-1 that contained multiple reverse transcriptase (RT) and protease (PR) mutations. In the absence of therapy, 5 of 12 drug resistance mutations reverted in a stepwise fashion to wild type over the course of 52 weeks. Reversion of the M184V mutation alone did not change viral replicative capacity (RC), but it led to enhanced resistance to zidovudine and tenofovir. However, reversions of a second RT mutation and 3 PR mutations were associated with an increase in viral RC, and this was temporally correlated with a marked decrease in CD4 cell number. This study demonstrates the gradual stepwise back-mutation of certain drug resistance mutations in vivo in the absence of ongoing drug selection pressure. Moreover, it suggests that, despite initially impaired viral fitness, a transmitted HIV-1 isolate with multiple drug resistance mutations can evolve to develop increased RC and significant pathogenicity. more...
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- 2003
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33. Influence of HLA-B57 on clinical presentation and viral control during acute HIV-1 infection.
- Author
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Altfeld M, Addo MM, Rosenberg ES, Hecht FM, Lee PK, Vogel M, Yu XG, Draenert R, Johnston MN, Strick D, Allen TM, Feeney ME, Kahn JO, Sekaly RP, Levy JA, Rockstroh JK, Goulder PJ, and Walker BD
- Subjects
- Acute Disease, Adult, Alleles, CD8-Positive T-Lymphocytes immunology, Epitopes, T-Lymphocyte immunology, Female, Genes, MHC Class I immunology, HIV Infections genetics, HIV-1 genetics, HIV-1 immunology, HLA-B Antigens genetics, Humans, Immunodominant Epitopes immunology, Male, Middle Aged, Mutation, T-Lymphocytes, Cytotoxic immunology, Virus Replication genetics, HIV Infections immunology, HIV-1 physiology, HLA-B Antigens immunology, Virus Replication immunology
- Abstract
Background: HLA-B57, as well as cytotoxic T-lymphocyte (CTL) responses restricted by this allele, have been strongly associated with long-term non-progressive chronic HIV-1 infection. However, their impact on viral replication during acute HIV-1 infection is not known., Methods: Clinical and immunological parameters during acute and early HIV-1 infection in individuals expressing HLA-B57 were assessed. HIV-1-specific T-cell responses were determined by peptide-specific interferon-gamma production measured using Elispot assay and flow-based intracellular cytokine quantification., Results: Individuals expressing HLA-B57 presented significantly less frequently with symptomatic acute HIV-1 infection (4/116, 3.4%) than expected from the frequency of chronically infected individuals expressing this allele (43/446, 9.6%; P < 0.05). During acute infection, virus-specific CD8 T-cell responses were dominated by HLA-B57-restricted responses, with significantly broader (P < 0.02) and stronger (P < 0.03) responses restricted by HLA-B57 than restricted by all other co-expressed HLA class I alleles combined. Six out of nine individuals expressing HLA-B57 controlled HIV-1 viremia in the absence of therapy at levels < 5000 copies/ml (median, 515 copies/ml) during up to 29 months following acute infection., Conclusion: These data demonstrate that host genetic factors can influence the clinical manifestations of acute HIV-1 infection and provide a functional link between HLA-B57 and viral immune control. more...
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- 2003
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34. Enhanced detection of human immunodeficiency virus type 1-specific T-cell responses to highly variable regions by using peptides based on autologous virus sequences.
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Altfeld M, Addo MM, Shankarappa R, Lee PK, Allen TM, Yu XG, Rathod A, Harlow J, O'Sullivan K, Johnston MN, Goulder PJ, Mullins JI, Rosenberg ES, Brander C, Korber B, and Walker BD
- Subjects
- Amino Acid Sequence, Flow Cytometry, HIV Infections immunology, Humans, Immunity, Cellular, Molecular Sequence Data, Sequence Homology, Amino Acid, Viral Proteins chemistry, Viral Proteins immunology, CD8-Positive T-Lymphocytes immunology, HIV-1 immunology, Peptides chemistry
- Abstract
The antigenic diversity of human immunodeficiency virus type 1 (HIV-1) represents a significant challenge for vaccine design as well as the comprehensive assessment of HIV-1-specific immune responses in infected persons. In this study we assessed the impact of antigen variability on the characterization of HIV-1-specific T-cell responses by using an HIV-1 database to determine the sequence variability at each position in all expressed HIV-1 proteins and a comprehensive data set of CD8 T-cell responses to a reference strain of HIV-1 in infected persons. Gamma interferon Elispot analysis of HIV-1 clade B-specific T-cell responses to 504 overlapping peptides spanning the entire expressed HIV-1 genome derived from 57 infected subjects demonstrated that the average amino acid variability within a peptide (entropy) was inversely correlated to the measured frequency at which the peptide was recognized (P = 6 x 10(-7)). Subsequent studies in six persons to assess T-cell responses against p24 Gag, Tat, and Vpr peptides based on autologous virus sequences demonstrated that 29% (12 of 42) of targeted peptides were only detected with peptides representing the autologous virus strain compared to the HIV-1 clade B consensus sequence. The use of autologous peptides also allowed the detection of significantly stronger HIV-1-specific T-cell responses in the more variable regulatory and accessory HIV-1 proteins Tat and Vpr (P = 0.007). Taken together, these data indicate that accurate assessment of T-cell responses directed against the more variable regulatory and accessory HIV-1 proteins requires reagents based on autologous virus sequences. They also demonstrate that CD8 T-cell responses to the variable HIV-1 proteins are more common than previously reported. more...
- Published
- 2003
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35. Viremia control despite escape from a rapid and potent autologous neutralizing antibody response after therapy cessation in an HIV-1-infected individual.
- Author
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Montefiori DC, Altfeld M, Lee PK, Bilska M, Zhou J, Johnston MN, Gao F, Walker BD, and Rosenberg ES
- Subjects
- Adult, Amino Acid Sequence, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes virology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes virology, Drug Administration Schedule, Epitopes, T-Lymphocyte analysis, Epitopes, T-Lymphocyte immunology, HIV Antibodies analysis, HIV Envelope Protein gp120 analysis, HIV Envelope Protein gp120 immunology, HIV Infections virology, HIV-1 genetics, HIV-1 isolation & purification, Humans, Male, Molecular Sequence Data, Neutralization Tests, Peptide Fragments analysis, Peptide Fragments immunology, Virus Replication immunology, Antiretroviral Therapy, Highly Active methods, HIV Antibodies biosynthesis, HIV Infections drug therapy, HIV Infections immunology, HIV-1 drug effects, HIV-1 immunology, Viremia immunology, Viremia virology
- Abstract
The neutralizing Ab response after primary HIV-1 infection is delayed relative to the virus-specific CD8(+) T cell response and the initial decline in plasma viremia. Because nearly all HIV-1 infections result in AIDS, it would be instructive to study cases where neutralizing Ab production commenced sooner. This was done in subject AC10, an individual treated during early infection and in whom a rapid autologous neutralizing Ab response was detected after therapy cessation as rebound viremia declined and remained below 1000 RNA copies/ml of blood for over 2.5 years. This subject's Abs were capable of reducing the infectivity of his rebound virus by >4 logs in vitro at a time when rebound viremia was down-regulated and virus-specific CD8(+) T cells were minimal, suggesting that neutralizing Abs played an important role in the early control of viremia. The rebound virus did not exhibit an unusual phenotype that might explain its high sensitivity to neutralization by autologous sera. Neutralization escape occurred within 75 days and was proceeded by neutralizing Ab production to the escape variant and subsequent escape. Notably, escape was not associated with a significant rise in plasma viremia, perhaps due to increasing CD8(+) T cell responses. Sequence analysis of gp160 revealed a growing number of mutations over time, suggesting ongoing viral evolution in the face of potent antiviral immune responses. We postulate that an early effective neutralizing Ab response can provide long-term clinical benefits despite neutralization escape. more...
- Published
- 2003
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36. Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load.
- Author
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Addo MM, Yu XG, Rathod A, Cohen D, Eldridge RL, Strick D, Johnston MN, Corcoran C, Wurcel AG, Fitzpatrick CA, Feeney ME, Rodriguez WR, Basgoz N, Draenert R, Stone DR, Brander C, Goulder PJ, Rosenberg ES, Altfeld M, and Walker BD more...
- Subjects
- Acquired Immunodeficiency Syndrome virology, Amino Acid Sequence, Epitopes, T-Lymphocyte, Female, Gene Products, nef immunology, HIV Core Protein p24 immunology, Humans, Interferon-gamma biosynthesis, Male, Molecular Sequence Data, Peptide Fragments immunology, Viral Load, nef Gene Products, Human Immunodeficiency Virus, Acquired Immunodeficiency Syndrome immunology, Genome, Viral, HIV-1 immunology, T-Lymphocytes immunology
- Abstract
Cellular immune responses play a critical role in the control of human immunodeficiency virus type 1 (HIV-1); however, the breadth of these responses at the single-epitope level has not been comprehensively assessed. We therefore screened peripheral blood mononuclear cells (PBMC) from 57 individuals at different stages of HIV-1 infection for virus-specific T-cell responses using a matrix of 504 overlapping peptides spanning all expressed HIV-1 proteins in a gamma interferon-enzyme-linked immunospot (Elispot) assay. HIV-1-specific T-cell responses were detectable in all study subjects, with a median of 14 individual epitopic regions targeted per person (range, 2 to 42), and all 14 HIV-1 protein subunits were recognized. HIV-1 p24-Gag and Nef contained the highest epitope density and were also the most frequently recognized HIV-1 proteins. The total magnitude of the HIV-1-specific response ranged from 280 to 25,860 spot-forming cells (SFC)/10(6) PBMC (median, 4,245) among all study participants. However, the number of epitopic regions targeted, the protein subunits recognized, and the total magnitude of HIV-1-specific responses varied significantly among the tested individuals, with the strongest and broadest responses detectable in individuals with untreated chronic HIV-1 infection. Neither the breadth nor the magnitude of the total HIV-1-specific CD8+-T-cell responses correlated with plasma viral load. We conclude that a peptide matrix-based Elispot assay allows for rapid, sensitive, specific, and efficient assessment of cellular immune responses directed against the entire expressed HIV-1 genome. These data also suggest that the impact of T-cell responses on control of viral replication cannot be explained by the mere quantification of the magnitude and breadth of the CD8+-T-cell response, even if a comprehensive pan-genome screening approach is applied. more...
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- 2003
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37. HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus.
- Author
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Altfeld M, Allen TM, Yu XG, Johnston MN, Agrawal D, Korber BT, Montefiori DC, O'Connor DH, Davis BT, Lee PK, Maier EL, Harlow J, Goulder PJ, Brander C, Rosenberg ES, and Walker BD
- Subjects
- Amino Acid Sequence, CD4 Lymphocyte Count, HIV Antigens chemistry, HIV Antigens immunology, HIV-1 chemistry, HIV-1 classification, Humans, Interferon-gamma analysis, Molecular Sequence Data, Neutralization Tests, Phylogeny, T-Lymphocytes, Helper-Inducer immunology, Viral Load, Viremia immunology, Viremia virology, CD8-Positive T-Lymphocytes immunology, Epitopes, T-Lymphocyte immunology, HIV-1 immunology, HIV-1 physiology, Superinfection immunology, Superinfection virology, Virus Replication
- Abstract
Early treatment of acute HIV-1 infection followed by treatment interruptions has shown promise for enhancing immune control of infection. A subsequent loss of control, however, allows the correlates of protective immunity to be assessed. Here we show that sudden breakthrough of plasma viraemia occurred after prolonged immune containment in an individual infected with HIV-1 at a time when 25 distinct CD8+ T-cell epitopes in the viral proteins Gag, RT, Integrase, Env, Nef, Vpr, Vif and Rev were being targeted. Sequencing of the virus in plasma and cells showed that superinfection with a second clade-B virus was coincident with the loss of immune control. This sudden increase in viraemia was associated with a decline in half of the CD8+ T-cell responses. The declining CD8+ T-cell responses were coupled with sequence changes relative to the initial virus that resulted in impaired recognition. Our data show that HIV-1 superinfection can occur in the setting of a strong and broadly directed virus-specific CD8+ T-cell response. The lack of cross-protective immunity for closely related HIV-1 strains, despite persistent recognition of multiple CD8 epitopes, has important implications for public health and vaccine development. more...
- Published
- 2002
- Full Text
- View/download PDF
38. Consistent patterns in the development and immunodominance of human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses following acute HIV-1 infection.
- Author
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Yu XG, Addo MM, Rosenberg ES, Rodriguez WR, Lee PK, Fitzpatrick CA, Johnston MN, Strick D, Goulder PJ, Walker BD, and Altfeld M
- Subjects
- Acute Disease, Amino Acid Sequence, Antiretroviral Therapy, Highly Active, Cell Line, Drug Administration Schedule, HIV Infections drug therapy, HIV Infections virology, HIV-1 chemistry, HLA-A3 Antigen metabolism, HLA-B7 Antigen metabolism, Humans, Immunodominant Epitopes chemistry, Molecular Sequence Data, Peptides chemical synthesis, Peptides chemistry, Peptides immunology, Viral Proteins chemical synthesis, Viral Proteins chemistry, Viral Proteins immunology, CD8-Positive T-Lymphocytes immunology, HIV Infections immunology, HIV-1 immunology, Immunodominant Epitopes immunology
- Abstract
Human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses generated during acute infection play a critical role in the initial control of viremia. However, little is known about the viral T-cell epitopes targeted during acute infection or about their hierarchy in appearance and relative immunodominance over time. In this study, HIV-1-specific CD8+ T-cell responses in 18 acutely infected individuals expressing HLA-A3 and/or -B7 were characterized. Detailed analysis of CD8 responses in one such person who underwent treatment of acute infection followed by reexposure to HIV-1 through supervised treatment interruptions (STI) revealed recognition of only two cytotoxic T-lymphocyte (CTL) epitopes during symptomatic acute infection. HIV-1-specific CD8+ T-cell responses broadened significantly during subsequent exposure to the virus, ultimately targeting 27 distinct CTL epitopes, including 15 different CTL epitopes restricted by a single HLA class I allele (HLA-A3). The same few peptides were consistently targeted in an additional 17 persons expressing HLA-A3 and/or -B7 during acute infection. These studies demonstrate a consistent pattern in the development of epitope-specific responses restricted by a single HLA allele during acute HIV-1 infection, as well as persistence of the initial pattern of immunodominance during subsequent STI. In addition, they demonstrate that HIV-1-specific CD8+ T-cell responses can ultimately target a previously unexpected and unprecedented number of epitopes in a single infected individual, even though these are not detectable during the initial exposure to virus. These studies have important implications for vaccine design and evaluation. more...
- Published
- 2002
- Full Text
- View/download PDF
39. Constitutive and stimulated expression of ICAM-1 protein on pulmonary endothelial cells in vivo.
- Author
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Fingar VH, Taber SW, Buschemeyer WC, ten Tije A, Cerrito PB, Tseng M, Guo H, Johnston MN, and Wieman TJ
- Subjects
- Animals, Endothelium, Vascular cytology, Fluorescence, Lung metabolism, Microspheres, Rats, Rats, Sprague-Dawley, Up-Regulation, Videotape Recording, Endothelium, Vascular metabolism, Intercellular Adhesion Molecule-1 biosynthesis, Lung blood supply
- Abstract
The expression of intercellular adhesion molecule-1 (ICAM-1) on pulmonary endothelial cells after stimulus and subsequent binding of neutrophils is a first step leading to lung injury. A similar process may dictate the binding of tumor cells to the pulmonary endothelium during metastasis. We report the development of a new technique that allowed us to monitor the location and relative expression of ICAM-1 levels on the luminal surface of the pulmonary microvasculature in vivo. This technique uses intravital microscopy together with a two-step labeling procedure involving fluorescent microspheres. Constitutive expression of ICAM-1 was not detectable to a significant level by our model, but expression was observed after upregulation by the systemic administration of TNF alpha. Sprague-Dawley rats were injected with 0-5.0 micrograms/kg TNF alpha and ICAM-1 expression was monitored through 24 hr. ICAM-1 expression was related to both the dose of TNF alpha administered and the time elapsed between injection of TNF alpha and observation. Injection of 5 micrograms/kg TNF alpha caused upregulation of ICAM-1 protein expression from 0.30 +/- 2.76 binding events/175,000 microns2 to 62.6 +/- 5.48 through 4 hr observation, after which levels returned to near baseline within 24 hr. The delay required for maximal expression is likely related to the time required for the cell to respond to the stimulus and generate ICAM-1 protein. Reductions in the relative numbers of ICAM-1 protein expressed between 4 and 24 hr in vivo are likely a result of protein turnover after the initial stimulus. more...
- Published
- 1997
- Full Text
- View/download PDF
40. Bepridil protects sickle cells against the adverse rheological effects of cyclical deoxygenation.
- Author
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Johnston MN, Ellory JC, and Stuart J
- Subjects
- Humans, Anemia, Sickle Cell blood, Bepridil pharmacology, Erythrocyte Deformability drug effects, Erythrocytes, Abnormal drug effects, Oxygen blood
- Abstract
Calcium influx into sickle cells, with consequential activation of the Ca2(+)-activated K+ efflux (Gardos) channel, is a potential cause of cellular dehydration and loss of deformability. Bepridil, a recently described inhibitor of the Gardos channel, was found at pharmacological concentration (1 mumol/l) to inhibit significantly (P less than 0.01) the loss of deformability when sickle cells were subjected to cycles of oxygenation-deoxygenation for 15 h at 37 degrees C. Bepridil also inhibited significantly (P less than 0.005) the formation of irreversibly sickled cells. Drugs that preserve the K+ and therefore water content of erythrocytes are of potential value for hydrotherapy of sickle cell disease. more...
- Published
- 1989
- Full Text
- View/download PDF
41. Korean vivax malaria. III. Curative effect and toxicity of primaquine in doses from 10 to 30 mg. daily.
- Author
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JONES R Jr, JACKSON LS, DI LORENZO A, MARX RL, LEVY BL, KENNY EC, GILBERT M, JOHNSTON MN, and ALVING AS
- Subjects
- Humans, Antimalarials therapeutic use, Asian People, Malaria, Malaria, Vivax, Primaquine
- Published
- 1953
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