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1.
J Gen Virol ; 90(Pt 11): 2622-2633, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19641045

ABSTRACT

Adeno-associated virus serotype 2 (AAV-2) has been developed as a gene therapy vector. Antibody and cell-mediated immune responses to AAV-2 or AAV-2-transfected cells may confound the therapeutic use of such vectors in clinical practice. In one of the most detailed examinations of AAV-2 immunity in humans to date, cell-mediated and humoral immune responses to AAV-2 were characterized from a panel of healthy blood donors. The extent of AAV-2-specific antibody in humans was determined by examination of circulating AAV-2-specific total IgG levels in plasma from 45 normal donors. Forty-one donors were seropositive and responses were dominated by IgG1 and IgG2 subclasses. Conversely, AAV-2-specific IgG3 levels were consistently low in all donors. Cell-mediated immune recall responses were detectable in nearly half the population studied. In vitro restimulation with AAV-2 of peripheral blood mononuclear cell cultures from 16 donors elicited gamma interferon (IFN-gamma) (ten donors), interleukin-10 (IL-10) (eight donors) and interleukin-13 (IL-13) (four donors) responses. Using a series of overlapping peptides derived from the sequence of the VP1 viral capsid protein, a total of 59 candidate T-cell epitopes were identified. Human leukocyte antigen characterization of donors revealed that the population studied included diverse haplotypes, but that at least 17 epitopes were recognized by multiple donors and could be regarded as immunodominant. These data indicate that robust immunological memory to AAV-2 is established. The diversity of sequences recognized suggests that attempts to modify the AAV-2 capsid, as a strategy to avoid confounding immunity, will not be feasible.


Subject(s)
Capsid Proteins/immunology , Dependovirus/immunology , Epitopes, T-Lymphocyte/immunology , Antibodies, Viral/blood , Blood Donors , Cells, Cultured , Genetic Variation , HLA Antigens/genetics , Haplotypes , Humans , Immunoglobulin G/blood , Interferon-gamma/metabolism , Interleukin-10/metabolism , Interleukin-13/metabolism , Leukocytes, Mononuclear/immunology
2.
Behav Neurosci ; 122(4): 805-15, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18729634

ABSTRACT

Hippocampal protein synthesis is dependent upon a number of different molecular and cellular mechanisms that act together to make previously labile memories more stable and resistant to disruption. Both brain-derived neurotrophic factor (BDNF) and extracellular signal-regulated kinase (ERK) are known to play an important role in protein synthesis-dependent memory consolidation, via the mitogen-activated protein-kinase (MAP-K) signaling pathway during the transcription phase of protein synthesis. The current study investigates the influence of protein synthesis inhibition (PSI) by cycloheximide on spatial learning and memory. In an initial experiment, the authors utilized two doses of cycloheximide (0.5 mg/kg and 1.0 mg/kg, intraperitoneally) to determine the dose at which long-term (>24 hours) memories are impaired. A second experiment was designed to investigate the effect of PSI on the formation of cue-platform associations in the watermaze, and on BDNF and ERK expression in the hippocampus. At the higher dose (1.0 mg/kg) cycloheximide resulted in impaired retention of the water maze. BDNF and ERK expression was also down-regulated in animals injected with this dose of cycloheximide. Our results demonstrate a role of protein synthesis in spatial memory retention, along with a possible relationship between protein synthesis and hippocampal BDNF/ERK expression.


Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Maze Learning/physiology , Memory/physiology , Protein Biosynthesis/physiology , Space Perception/physiology , Animals , Avoidance Learning/drug effects , Behavior, Animal/drug effects , Behavior, Animal/physiology , Cycloheximide/pharmacology , Gene Expression Regulation/drug effects , Hippocampus/drug effects , Hippocampus/metabolism , Male , Maze Learning/drug effects , Memory/drug effects , Oligopeptides/pharmacology , Protein Biosynthesis/drug effects , Protein Synthesis Inhibitors/pharmacology , Rats , Rats, Wistar , Reaction Time/drug effects , Space Perception/drug effects
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