One hallmark of Alzheimer disease is the accumulation of amyloid beta-peptide in the brain and its deposition as plaques. Mice transgenic for an amyloid beta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter (PDAPP mice), which overexpress one of the disease-linked mutant forms of the human amyloid precursor protein, show many of the pathological features of Alzheimer disease, including extensive deposition of extracellular amyloid plaques, astrocytosis and neuritic dystrophy. Active immunization of PDAPP mice with human amyloid beta-peptide reduces plaque burden and its associated pathologies. Several hypotheses have been proposed regarding the mechanism of this response. Here we report that peripheral administration of antibodies against amyloid beta-peptide, was sufficient to reduce amyloid burden. Despite their relatively modest serum levels, the passively administered antibodies were able to enter the central nervous system, decorate plaques and induce clearance of preexisting amyloid. When examined in an ex vivo assay with sections of PDAPP or Alzheimer disease brain tissue, antibodies against amyloid beta-peptide triggered microglial cells to clear plaques through Fc receptor-mediated phagocytosis and subsequent peptide degradation. These results indicate that antibodies can cross the blood-brain barrier to act directly in the central nervous system and should be considered as a therapeutic approach for the treatment of Alzheimer disease and other neurological disorders.
Efficient and sustained protection from sexual acquisition of HSV-2 infection will require more than high titers of specific neutralizing antibodies. Protection against sexually transmitted viruses involving exposure over a prolonged period will require a higher degree of vaccine efficacy than that achieved in this study.
Herpes simplex virus type 1 (HSV-1) and HSV-2 plaque production was inhibited by treating cells with soluble forms of HSV-1 glycoprotein D (gD-lt) and HSV-2 glycoprotein D (gD-2t). Both glycoproteins inhibited entry of HSV-1 and HSV-2 without affecting virus adsorption. In contrast, a soluble form of HSV-2 glycoprotein B had no effect on virus entry into cells. Specific binding of gD-lt and gD-2t to cells was saturable, and approximately 4 x 105 to 5 x 105 molecules bound per cell. Binding of gD-lt was markedly reduced by treating cells with certain proteases but was unaffected when cell surface heparan sulfate glycosaminoglycans were enzymatically removed or when the binding was carried out in the presence of heparin. Together, these results suggest that gD binds to a limited set of cell surface receptors which may be proteins and that these interactions are essential for subsequent virus entry into cells. However, binding of gD to its receptors is not required for the initial adsorption of virus to the cell surface, which involves more numerous sites (probably including heparan sulfate) than those which mediate gD binding.
A phase I randomized, double-blind, placebo-controlled trial was done with a cytomegalovirus (CMV) vaccine based on the envelope glycoprotein, gB, combined with a novel adjuvant, MF59. Participants received CMV gB vaccine with MF59 or CMV gB with alum or placebo at 0, 1, and 6 months. A fourth vaccine was given at 12 months to a subgroup. Levels of neutralizing antibody and antibody to gB 2 weeks after the third dose of vaccine exceeded those in seropositive control subjects. the formulation with MF59 was more immunogenic than that with alum. The optimal dose of gB appeared to be between 5 and 30 microg. The fourth dose produced a prompt rise in antibody level. There were no serious adverse events associated with vaccine. Local and systemic reactions were generally mild and, except for pain at the injection site, occurred with similar frequency in recipients of placebo and CMV vaccine.
The natural history of initial and subsequent recurrent herpes simplex virus (HSV) genital infection was studied in guinea pigs immunized with HSV glycoprotein vaccines before vaginal challenge with HSV-2. The vaccines used included HSV-1 glycoprotein B and HSV-1 glycoprotein D, both prepared by recombinant DNA techniques, and mixtures of HSV-1 or HSV-2 glycoproteins, prepared from infected cell monolayers by lectin chromatography. Immunizing guinea pigs with subunit HSV glycoprotein vaccines favorably altered the clinical and virological course of initial infection and substantially reduced the incidence, frequency, and duration of recurrent herpetic infections. The extent of protection was influenced by the nature of the glycoprotein vaccine, the immunizing dose, and the co-administration of adjuvant.
This subunit vaccine induces both humoral and cellular responses to HSV-2 that are equal to or greater than those of persons with naturally acquired HSV-2 infection. Studies to evaluate this vaccine for the prevention of genital herpes appear warranted.
The bacteriophage T4 helix-destabilizing protein, the product of gene 32, has been immobilized on an agarose matrix and used for affinity chromatography of lysates of T4-infected Escherichia coli cells. At least 10 T4-encoded early proteins and 3 or 4 host proteins are specifically retained by this gene 32 protein column. Nine of the T4 proteins have been identified as being involved in either DNA replication or genetic recombination. Notably, the T4 DNA polymerase (gene 43 protein) and two major proteins in the recombination pathway (the products of genes uvsX and uvsY) are specifically bound. On a preparative scale, the column is useful for purification of the bound proteins.Gene 32 of bacteriophage T4 encodes a helix-destabilizing protein that is known to be required for the processes of T4 DNA replication, recombination, and repair (1). The purified gene 32 protein has been shown to be an essential component of the T4 in vitro DNA replication system that has been reconstituted from purified proteins (2, 3). Many of the protein-protein interactions involved in bacteriophage DNA metabolism appear to be relatively weak ones. Moreover, the results to be described reveal that a large number of different proteins are involved. For these reasons, we have undertaken the task of cataloguing the protein-protein interactions involving gene 32 protein by protein-affinity chromatography. This approach has several advantages: (i) high concentrations of immobilized proteins can be used, and the resulting high concentration of binding sites on affinity columns makes even weak protein-protein interactions detectable; (ii) both crude lysates and purified proteins can be tested for their binding to such matrices, allowing us both to examine known proteins for their binding to gene 32 protein and to search for unknown ones; and (iii) the method can be used either analytically or preparatively, facilitating large-scale purification of those proteins that bind to the column.As part of our goal of understanding the detailed structure of the T4 DNA replication apparatus, we have used protein affinity chromatography to detect interactions between various different T4 replication proteins (7). Here we describe the associations detected between gene 32 protein and the other proteins present in a T4 bacteriophage-infected cell at early times of infection, when the central genetic processes of DNA replication, recombination, transcription, and repair are underway. This approach has allowed us to identify and to purify several proteins known to be involved in genetic recombination, and it has also given us a new tool for the purification of the T4 DNA polymerase. Greenblatt (8) has described a similar approach in the study of the function of the gene N protein of bacteriophage A.
METHODSBuffers. Column buffer was 20 mM Tris-HCl, pH 8.1/1 mM Na3EDTA/1 mM 2-mercaptoethanol/5 mM MgCl2/10% (wt/ vol) glycerol; it was supplemented with 0.05, 0.2, 0.6, or 2.0 M NaCl as noted. Lysis buffer consisted of column buffer supplemented with 50...
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