Neutralizing polyclonal antibody to respiratory syncytial virus (RSV) has been shown to be an effective prophylactic agent when administered intravenously in high-risk infants. This study describes the generation of a humanized monoclonal antibody, MEDI-493, that recognizes a conserved neutralizing epitope on the F glycoprotein of RSV. The affinity of MEDI-493 was found to be equal to or slightly better than an isotype-matched chimeric derivative of the parent antibody. In plaque reduction, microneutralization, and fusion-inhibition assays, MEDI-493 was significantly more potent than the polyclonal preparation. Broad neutralization of a panel of 57 clinical isolates of the RSV A and B subtypes was demonstrated. Pretreatment of cotton rats with MEDI-493 resulted in 99% reduction of lung RSV titers at a dose of 2.5 mg/kg, corresponding to a serum concentration of 25-30 microg/mL. Further, MEDI-493 did not induce increased RSV infection or pathology in either a primary or a secondary challenge.

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The initial encounter of a microbial pathogen with the host often involves the recognition of host receptors by different kinds of bacterial adhesive organelles called pili, fimbriae, fibrillae or afimbrial adhesins. The development of over 26 of these architecturally diverse adhesive organelles in various Gram‐negative pathogens depends on periplasmic chaperones that are comprised of two immunoglobulin‐like domains. All of the chaperones possess a highly conserved sheet in domain 1 and a conserved interdomain hydrogen‐bonding network. Chaperone‐subunit complex formation depends on the anchoring of the carboxylate group of the subunit into the conserved crevice of the chaperone cleft and the subsequent positioning of the COOH terminus of subunits along the exposed edge of the conserved sheet of the chaperone. We discovered that the chaperones can be divided into two distinct subfamilies based upon conserved structural differences that occur in the conserved sheet. Interestingly, a subdivision of the chaperones based upon whether they assemble rod‐like pili or non‐pilus organelles that have an atypical morphology defines the same two subgroups. The molecular dissection of the two chaperone subfamilies and the adhesive fibers that they assemble has advanced our understanding of the development of virulence‐associated organelles in pathogenic bacteria.

SummaryThe frequencies of human T cell lymphotropic virus type 1 (HTLV-1)-speciflc CD8 + precursor cytotoxic T lymphocytes (pCTL) were quantitated from lymphocytes obtained from the peripheral blood and cerebrospinal fluid (CSF) of infected individuals with and without HTLV-l-associated neurological disease. An estimate of the pCTL was obtained by separating CD8 + cells, plating these cells in limiting dilution, and testing weUs for HTLV-1 specific lysis. Targets consisted of autologous lymphoblastoid cell lines (LCL) infected with vaccinia constructs expressing HTLV-1 gene products or LCL pulsed with HTLV-1 synthetic peptides. In patients with HTLV-l-associated myelopathy/tropical spastic paraparesis (HAM/TSP), the frequency of HTLV-1 p40X-specific pCTL was at least 40-280-fold higher than in asymptomatic HTLV-l-infected individuals. All HAM/TSP patients (five of five) predominantly recognized HTLV-1 products encoded within the pX region. Lower pCTL to env were demonstrated in three patients, and only one of five HAM/TSP patients had pCTL to gag. A synthetic peptide corresponding to the tax region of HTLV-1 (peptide 11-19, amino acid sequence LLFGYPVYV) was recognized in association with human histocompatibility leukocyte antigen (HLA)-A2 in two HLA-A2 HAM/TSP patients with a high CD8 + pCTL frequency of 1/325 and 1/265, respectively. A second immunodominant region of HTLV-1 tax (peptide 90-55, amino acid sequence VPYKtLIEEL) was identified to be restricted by HLA-B14 in two HLA-B14 HAM/TSP patients with a CD8 + pCTL frequency of 1/640 and 1/1,125, respectively. Lymphocytes from the CSF of a patient with HAM/TSP also showed a pCTL frequency against p40X of similar magnitude to that demonstrated from peripheral blood lymphocytes (PBL). The HLA-A2-mediated CSF pCTL activity to the immunodominant tax-specific peptide 11-19 was also comparable to pCTL from PBL. These results indicate that an extremely high pCTL frequency to HTLV-1 tax-encoded peptides may be related to pathogenesis of myeloneuropathy associated with HTLV-1.