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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recombinant CD4-immunoglobulin G (rCD4-IgG) is a 98-kDa human immunoglobulin-like protein that is produced by fusing the gp120 binding domain of CD4 to the Fc portion of the human IgG1 heavy chain. This hybrid molecule was given to human immunodeficiency virus (HIV)-infected pregnant women at the onset of labor by intravenous bolus at 1 mg/kg of body weight (group A; n = 3) and 1 week prior to and at the onset of labor by the same route and at the same dose (group B; n = 3). In addition to pharmacokinetic studies, safety in the mothers and infants was determined through routine chemistries, hematology, and urinalysis; immunologic and HIV infection statuses in the infants were assessed through lymphocyte cultures, p24 antigen level determination, culture of HIV from plasma, PCR, lymphocyte subset enumeration, quantitative immunoglobulin analysis, and lymphocyte proliferation. Thirty minutes after the rCD4-IgG injection, concentrations in maternal serum were 12 to 23 micrograms/ml. These concentrations declined slowly, with initial and terminal half-lives (mean +/- standard deviation) of 9.95 +/- 3.23 and 47.6 +/- 22.3 h, respectively. Infants were born 2.6 to 46.5 h after rCD4-IgG administration; concentrations of rCD4-IgG in cord blood ranged from 28 to 107 ng/ml. The half-life of rCD4-IgG in infants ranged from 5 to 29 h. These data demonstrate that the transfer of rCD4-IgG from the mother to the fetus is rapid and that newborns do not appear to have any difficulty eliminating rCD4-IgG. No safety concerns in mothers or infants were encountered. Although the study did not address the question of efficacy, none of the infants was HIV type 1 infected 36 months later. In summary, these findings document that bifunctional immune molecules can be transported across the placenta, and this general approach may be used in the future to block vertical transmission of HIV type 1.
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PMID:Transport of recombinant human CD4-immunoglobulin G across the human placenta: pharmacokinetics and safety in six mother-infant pairs in AIDS clinical trial group protocol 146. 766 72

Genes encoding the immunoglobulin variable regions of a human anti-HIV-1 IgG1 kappa monoclonal antibody were rescued from a hybridoma, derived from a sero-negative donor, using PCR cloning and expression in Escherichia coli. The ELISA binding results obtained from the expressed Fab fragment confirmed the anti-V3 loop specificity for HIV-1 (LAI) of the original antibody. In addition, an amino acid sequence derived from the second complementarity determining region (CDRH2) of the heavy chain was found to be very similar to the catalytic motif of CD26, a T-cell activation antigen. Furthermore, synthetic peptides containing both the catalytic domain of CD26 and CDRH2 of the antibody showed specific binding to an HIV peptide representing the V3 region in a dose-dependent manner. This suggests an involvement of CD26 as a possible coreceptor for HIV-1.
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PMID:Molecular characterization of a human anti-HIV 1 monoclonal antibody revealed a CD26-related motif in CDR2. 772 39

We recently showed that a synthetic peptide corresponding to the third complementary determining region of the heavy chain (CDRH3) of a monoclonal antibody (mAb) directed to the V3 domain of HIV-1 gp120 neutralizes HIV-1 in vitro. From the CDRH3 sequence we have now produced bifunctional antigen/antibody specificity exchanger (A/ASE) peptides containing both the HIV-1 mAb derived CDRH3 sequence and antigenic region sequences from the hepatitis B virus core/e antigen (HBc/eAg) and the poliovirus VP1. These A/ASE peptides were able to re-direct HBc/eAg and enteroviral VP1 specific mAbs, as well as polyclonal human HIV-1 negative sera to recognize the V3 domain of HIV-1. Furthermore, two out of three A/ASE peptides were able to neutralize HIV-1 in vitro. These bifunctional A/ASE peptides have a potential to be used as tools in research, diagnostics and maybe even therapeutics.
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PMID:The antigen/antibody specificity exchanger: a new peptide based tool for re-directing antibodies of other specificities to recognize the V3 domain of HIV-1 gp120. 780 74

In previous work, it was found that the heavy chain variable gene (VH) repertoire of human antibodies to HIV is markedly skewed and that the gp120 molecule is a ligand for VH3 gene products. Here, we have analysed the light chain (L-chain) variable region genes (VL) expressed by a panel of human monoclonal antibodies derived from an immunized volunteer, an AIDS patient and seropositive asymptomatic donors, and specific for HIV-1 p25, gp41 and gp120 proteins. We found that, in contrast to VH gene-family use, the VL repertoire does not exhibit a family-bias. We noticed however, a tendency to the use of VL genes that map to the downstream portion of the kappa locus. The VL genes expressed have mutated at lower rates than the corresponding VH genes and show no clustering of the replacement mutations in the hypervariable regions. We also found that the third hypervariable regions (CDR3) of the L-chains have undergone a marked diversification, with addition of untemplated nucleotides, frequent truncation at the 3' end of the VLs and somatic mutation. These molecular events result in a length heterogeneity of the CDR3s and an apparently positive selection of specific highly reactive amino acids. We conclude that the specificity of, at least some of the anti-HIV antibodies, is dictated by the L-chain CDR3 regions which bear the imprints of antigenic selection.
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PMID:Variable region light chain genes encoding human antibodies to HIV-1. 787 59

We have reported the generation and characterization of four HIV-1 neutralizing human monoclonal antibodies. Three antibodies recognize a conformational epitope within the CD4-binding site of HIV-1 gp120 and one recognizes a linear epitope located within the hypervariable V3 domain of gp120. In the present study we report the nucleotide sequences of the cDNAs encoding the variable regions of the heavy and light chains of these antibodies. Molecular characteristics, closet germline genes, and the putative extent of somatic mutation are presented. Two of the four heavy chain variable (VH) regions are derived from the VH1 gene family, one from the VH3 gene family, and one from the VH5 gene family. In addition, the VH chain of a previously described human monoclonal antibody, directed against HIV-1 gp41, is derived from the VH3 gene family. The degree of nucleotide variation between these five antibodies and their closest germline counterparts ranges from 4 to 12%, mainly located in the complementarity-determining regions. Significant nucleotide sequence homology with previously described germline diversity (D) genes could be found for only two of five antibody D segments. Joining (JH) gene segments utilized are JH4 or JH6. Two light chain variable (VL) regions are derived from a VK1 gene segment, one from a V kappa 4, one from a V lambda 2, and one from a lambda 6 gene segment.
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PMID:Molecular characterization of variable heavy and light chain regions of five HIV type 1-specific human monoclonal antibodies. 788 23

Peripheral blood mononuclear cells (PBMC) from human immunodeficiency virus (HIV)-infected patients, asymptomatic or with acquired immunodeficiency virus, produced 10-fold less interleukin 12 (IL-12) free heavy chain and fivefold less biologically active IL-12 heterodimer than PBMC from uninfected healthy donors when challenged in vitro with the common human pathogen Staphylococcus aureus. In contrast, PBMC from HIV-infected individuals and uninfected control donors produced similar levels of tumor necrosis factor alpha, IL-1 beta, and IL-10, and PBMC from HIV-infected individuals produced three- to fourfold more IL-6 compared with PBMC from uninfected control donors. The defect in IL-12 production is not due to hyperproduction of IL-10, a cytokine exerting an autocrine-negative feedback on IL-12 production, but was directly related to HIV infection, as suggested by the reduced ability of monocytes infected in vitro with HIV to produce IL-12. IL-12 deficiency may be an important component of the immunodeficiency associated with HIV infection.
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PMID:Impaired interleukin 12 production in human immunodeficiency virus-infected patients. 790 24

The rapid whole blood test, developed for the detection of circulating antibodies to human immunodeficiency virus type 1 (HIV-1), is based on agglutination of autologous red blood cells using an anti-human glycophorin antibody conjugated to the HIV-1 immunodominant epitope of gp41 (579-613). A simplified procedure for preparing antibody-peptide conjugates for use in the autologous red cell agglutination test is described. F(ab')2 fragments of the anti-glycophorin antibody were prepared by pepsin digestion and reduced to F(ab') fragments with the use of tri-n-butylphosphine (TBP). This permitted the simultaneous reduction of the F(ab') fragments and coupling of a bromoacetyl derivative of the synthetic immunodominant peptide gp41 (579-613) [Cys-Acm 598, Lys-BrAc 604] containing epsilon-bromoacetyl-lysine at residue 604 to the resultant F(ab') fragment. Conjugation to the F(ab') fragment resulted in a stable thio-ether linkage between the peptide Lys-604 and the inter heavy chain cysteines of the F(ab'). The resultant F(ab')-peptide conjugate was comparable to the previously described disulfide coupled conjugate when used in the autologous red cell agglutination test. This simplified conjugation chemistry may also be useful for the development of reagents for FACS analysis as well as targetted vaccines.
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PMID:Simplified conjugation chemistry for coupling peptides to F(ab') fragments: autologous red cell agglutination assay for HIV-1 antibodies. 793 Jun 54

The human monoclonal antibodies (mAbs) 15e and 21h are derived from HIV-1-infected individuals. They block CD4 binding, recognize conformation-dependent discontinuous epitopes on gp120 and neutralize a broad range of laboratory strains and primary isolates of HIV-1. To determine if a structural basis for neutralization could be identified, analysis of these CD4-binding site anti-gp120 human mAbs was performed, common features and differences were identified and a comparison was made with F105, a previously reported CD4-binding site anti-gp120 human mAb. The 15e and 21h mAb heavy chains are derived from different V region genes, i.e. V2-1 and VDP-35, which are members of the VHIV and VHIII families, respectively. Analysis of the genes encoding the heavy chain complementarity determining region (CDR) 3 revealed that both mAbs show a long DH segment of similar size that could arise from D-D fusions of the dxp1/dlr1 and daudi/d22-12 germline DH genes along with use of the JH6 and JH5 germline segments. Similarly, the 15e and 21h light chains are derived from different V region genes, i.e. Hum01/012 and Hum1v318, that are members of the V kappa I and V lambda IIIa gene families, respectively. These V genes are rearranged with J kappa 1 and J lambda 2 germline genes. For both mAbs, the pattern of replacement mutations in the V region genes of the heavy and light chains is consistent with a process of somatic mutation and antigen-driven clonal selection. By comparing the CDRs of 15e, 21h and F105, eight positions in the rearranged heavy chains and two positions in the rearranged light chains were found to have identical amino acids. These studies suggest that there is no absolute restriction in the use of V region germline genes and form the foundation for understanding the humoral immune response to the CD4-binding site of gp120.
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PMID:Structural characterization of broadly neutralizing human monoclonal antibodies against the CD4 binding site of HIV-1 gp120. 793 3

A combination of saturation and site-directed mutagenesis was utilized to disrupt the alpha 2 domain disulfide bridge of HLA-A*0201. Mutation of cysteine 101 to a serine (C101S) or of cysteine 164 to alanine (C164A) decreased the rate of maturation of the heavy chain, the total amount of mature heavy chain within the cell, and the level of surface expression. Cells expressing these genes and loaded with a synthetic peptide derived from the influenza A matrix protein (58-66) were recognized poorly by HLA-A*0201-restricted, peptide-specific CTLs. Cells expressing mutant HLA-A*0201 loaded with a synthetic peptide derived from the HIV-1 pol protein (476-484) were not recognized by pol IV-9-specific CTLs. Mutant C164A cells infected with influenza virus were partially recognized by influenza matrix peptide-specific CTLs, while C101S cells were not lysed. Surprisingly, endogenous peptide loading of cells expressing mutant HLA-A*0201 using a minigene coding for either the influenza A matrix peptide 58-66, or HIV-1 pol peptide 476-484, resulted in efficient CTL recognition. This suggests different structural constraints for peptide binding in the endoplasmic reticulum during biosynthesis and for binding to exported molecules on the cells surface.
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PMID:Mutation of the alpha 2 domain disulfide bridge of the class I molecule HLA-A*0201. Effect on maturation and peptide presentation. 807 Nov 1

Anti-CD4 monoclonal antibodies (mAbs) have shown considerable promise in the treatment of rheumatoid arthritis, psoriasis, and allograft rejection and may have potential use in blocking HIV-1 infection. One such anti-CD4 mAb we have developed, chimeric M-T412 (or cM-T412), has been used in clinical trials to treat rheumatoid arthritis, generalized postular psoriasis, and other autoimmune diseases. Here we report the cloning and expression of a second chimeric anti-CD4 mAb using M-T413, a murine mAb that blocks HIV-1 infection of H9 cells. We cloned the immunoglobulin light and heavy chain variable regions of M-T413, combined them with the human kappa (light chain) or G1, G2, G3 and G4 (heavy chain) constant regions in human expression vectors, and expressed these chimeric mAbs in 653 cells. Like chimeric M-T412 IgG1, the chimeric M-T413 mAbs inhibit T-cell proliferation in the mixed lymphocyte response and thus can act to immunosuppress CD4+ T-cell response. In contrast to M-T412, however, the M-T413 chimeric mAbs have reduced activity in an antibody-dependent cell-mediated cytotoxicity (ADCC) assay using human CD4+ target and effector cells. We conclude that the chimeric M-T413 mAbs have potential utility in treating autoimmune disease and may be useful as prophylactics in preventing HIV-1 infection.
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PMID:Expression and characterization of cM-T413, a chimeric anti-CD4 antibody with in vitro immunosuppressive activity. 808 58


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