Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A complementarity-determining region (CDR) of the mouse monoclonal antibody (mAb) F58 was constructed with specificity to a neutralization-inducing region of human immunodeficiency virus type 1 (HIV-1). The mAb has its major reactivity to the amino acid sequence I--GPGRA in the V3 viral envelope region. All CDRs including several framework amino acids were synthesized from the sequence deduced by cloning and sequencing mAb F58 heavy- and light-chain variable domains. Peptides derived from the third heavy-chain domain (CDR-H3) alone or in combination with the other CDR sequences competed with F58 mAb for the V3 region. The CDR-H3 peptide was chemically modified by cyclization and then inhibited HIV-1 replication as well as syncytium formation by infected cells. Both the homologous IIIB viral strain to which the F58 mAb was induced and the heterologous SF2 strain were inhibited. This synthetic peptide had unexpectedly potent antiviral activity and may be a potential tool for treatment of HIV-infected persons.
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PMID:A complementarity-determining region synthetic peptide acts as a miniantibody and neutralizes human immunodeficiency virus type 1 in vitro. 768

The third variable (V3) domain of the human immunodeficiency virus type 1 (HIV-1) external envelope glycoprotein gp120 is a major target of neutralizing antibodies in infected persons and in experimental immunized animals. Given the high degree of sequence variability of V3, the humoral response toward this region is very type-specific. In the present study, we evaluated the potential of a single peptide and an anti-idiotypic antibody to broaden the anti-V3 antibody specificity in BALB/c mice. We show that a synthetic peptide derived from the V3 determinant of HIV-1 MN isolate (V3MN), when used as an immunogen, was able to induce an antibody response to multiple (up to six) HIV-1 strains. The extent of this cross-reactivity, which tended to enlarge as the injections increased, appeared to be inversely correlated with the binding affinity to V3MN peptide. These data thus present evidence that, despite its great sequence heterogeneity, the V3 loop encompasses conserved amino-acid positions and/or stretches which may be less immunogenic than their variable counterparts. We additionally demonstrate that a rabbit anti-idiotype (Ab2), recognizing a binding site related idiotype on a V3-specific mouse monoclonal antibody (Ab1), could mount a broadened humoral response (Ab3) in mice. Unlike nominal antibody Ab1 which strictly reacted with the European HIV-1 LAI isolate, elicited Ab3 recognized the two divergent HIV-1 strains SF2 and 1286, originating respectively from North America and Central Africa, in addition to LAI. The reasons accounting for this Ab2-induced enlargement of the V3 antibody response are discussed. Our findings suggest that single peptide and anti-idiotype based immunizations may provide viable approaches to overcome, at least in part, HIV epitope variability.
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PMID:Single peptide and anti-idiotype based immunizations can broaden the antibody response against the variable V3 domain of HIV-1 in mice. 778 49

An oligonucleotide encoding the amino acids 731-752 of the gp41 envelope protein of the human immunodeficiency virus type 1 strain IIIB, which is known to induce cross-reactive neutralizing antibodies in humans, was inserted into a full-length clone of the RNA encoding the coat proteins of cowpea mosaic virus (RNA 2 of CPMV). When transfected together with RNA 1 of CPMV, transcribed RNA 2 was able to replicate in plants and form infectious virions (CPMV-HIV). Purified virions were injected subcutaneously with alum adjuvant into adult C57/BL6 mice to determine their ability to stimulate ELISA and neutralizing antibody specific for HIV-1. Antisera to CPMV-HIV obtained after only two injections gave a strong ELISA response (mean of 1:25,800) using the free gp41 peptide as antigen, showing that the gp41 peptide incorporated into the chimera was immunogenic. The same antisera gave 97% neutralization of HIV-1 IIIB at 1:100 dilution, with a highly uniform response in all (six of six) animals tested. A third injection barely increased the neutralization titer. Normal mouse serum had no neutralizing activity. Antisera also strongly neutralized the HIV-1 strains RF and SF2. ELISA and neutralizing activity to HIV-1 IIIB declined after the second injection and were undetectable after 7 weeks, but were restimulated to the same level after the third injection. Neutralization was marginally more stable after the third injection. Antibody specific for CPMV epitopes was equally short lived. A bonus of this system was unexpected neutralizing activity specifically stimulated by unmodified CPMV virions, although this amounted to no more than 10% of the neutralizing activity stimulated by the CPMV-HIV chimera.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human immunodeficiency virus type 1-neutralizing antibodies raised to a glycoprotein 41 peptide expressed on the surface of a plant virus. 778 79

We have established a hybridoma clone, designated 2F5, secreting a neutralizing human monoclonal antibody (MAb) specific for gp41 of human immunodeficiency virus type 1 (HIV-1). The epitope of MAb 2F5 was mapped to amino acid sequence Glu-Leu-Asp-Lys-Trp-Ala on the ectodomain of gp41. In this study different in vitro test systems were used to characterize the neutralizing properties of MAb 2F5. In syncytium inhibition assays, fusion inhibition experiments, and neutralization assays on different HIV-susceptible cells (H9, U937, and peripheral blood mononuclear cells) MAb 2F5 showed broad-spectrum neutralizing capacity against HIV-1 laboratory isolates IIIB, MN, RF, and SF2. In addition, primary isolates from AIDS patients were also neutralized.
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PMID:A broadly neutralizing human monoclonal antibody against gp41 of human immunodeficiency virus type 1. 788 24

We report a new approach in peptide vaccine strategy based on combinatorial synthesis. A library of 7.5 x 10(5) related peptides, termed mixotope, was derived from the sequence of the third hypervariable domain (V3 loop) of the human immunodeficiency virus (HIV) envelope protein. This preparation induced a strong immune response in all syngeneic and outbred rodents tested. The response directed against the mixotope included antibodies, CD4+ T helper cells (TH1 and TH2) and CD8+ T cells. In rodents immunized with the mixotope, the T cell response directed against individual V3 peptide sequences (BRU, MN, RF, SF2, and ELI) as measured by T cell proliferation and interleukin (IL)-2 production, was found to be major histocompatibility complex haplotype-dependent. However, additional experiments performed in mice indicated that selectivity was less restrictive when using IL-3 secretion to explore T cell activation. This combinatorial antigen could be considered as a series of agretopic motifs framing a multiplicity of closely related epitopes for T cell recognition and able to elicit a T cell and B cell repertoire. This new construct may therefore provide a basis for the design of future vaccine strategies.
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PMID:The mixotope: a combinatorial peptide library as a T cell and B cell immunogen. 795 71

With T-cell lines constitutively expressing Nef from the SF2 strain of human immunodeficiency virus type 1 (HIV-1SF2) in the form of a hybrid CD8-Nef fusion protein or T-cell lines chronically infected with HIV-1SF2, a cellular serine kinase was found that specifically associates with Nef. Proteins of 62 kDa and 72 kDa, which coimmunoprecipitated with Nef, were phosphorylated in in vitro kinase assays. This Nef-associated serine kinase activity was not blocked by inhibitors of protein kinase C or protein kinase A and was lost when Nef was truncated at amino acid 94 or 99. These findings present evidence that a serine kinase activity is associated with Nef expressed in human T lymphocytes.
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PMID:Human immunodeficiency virus type 1 Nef associates with a cellular serine kinase in T lymphocytes. 810 42

The gp160 envelope glycoprotein of human immunodeficiency virus type-1 (HIV-1) is an essential component of current vaccine trials. The glycans of gp160, part of which are highly sialylated, have been shown to influence gp160 immunogenicity. Here, using a panel of synthetic V3 peptides, we characterized the anti-V3 antibodies generated in rabbits immunized by desialylated recombinant gp160LAI. Amino acid residues flanking the GPGR tip of V3 were necessary for the recognition by anti-V3 antibodies raised against either the native or desialylated gp160. Both types of antibodies reacted to V3 peptides of MN and SF2 strains and with a North American/European V3 consensus peptide, while anti-desialylated gp160LAI antibodies reacted in addition to the V3 of CDC4, WMJ2 and NY5 strains. Yet, the V3 peptides did not significantly differ in their secondary structure, as determined by circular dichroism. The titer and avidity for V3MN of anti-desialylated gp160LAI antibodies were significantly lower than those of anti-native gp160LAI, which likely accounts for the inability of anti-desialylated gp160LAI sera to neutralize HIV-1MN-induced syncytia. These results indicate that V3 immunogenicity may be influenced by subtle directed changes in the gp160 glycosylation pattern.
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PMID:Effect of sialic acid removal on the antibody response to the third variable domain of human immunodeficiency virus type-1 envelope glycoprotein. 813 47

HIV-1 Nef down-modulates expression of human CD4, the human immunodeficiency virus (HIV) receptor, at the cell surface. Down-modulation of retrovirus receptors has been shown to be important in the survival of infected cells. To relate this observation to AIDS pathogenesis, we compared the ability of Nef from the SIVmac239open and HIV-1 SF2 isolates to suppress CD4 surface levels. We first obtained the simian immunodeficiency virus (SIV)nef gene by PCR and cloned it into the retroviral vector pLXSN. We then established high titer (1 x 10(6) CFU/ml) amphotropic retrovirus producer lines (PA317/LSnefSN). Using LSnefSN we obtained populations of CD4+ human and mouse T-cells, human B-cells, and mouse fibroblasts that expressed SIV or HIV Nef. In the two human cell lines, both HIV and SIV Nef expression correlated with a significant decrease in CD4 cell surface levels. However, Nef expression did not alter the cell surface levels of CD3, CD18, and MHC class I. Both Nef proteins also suppressed human CD4 surface expression in mouse fibroblasts. Interestingly, SIV Nef failed to suppress cell surface expression of mouse CD4 under conditions where HIV-1 Nef did. Human CD4 down-modulation is a conserved function of SIV and HIV Nef likely to be important for pathogenesis.
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PMID:Specific suppression of human CD4 surface expression by Nef from the pathogenic simian immunodeficiency virus SIVmac239open. 818 46

Vaccine therapy studies in HIV-seropositive volunteers over the next year should provide additional insights into whether different vaccine viral strains (LAI, IIIB, MN, SF2), different protein sources (whole virus particles, recombinant protein, peptides), different expression systems (baculovirus, mammalian), or different adjuvants (incomplete Freund's, MTP-PE, MF59, alum) generate significantly different immune responses at the cellular and humoral level. In addition, differences in the ability of each vaccine to induce humoral immune responses to epitopes in the constant regions vs. variable regions, contiguous or noncontiguous "conformational" epitopes, with high vs. low antibody affinity can be evaluated. The roles of antibody-dependent cellular cytotoxicity (ADCC), cellular recognition, nonspecific natural killing, and MHC-restricted cytotoxicity can also be explored. To date, the majority of the immunogens have proven to be safe. Many induce new humoral and cellular immune responses against HIV. The final important question remains, whether any of these vaccines used as therapeutic immunogens generate immune responses that induce an altered disease course with a prolonged asymptomatic period without immunodeficiency, whether vaccines can affect increased viral clearance, or decreased transmission/infectivity? There remains no in vitro assay known to correlate with lack of disease progression, no immune profile consistent with a prolonged asymptomatic period. The vaccine therapy trial researchers seek the answers to these important questions. No single research organization can begin to address all the possibilities, so the overall pace of exploration of this therapeutic concept is likely to be dictated by the level of cooperation between the many groups involved in these studies. Open collaboration between researchers and open exchange of reagents, immunogens for in vitro experiments, and sera will allow faster dissection of the many questions and issues raised in this chapter. Whether vaccine therapy proves to have a useful role in the treatment of HIV-1-induced disease, these studies will ultimately lead to the development of useful techniques and provide new insights into the nature of the immunological responses, as the investigation of vaccine therapy did over a century ago.
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PMID:Vaccines directed against HIV: preventive and therapeutic strategies. 821

A human T-cell line constitutively expressing the nef gene from the human immunodeficiency virus type 1 SF2 isolate was used to examine the distribution of the Nef protein in the nucleus. High-resolution immunogold labeling/electron microscopic studies with polyclonal anti-Nef antibodies on nef+ and nef- cells revealed that a small fraction of Nef is in the nucleus and it is localized in specific curvilinear tracks that extend between the nuclear envelope and the nucleoplasm. An examination of the sequence of the SF2 nef gene revealed a putative nuclear targeting sequence that was previously found in several other eukaryotic nucleoplasmic proteins. The nuclear localization of Nef suggests a potential nuclear function for this protein. The presence of Nef in distinct nuclear tracks suggests that Nef is transported along a specific pathway that extends from the nuclear envelope into the nucleoplasm. A previous study [Meier, U. T. & Blobel, G. (1992) Cell 70, 127-138] has shown that the nucleolar protein of rat liver cells (Nopp140) shuttles from the nucleolus to the nuclear envelope on distinct tracks. The present study has suggested that the transport of a nucleoplasmic protein may also occur on distinct nuclear pathways.
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PMID:Highly localized tracks of human immunodeficiency virus type 1 Nef in the nucleus of cells of a human CD4+ T-cell line. 826 44


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