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)

The human immunodeficiency virus type 1 (HIV-1) nef gene was originally described as a negative regulator of transcription from the viral long terminal repeat promoter. This observation has been disputed, and the function of Nef remains unclear. In vivo experiments have indicated that an intact nef gene is required for disease progression in macaques infected with simian immunodeficiency virus, suggesting a role for Nef in the pathogenesis of AIDS. We and others have previously shown that expression of Nef in cells bearing surface CD4 results in a sustained decrease in surface CD4 expression. This was demonstrated for Nef from two laboratory strains of HIV-1, Bru and SF2. Because both of these isolates were passaged in vitro prior to molecular cloning and in vitro passage can result in mutations which might alter nef gene function, we have analyzed two primary isolates of Nef for their ability to suppress cell surface CD4 expression. The nef genes of HIV-1 isolates from two patients with fewer than 200 CD4+ T cells per mm3 of blood were introduced into human and mouse T-cell lines by retrovirus-mediated gene transfer. Expression of Nef from both isolates correlated with a decrease in surface expression of both human and mouse CD4. To determine whether the ability to suppress surface CD4 expression is a general function of Nef, we also tested an artificially generated consensus nef gene derived from analysis of 54 patient isolates of HIV-1. Expression of the consensus Nef protein also correlated with decreased cell surface CD4 expression in both mouse and human T-cell lines. These results suggest that the ability to suppress cell surface CD4 expression is an intrinsic feature of HIV-1 Nef.
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PMID:Nef from primary isolates of human immunodeficiency virus type 1 suppresses surface CD4 expression in human and mouse T cells. 833 33

Dendritic cells (DC) are members of a distinct family of bone marrow-derived leukocytes. DC are potent accessory cells for a number of T cell-mediated immune responses, including autologous and allogeneic mixed leukocyte reactions, and mitogen- and antigen-stimulated lymphocyte proliferation. In the present study, DC purified from human peripheral blood were inoculated with various strains (IIIB, SF2, WMJ1, SF162, 89.6 and clone HXB2) of human immunodeficiency virus type 1 (HIV-1) displaying different patterns of cellular tropism. Viral replication was demonstrated by detection of p24 antigen (Ag) intracellularly and in culture supernatants, and by Southern and Northern blot analyses for the presence of HIV DNA and RNA, respectively, within infected cells. Cell-free and cell-associated p24 Ag levels rose substantially when DC were inoculated with strains SF162, 89.6 and clone HXB2. In contrast, p24 Ag levels rose only marginally after inoculation of DC with strains IIIB, SF2 and WMJ1. Purified DC did not express detectable membrane CD4, although CD4 mRNA was detected by reverse transcriptase PCR. The presence of anti-CD4 monoclonal antibodies failed to block infection of DC by any of the HIV strains tested, suggesting the existence of a CD4-independent alternative pathway of viral entry. The possibility that DC serve as a reservoir for HIV-1 must be considered.
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PMID:CD4-independent infection of human peripheral blood dendritic cells with isolates of human immunodeficiency virus type 1. 833 19

We investigated how amino acid changes within and outside the V3 loop of the envelope glycoprotein of human immunodeficiency virus type 1 influence the infectivity, host range, and syncytium-forming ability of the virus. Our studies show that on the genomic backgrounds of the human immunodeficiency virus type 1 strains SF2 and SF13, a reciprocal exchange of full-loop sequences does not alter the syncytium-forming ability of the viruses, indicating that a determinant(s) for this biological property maps outside the loop. However, specific amino acid substitutions, both within and outside the V3 loop, resulted in loss of infectivity, host range, and syncytium-forming potential of the virus. Furthermore, it appears that a functional interaction of the V3 loop with regions in the C2 domain of envelope gp120 plays a role in determining these biological properties. Structural studies of mutant glycoproteins show that the mutations introduced affect the proper association of gp120 with the transmembrane glycoprotein gp41. Our results suggest that mutations that alter the structure of the V3 loop can affect the overall conformation of gp120 and that, reciprocally, the structure of the V3 loop is influenced by the conformation of other regions of gp120. Since the changes in the replicative potential, host range, and fusogenic ability of the mutant viruses correlate well with the changes in gp120 conformation, as monitored by the association of gp120 with gp41, our results support a close relationship between envelope gp120 structural conformation and the biological phenotype of the virus.
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PMID:Evidence that the structural conformation of envelope gp120 affects human immunodeficiency virus type 1 infectivity, host range, and syncytium-forming ability. 835 Apr 16

The functional ability of the human monoclonal antibody (HMab) F105 to neutralize commonly available laboratory strains and a selection of primary isolates of human immunodeficiency virus (HIV)-1 was studied. F105 is representative of a class of human antibodies that react with conformational epitopes within the discontinuous CD4 binding site on HIV-1 envelope glycoprotein gp120. F105 binds with relatively similar affinities to native antigen expressed on the surfaces of cells infected with each of five laboratory isolates tested (IIIB, SF2, MN, RF, and CC) and neutralizes SF2, IIIB, and MN with concentrations of antibody ranging from 140 ng to 10 micrograms/ml. Nonetheless, neutralization by F105 alone of RF and CC is poor at modest antibody concentrations despite high affinity binding to surface gp120 on infected cells. Neutralization of HIV-1 strains by F105 is unaffected by normal sera and cooperativity is observed with serum samples from HIV-1 infected patients. Of significance, neutralization of RF and MN by F105 is enhanced by some HIV-seropositive sera at low concentrations. F105 also neutralized 30% of HIV-1 primary isolates in lymphocyte cultures. Although it is unclear how relevant in vitro studies will be to in vivo events, these data allow comparison of F105 with other HMabs to the CD4 binding site and V3 loop and provide an in vitro reference for in vivo activity. These studies demonstrate that antibody interactions among different classes of antibodies may be important in in vivo neutralization of HIV-1.
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PMID:Neutralization of HIV-1 by F105, a human monoclonal antibody to the CD4 binding site of gp120. 841 77

To evaluate the ability of murine anti-human immunodeficiency virus type 1 (HIV-1) IIIB env cytotoxic T lymphocytes (CTL) to recognize and lyse HIV-1-infected cells, we have constructed a human cell line (Hu/Dd) expressing both the CD4 receptor and the murine H-2Dd major histocompatibility complex (MHC) class I protein. This cell line can be productively infected with HIV-1 and can also function as a target for murine CD8+, class I MHC-restricted CTL directed against the envelope glycoprotein of HIV-1 IIIB. The ability of BALB/c anti-HIV-1 IIIB env CTL to specifically recognize and lyse Hu/Dd target cells infected with divergent HIV-1 strains was tested by using both prototypic and clinical HIV-1 strains. CTL generated by immunization of mice with syngeneic cells expressing either the native or V3 loop-deleted (delta V3) envelope glycoprotein from HIV-1 IIIB were able to recognize and specifically lyse Hu/Dd target cells infected with the HIV-1 prototypic isolates IIIB, MN, WMJ II, SF2, and CC as well as several HIV-1 clinical isolates. These results demonstrate that CTL determinants for HIV-1 env exist outside the hypervariable V3 region, anti-HIV-1 IIIB env CTL appear to recognize common determinants on diverse HIV-1 strains, and classification of HIV-1 strains based on neutralizing antibody reactivities does not appear to correspond to CTL recognition and lysis. The results suggest that the cell-mediated components of the immune system may have a broader recognition of divergent HIV-1 strains than do the humoral components.
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PMID:Cross-reactive lysis of human targets infected with prototypic and clinical human immunodeficiency virus type 1 (HIV-1) strains by murine anti-HIV-1 IIIB env-specific cytotoxic T lymphocytes. 849 58

To test whether the protective effects of attenuated simian immunodeficiency virus vaccines in macaques were applicable to the human immunodeficiency virus type 1 (HIV-1)-chimpanzee system, two groups of animals, previously infected with HIV-1(IIIB) or HIV-1(SF2) were each challenged with a heterologous clade B virus, HIV-1(DH12). Following challenge, the parameters measured included virus isolation (from plasma, peripheral blood mononuclear cells, and lymph node tissue); quantitative DNA PCR using primers capable of distinguishing HIV-1(IIIB), HIV-1(SF2), and HIV-1(DH12) from one another; and serologic assays to monitor changes in binding and neutralizing antibodies. In contrast to an HIV-1-naive chimpanzee that rapidly became infected following the inoculation of HIV-1(DH12), the two chimpanzees previously infected with HIV-1(IIIB) resisted repeated and escalating inoculations of HIV-1(DH12), as monitored by virus isolation and PCR. The two animals previously infected with HIV-1(SF2) became infected with HIV-1(DH12) but in contrast to the case with the HIV-1-naive chimpanzee, no cell-free viral RNA was detected in the plasma by the branched DNA procedure and levels of peripheral blood mononuclear cell-associated viral DNA were reduced 35- to 50-fold.
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PMID:Resistance of previously infected chimpanzees to successive challenges with a heterologous intraclade B strain of human immunodeficiency virus type 1. 867 59

The nef genes of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) encode a 27- to 34-kDa myristoylated protein which induces downregulation of CD4 surface levels and enhances virus infectivity. In adult macaques, Nef has been implicated in pathogenesis and disease progression. Both HIV-1 SF2 Nef and SIVmac239 Nef have been shown to associate with a cellular serine/threonine kinase. We tested five functional Nef isolates to examine whether this kinase association is a property conserved among different isolates. HIV-1 SF2 and 248 and SIVmac239 Nef proteins were found associated with the kinase. HIV-1 NL4-3 and 233 Nef proteins were found weakly associated or not associated with the kinase. All five Nef isolates efficiently downregulated CD4 cell surface expression, suggesting that the association with this cellular kinase is not required for Nef to downregulate CD4. Comparison of the SF2 and NL4-3 isolates shows a differential ability of Nef to enhance infectivity that suggests a possible correlation between kinase association and enhancement of infectivity.
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PMID:The association of Nef with a cellular serine/threonine kinase and its enhancement of infectivity are viral isolate dependent. 870 88

The ability of antibody induced by MN and IIIB recombinant gp120 (rgp120) human immunodeficiency virus type 1 (HIV-1) vaccines the bind to oligomeric native and monomeric recombinant HIV-1 envelope glycoproteins (rgp 120) was measured in 25 uninfected, healthy adult volunteers. A major focus was to evaluate the effect of simultaneous and sequential immunization with vaccines representing different strains of HIV-1 on the ability to broaden cross-reactivity of antibodies against these and other HIV-1 strains. A flow cytometric indirect immunofluorescence assay (FIFA) to detect vaccine-induced antibody to envelope glycoprotein expressed by infected and rgp120-coated target cells was used, MN rgp120 HIV-1 vaccine given alone and coadministered with IIIB rgp120 HIV-1 vaccine elicited antibody which bound to cells infected with HIV-1MN, HIV-IIIB, HIV-1RF, and HIV-1-SF2. The presence of envelope glycoprotein-binding antibody detected by FIFA correlated to a moderate degree with functional antibody against HIV-1MN and HIV-IIIB. Priming immunization with IIIB rgp120 HIV-1 vaccine followed by booster injections of MN rgp120 HIV-1 vaccine resulted in increased cross-reactive antibody binding to these and heterologous clade B HIV-1 strains infecting cells. MN rgp120 HIV-1 vaccine given alone was better able to induce cross-reactive antibody to cells infected with heterologous HIV-1 laboratory strains than was IIIB rgp120 HIV-1 vaccine given alone. The vaccines induced binding antibody to rgp120 possessing the amino acid sequence of a clade E HIV-1 strain as measured by enzyme-linked immunosorbent assay. Levels of antibody binding to cells infected with clade B HIV-1 and cells coated with monomeric rgp120 were greater than that induced by HIV-1IIIB-based gp160 vaccines in previous studies.
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PMID:Antibody to native human immunodeficiency virus type 1 envelope glycoproteins induced by IIIB and MN recombinant gp120 vaccines. The NIAID AIDS Vaccine Evaluation Group. 880

The role of the CDR-3-like loop of the first domain of the CD4 molecule in infection by the human immunodeficiency virus type 1 (HIV-1) is controversial. In an attempt to determine whether the strong negative charge in the CDR-3-like loop influences HIV-1 infection we have substituted by mutagenesis negative for positively charged residues at position 87/88 and 91/92. These mutations were shown to have no obvious effect on CD4 conformation outside of the CDR-3-like loop. Infection of cells expressing the E87K/D88K substitution mutant resulted in a selective reduction in infectivity for certain HIV-1 viruses compared to cells expressing wile-type CD4. Viruses Hx10, HxB2, and MN were 4- to 13-fold less efficient at infecting the E87K/D88K mutant, whereas SF2, RF, and NDK yielded an efficiency of infection similar to, or slightly greater than, that of the wild type. To investigate the step at which infectivity was selectively reduced, we compared early events in the life cycles of Hx10 and SF2 viruses using PCR entry and gp120-binding assays. Both gp120 binding and virus entry were reduced for Hx10 on the mutant CD4-expressing cells as compared to wild-type CD4-expressing cells, whereas no difference was seen in either assay with SF2. Although relatively small in magnitude, the contribution of the CDR-3-like loop to the overall CD4-gp120 interaction may serve to modify the binding and entry of certain virus isolates.
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PMID:Selective effects of electrostatic changes in the CD4 CDR-3-like loop on infection by different human immunodeficiency virus type 1 isolates. 882 16

The effect of maternally transferred monoclonal antibody (MAb) on the offspring antibody response to rgp120SF2 was examined in a murine model. Two MAbs were studied: MAb 83.1, which recognizes a determinant in the V3 loop of gp120 from human immunodeficiency virus-1 (HIV-1) SF2, and MAb 26.2D3, which recognizes a conserved N-terminal region of gp120 from HIV-1SF2. Offspring were immunized at 18-21 days of age with 100 micrograms of rgp120SF2 in complete Freund's adjuvant. Offspring immunized in the presence of preexisting MAb 83.1 but not MAb 26.2D3 demonstrated inhibition of the IgG anti-V3 response. The total IgG anti-rgp120SF2 response was not affected by preexisting MAb. Since newborns at risk for HIV may be immunized in the presence of maternal or administered anti-HIV antibody, alternative strategies may be required to circumvent inhibition of the infant's epitope-specific response to HIV immunization by preexisting antibody.
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PMID:Maternal monoclonal antibody to the V3 loop alters specificity of the response to a human immunodeficiency virus vaccine. 884 32


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