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

A full-length infectious molecular clone was derived from the noncytopathic human immunodeficiency virus type 2 UC1 strain (HIV-2UC1) that was originally recoverd from an individual from the Ivory Coast. Like the parental isolate, the molecularly cloned virus (HIV-2UC1mc or UC1 mc) demonstrates a reduced ability to induce syncytium formation, to kill cells, and to down-modulate the cell surface CD4 receptor in infected cells. Phylogenetic analysis of the DNA sequence of UC1mc revealed that it is the first full-length infectious molecular clone in the second HIV-2 subgroup previously identified by partial sequence analysis of the HIV-2D205 and HIV-2GH-2 strains. These highly divergent HIV-2 strains appear to be genetically equidistant from other HIV-2 and simian immunodeficiency virus SIVmac/sm strains. UC1mc is unlike any other HIV-2 or SIVmac/sm strain in that it lacks a cysteine residue at the proposed signal peptide cleavage site in Env. However, site-directed mutagenesis experiments indicate that this missing cysteine is not alone important in the noncytopathic phenotype of UC1mc. Like other HIV-2 and SIV strains, the UC1mc Env transmembrane protein (gp43) is mutated to a truncated form (gp34) after passage in certain T-cell lines. The UC1 molecular clone should be helpful in determining the genetic sequences associated with HIV-2 cytopathicity.
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PMID:Distinguishing features of an infectious molecular clone of the highly divergent and noncytopathic human immunodeficiency virus type 2 UC1 strain. 841 35

A new human retrovirus, HIV-2, serologically distinct from human immunodeficiency virus type 1 (HIV-1), was first reported in 1985 and isolated in 1986 from 2 AIDS patients from Guinea-Bissau and Cape Verde Islands. Findings related to the characterization of HIV-2 antigenic and immunogenic sites that stimulate strain and type-cross-reactive immunity are illustrated; data from preliminary studies of simian immunodeficiency virus (SIV) are presented; and epidemiological and biological characteristics of HIV-2 infection are also reviewed. Prevention of HIV-2 and SIVsm infection has been achieved in cynomolgus macaques by passive transfer of an anti-SIVsm serum pool with high antibody titres. The identification of antibody-binding regions of HIV is critical for vaccine development studies. The presence of highly immunogenic domains in the extracellular proteins of HIV-2 has also been demonstrated by Western blot analysis using bacterially expressed contiguous segments representing the HIV-2 envelope products. Over 95% of HIV-2 positive sera from Senegal reacted with these protein segments. The antibody-reactive peptide scanning method defined 8 distinct antibody-binding sites in the transmembrane protein gp36 of the HIV-2 strain ROD in addition to the highly immuno-dominant site present at the amino terminus of gp36. Antibody reactions of SIVm-infected macaque sera against selected SIVm envelope peptides were very similar to those of HIV-2 and HIV-1-infected human sera to the corresponding linear antigenic sites, indicating the existence of immunological parallelism between human and simian lentiviruses. HIV-2-induced immunity in inoculated macaques has been shown to protect against SIV-associated disease, indicating that the 2 viruses share group-specific protective immunity. In a study of human sera, the occurrence of an intertype cross-reacting V3-region-specific activity correlated with the presence of cross-neutralizing activity in sera. These findings indicate that the V3 region may be an important neutralizing site not only in HIV-1 but also in HIV-2.
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PMID:Antigenic and immunogenic sites of HIV-2 glycoproteins. 845 54

Human immunodeficiency virus type 2 (HIV-2) is more closely related to certain simian immunodeficiency viruses than to HIV-1. The HIV-1 and HIV-2 envelope (env) glycoproteins share only approximately 40% amino acid (aa) sequence homology. Additionally, HIV-1 and HIV-2 seem to differ in pathogenicity and in host range. In order to identify the functional domains of the HIV-2 env glycoprotein, e.g., the CD4 binding region, the membrane anchor, and the fusion site, and to compare them to equivalent sites of HIV-1, a set of recombinant vaccinia viruses (VV) was constructed expressing N-terminal overlapping env proteins of 863 (full-length gp160), 708, 534 (full-length gp120), 438, 332, 198, and 488 aa (internal deletion of aa 333-707). Upon infection, only env proteins comprising the amino-terminal half of the transmembrane protein were expressed on the cell surface. Such VV constructs also induced syncytia in CD4-positive cells. The syncytia were smaller when the cytoplasmic domain of the transmembrane protein was removed. The CD4 binding site of HIV-2 was located between the carboxy terminus of gp120 (aa 512) and aa 438. Thus the amino-terminal half of the transmembrane protein of HIV-2 is sufficient for cell surface localization of the env protein and syncytia induction. These properties are shared with the HIV-1 env protein and demonstrate a functional conservation among HIV-1 and HIV-2 despite their genetic and phenotypic heterogeneity.
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PMID:Mapping of the human immunodeficiency virus type 2 envelope glycoprotein CD4 binding region and fusion domain with truncated proteins expressed by recombinant vaccinia viruses. 848 Apr 26

T-lymphocytes enter the brain in viral encephalitides. The monoclonal antibodies UCHL1 and Leu22 are widely used to identify these cells; however, both antibodies cross-react with peripheral blood monocytes, cells ontologically related to brain macrophages and microglia. This study examines the nature of UCHL1- and Leu22-positive cells in HIV-1 encephalitis, and investigates whether they carry the gp41 epitope of HIV-1. Formalin-fixed sections of brain from eight AIDS patients were double-stained using combinations of UCHL1 and Leu22 antibodies with the lectin Ricinus communis agglutinin (RCA), a lectin that binds to microglia, macrophages, and multinucleated giant cells (MNGC), or antibody to the gp41 transmembrane protein of HIV-1 and UCHL1. Some sections were also stained with the OPD4 antibody to helper/inducer T-cells. Small round cells were single-stained for UCHL1 and Leu22 in all cases. A few cells having morphologic characteristics of microglia, macrophages, and MNGC were observed using double stains employing UCHL1 or Leu22 and RCA, or UCHL1 or Leu22 and anti-gp41. Small round cells positive for both UCHL1 or Leu22 and gp41 could represent either macrophages or lymphocytes. The presence of small round cells positive only for UCHL1 or Leu22 in double-stained sections strongly suggests that T-cells are present in the brain in HIV encephalitis. Only a few of these cells were positive with OPD4 antibody for T-helper cells. Inability to demonstrate unequivocally HIV-1-infected T-cells suggests that microglia and macrophages, not T-cells, are the more important reservoirs of retrovirus in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immunocytochemical identification of T-cells in HIV-1 encephalitis: implications for pathogenesis of CNS disease. 848 86

A point mutation (Ala-589 to Thr) in the transmembrane protein of the human immunodeficiency virus type 1 (HIV-1) has been shown to decrease the sensitivity of the virus to the neutralizing effect of human HIV-1 specific antibodies [(1990) J. Virol. 64, 3240-3248]. Here 17-residue peptides with the parental and mutant sequences were compared: the parental peptide bound antibodies of sera from HIV-1 infected persons more frequently and with higher affinity than the mutant peptide. However, according to circular dichroism (CD), NMR spectroscopy and molecular modelling the peptides have indistinguishable backbone conformations under a variety of experimental conditions. These techniques showed for both peptides that no ordered helix was present in water solution. However, for both peptides in alcohol-water solutions approximately 60% alpha-helix could be induced. The three-dimensional structures of these peptides provide a basis for understanding how this mutation in the transmembrane protein may affect the interaction with both the outer envelope glycoprotein and with antibodies.
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PMID:Three-dimensional structure and antigenicity of transmembrane-protein peptides of the human immunodeficiency virus type 1. Effects of a neutralization-escape substitution. 849 50

We have investigated how truncation of the cytoplasmic domain of the transmembrane (TM) glycoprotein of simian immunodeficiency virus (SIV) modulates the host range of this virus. Termination codons were introduced into the env gene of SIVmac239 which resulted in the truncation of the transmembrane protein from a wild-type 354 amino acids (TM354) to 207 (TM207) and 193 (TM193) amino acids. Expression of the wild-type and mutant env genes from a simian virus 40-based vector resulted in normal biosynthesis and processing of the glycoproteins to gp130 and gp41 or the truncated TM proteins (gp28 and gp27). When expressed on the surface of COS-1 cells, all three glycoproteins mediated fusion of both CEMX174 and HUT78 cells. Virions containing the wild-type and mutant glycoproteins were capable of efficient replication in macaque peripheral blood lymphocytes and CEMX174 cells; in contrast, only virions that contained TM207 were capable of rapid infection of HUT78 cells. Both truncated glycoproteins were capable of efficiently mediating infection of both CEMX174 and HUT78 cells by an env-deficient human immunodeficiency virus. The wild-type SIV glycoprotein, however, was unable to mediate human immunodeficiency virus infection of HUT78 cells when assayed with this system. An analysis of the protein composition of SIV released from infected CEMX174 cells showed that the mutant virions contained significantly higher levels of glycoprotein compared with the wild type. These results demonstrate that truncation of the SIV cytoplasmic domain removes a block at the level of glycoprotein-mediated virus entry into HUT78 cells and points to a role for glycoprotein density in determining virus tropism.
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PMID:Truncations of the simian immunodeficiency virus transmembrane protein confer expanded virus host range by removing a block to virus entry into cells. 849 44

The N-terminal region of the envelope (env) transmembrane protein of human immunodeficiency virus type 1 (HIV-1) has a leucine zipper-like motif. This highly conserved zipper motif, which consists of a heptad repeat of leucine or isoleucine residues, has been suggested to play a role in HIV-1 env glycoprotein oligomerization. This hypothesis was tested by replacing the highly conserved leucine or isoleucine residues in the zipper motif with a strong alpha-helix breaker, proline. We report here that such substitutions did not abolish the ability of env protein to form oligomers, indicating that this highly conserved zipper motif does not have a crucial role in env protein oligomerization. However, the mutant viruses all showed impaired infectivity, suggesting that this conserved zipper motif can have an important role in the virus life cycle.
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PMID:Mutational analysis of the leucine zipper-like motif of the human immunodeficiency virus type 1 envelope transmembrane glycoprotein. 849 69

We selected HIV-1-LAI variants with the ability to induce syncytium formation of C8166 cells in the presence of a monoclonal antibody (MAb), 5A8, to domain 2 of CD4. Five biologically cloned variants with at least 60-fold greater resistance than wild type to 5A8-mediated inhibition of syncytium formation were obtained. The variants exhibited reduced relative sensitivity to inhibition of syncytium formation and virus infection, not only by the selecting anti-domain 2 MAb, but also by MAbs to domains 1 and 3 of CD4. By contrast, the sensitivity of these variants to neutralization by soluble CD4 and bivalent CD4-IgG was greater than for the parental clone. The affinities of soluble CD4 for Env protein, in either solubilized or membrane-anchored form, did not differ significantly between the variants and LAI. Analyses of sCD4-induced exposure of the transmembrane protein at 4 and 37 degrees C suggested, however, that the variants had acquired an increased susceptibility to the triggering of conformational changes in their Env oligomers at 37 degrees C. This may represent a mechanism of both the increased resistance to the CD4 MAbs and the enhanced sensitivity to soluble CD4.
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PMID:Altered CD4 interactions of HIV type 1 LAI variants selected for the capacity to induce membrane fusion in the presence of a monoclonal antibody to domain 2 of CD4. 882 17

In enveloped viruses, post-translational proteolytic activation is a critical step for the fusion activity and thus for the infectivity of the virus. In addition to the membrane receptors for the viruses, proteolytic activation is indispensable for effective virus spread in the infected host and it is a prime determinant for pathogenicity. Here we described the host cellular processing proteases, tryptase Clara and tryptase TL2, which proteolytically activate the infectivity of influenza A and Sendai viruses in the respiratory tract and HIV-1 in human CD4+ T cells, respectively. A novel trypsin-like protease, designated tryptase Clara, was purified from rat lung. The enzyme is localized in Clara cells of the bronchial epithelium and is secreted into the airway lumen. The enzyme specifically recognizes the consensus cleavage motif Gln(Glu)-X-Arg of influenza A and Sendai viruses and proteolytically activates the envelope fusion glycoproteins of the progeny viruses extracellularly in the airway lumen. Human mucus protease inhibitor and pulmonary surfactant in airway fluid inhibited the proteolytic activation of these viruses and also suppressed multiple cycles of viral replication in vitro. These results suggest that an imbalance between the amount of tryptase Clara and that of endogenous inhibitors in airway fluid is a prime determinant for pneumopathogenicity of the viruses. Therefore supplementing an endogenous inhibitor at therapeutic doses may protect against virus infection. In HIV-1 infection, binding of the gp120 envelope glycoprotein to the CD4 receptor is not sufficient in itself to allow virus entry, and an additional component(s) in the membrane is required for cell infection as a cofactor. We isolated a serine protease named tryptase TL2, in the membrane of CD4+ lymphocytes, which specifically binds to the V3 loop of HIV-1 gp120 as a cofactor. After binding, tryptase TL2 proteolytically processed gp120 into two protein species of 70 and 50 kDa and the cleavage was suppressed by a neutralizing antibody against the V3 loop. The amino acids that constitute the cleavage sites in the V3 loop of almost all HIV isolates are variable, but they are restricted to those which are susceptible to chymotryptic and/or tryptic enzyme. The multi-substrate specificity of tryptase TL2, which has tryptic and chymotryptic specificities, may correspond tot he variability of the V3 loop. The selective cleavage of the V3 loop by tryptase TL2 may lead to a conformational change of gp120, resulting in the dissociation of gp120 from gp41, exposing the fusogenic domain of the transmembrane protein gp41 following virus-host cell fusion.
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PMID:Cellular proteases involved in the pathogenicity of enveloped animal viruses, human immunodeficiency virus, influenza virus A and Sendai virus. 886 54

A mutant human immunodeficiency virus (HIV-1) provirus encoding an envelope (Env) protein with a truncated transmembrane protein cytoplasmic domain was defective for replication. Coexpression of the mutant with a wild-type (wt) HIV-1 provirus potently inhibited the production of infectious virus. The maximum inhibitory effect was reached when the ratio of mutant to wt proviral DNA was 2:1. This transdominant defect in infectivity conferred by the mutant Env did not appear to involve the late steps of virus replication, since the synthesis, precursor processing, and intracellular transport of the Env proteins were not blocked; nor did it prevent the incorporation of the envelope proteins into virions or the subsequent release of the virus. Although the mutant Env protein still retained syncytia-forming ability, the truncated protein was unable to mediate cell-to-cell transmission of the virus. Moreover, coexpression with the mutant effectively inhibited the ability of the wt Env to mediate cell-to-cell transmission. The mutant Env protein formed a complex with the wt protein when they were coexpressed, producing heterooligomeric structures which appeared to be severely defective in an early, post-CD4 binding step of the virus life cycle despite the inclusion of wt Env in the complexes.
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PMID:Characterization of an envelope mutant of HIV-1 that interferes with viral infectivity. 895 46

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