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

We have investigated the molecular basis of biological differences observed among cell line-adapted isolates of the human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) and the simian immunodeficiency virus (SIV) in response to receptor binding by using a soluble form of CD4 (sCD4) as a receptor mimic. We find that sCD4 binds to the envelope glycoproteins of all of the HIV-1 isolates tested with affinities within a threefold range, whereas those of the HIV-2 and SIV isolates have relative affinities for sCD4 two- to eightfold lower than those of HIV-1. Treatment of infected cells with sCD4 induced the dissociation of gp120 from gp41 and increased the exposure of a cryptic gp41 epitope on all of the HIV-1 isolates. By contrast, neither dissociation of the outer envelope glycoprotein nor increased exposure of the transmembrane glycoprotein was observed when sCD4 bound to HIV-2- or SIV-infected cells. Moreover, immunoprecipitation with sCD4 resulted in the coprecipitation of the surface and transmembrane glycoproteins from virions of the HIV-2 and SIV isolates, whereas the surface envelope glycoprotein alone was precipitated from HIV-1. However, treatment of HIV-1-, HIV-2-, and SIV-infected cells with sCD4 did result in an increase in exposure of their V2 and V3 loops, as detected by enhanced antibody reactivity. This demonstrates that receptor binding to the outer envelope glycoprotein induces certain conformational changes which are common to all of these viruses and others which are restricted to cell line-passaged isolates of HIV-1.
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PMID:Conformational changes induced in the envelope glycoproteins of the human and simian immunodeficiency viruses by soluble receptor binding. 769 70

T cells are made tolerant only to those self-peptides that are presented in sufficient amounts by antigen-presenting cells. They ignore cryptic self-determinants, such as either those not generated by processing machinery or generated in insufficient amounts. It is anticipated that mechanisms that either change antigen processing or increase the yield of previously "invisible" peptides may be capable of inducing T cell priming and, if they are self-maintained, may sustain autoimmune diseases. Herein, we demonstrate for the first time a mechanism by which the gp120 human immunodeficiency virus-I, by downregulating plasma membrane CD4 and increasing its processing, unveils hidden CD4 epitopes, inducing an autoimmune-specific T cell response.
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PMID:HIVgp120 activates autoreactive CD4-specific T cell responses by unveiling of hidden CD4 peptides during processing. 753 32

The primary cellular receptor for the human and simian immunodeficiency viruses HIV-1, HIV-2 and SIV is the CD4 antigen (Sattentau et al. 1988; Sattentau & Weiss 1988). HIV infection of CD4+ cells is initiated by binding of the virus to the cell surface, via a high-affinity interaction between the first domain of CD4 and the HIV outer envelope glycoprotein, gp120. The use of a soluble recombinant form of CD4 (sCD4) as a receptor mimic has simplified the analysis of receptor binding and post-binding events which result in virus-cell membrane fusion. With cell-line adapted isolates of HIV-1, sCD4 binding induces conformational changes in gp120, leading to the complete dissociation of gp120 from the transmembrane glycoprotein, gp41, and exposing cryptic epitopes of gp41. Similar observations have been made with cell-anchored CD4: recruitment of CD4 molecules leads to exposure of cryptic gp41 epitopes at the fusion interface between clusters of CD4 expressing and HIV-infected cells. It has therefore been proposed that CD4 binding induces exposure of fusogenic components of gp41 which mediate virus-cell membrane coalescence, a process termed receptor-mediated activation of fusion. With the related lentiviruses HIV-2 and SIV, the CD4 induced molecular rearrangements in gp120 are more subtle, implying that there is a spectrum of responses to sCD4 binding.
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PMID:The role of CD4 in HIV binding and entry. 790 48

Characterization of biological and immunological properties of human immunodeficiency virus type 1 (HIV-1) is critical to developing effective therapies and vaccines for AIDS. With the use of a novel CD4+ T-cell line (PM-1) permissive to infection by both monocytotropic (MT) and T-cell-tropic virus types, we present a comparative analysis of the immunological properties of a prototypic primary MT isolate of HIV-1 strain JR-CSF (MT-CSF) with those of a T-cell-tropic variant (T-CSF) of the same virus, which emerged spontaneously in vitro. The parental MT-CSF infected only PM-1 cells and was markedly resistant to neutralization by sera from HIV-1-infected individuals, rabbit antiserum to recombinant MT-CSF gp120, and anti-V3 monoclonal antibodies. The T-CSF variant infected a variety of CD4+ T-cell lines, contained positively charged amino acid substitutions in the gp120 V3 region, and was highly sensitive to antibody neutralization. Neutralization and antibody staining of T-CSF-expressing cells were significantly inhibited by HIV-1 V3 peptides; in contrast, the MT strain showed only weak V3-specific binding of polyclonal and monoclonal antibodies. Exposure of PM-1 cells to a mixture of both viruses in the presence of human anti-HIV-1 neutralizing antiserum resulted in infection with only MT-CSF. These results demonstrate that although the V3 region of MT viruses is immunogenic, the target epitopes in the V3 principal neutralizing domain on the membrane form of the MT envelope appear to be cryptic or hidden from blocking antibodies.
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PMID:Cryptic nature of envelope V3 region epitopes protects primary monocytotropic human immunodeficiency virus type 1 from antibody neutralization. 805 75

Rhodococcus equi is an emerging opportunistic pathogen of human immunodeficiency virus-infected patients. Thirty-nine isolates of R. equi from immunocompromised patients with and without AIDS were analyzed for the presence of virulence plasmid DNA, expression of 15- to 17-kDa antigens, and their pathogenicities in mice. Of the human isolates, eight contained an 85-kb virulence plasmid, expressed 15- to 17-kDa antigens, and were virulent in mice. Nineteen isolates carried cryptic plasmids of various sizes, and the remaining 12 isolates did not contain any plasmids. These 31 isolates did not express virulence-associated antigens and were not virulent in mice. The results suggested that opportunistic infections in immunocompromised patients could be caused by both virulent and avirulent R. equi strains and that the pathogenesis of R. equi infection in immunocompromised patients appears to be different from that which occurs in foals.
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PMID:Virulence of Rhodococcus equi isolates from patients with and without AIDS. 815 Sep 57

vpr is an accessory gene of human immunodeficiency virus I (HIV-I). Although unnecessary for viral replication in T cell lines, growing evidence suggests that it is essential for virus replication in monocytes/macrophages and for replication in vivo. We expressed HIV-I vpr in Escherichia coli and purified Vpr by affinity chromatography. In a coprecipitation assay, the purified Vpr interacted specifically with a cellular protein designated as Vpr-interacting protein, or RIP. Mutational analysis suggested that this interaction required a domain rich in leucine/isoleucine residues and highly conserved between HIV-I and SIVmac Vprs. During transient expression in mammalian cells, HIV-I Vpr was localized in the nucleus. However, mutational analysis failed to identify in Vpr a typical nuclear localization signal rich in basic amino acid residues. Instead, Vpr nuclear localization seemed to correlate with Vpr interaction with RIP. Mutations in the C-terminal 20-amino acid region containing a cryptic nuclear localization signal did not abolish Vpr nuclear localization or interaction with RIP, whereas point mutations in the leucine/isoleucine-rich domain abolished Vpr interaction with RIP and rendered Vpr unstable during transient expression. These results suggest that RIP may be involved in Vpr function.
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PMID:Biochemical mechanism of HIV-I Vpr function. Specific interaction with a cellular protein. 819 3

We examined the genetic basis for adenosine deaminase (ADA) deficiency in seven patients with late/delayed onset of immunodeficiency, an underdiagnosed and relatively unstudied condition. Deoxyadenosine-mediated metabolic abnormalities were less severe than in the usual, early-onset disorder. Six patients were compound heterozygotes; 7 of 10 mutations found were novel, including one deletion (delta 1019-1020), three missense (Arg156 > His, Arg101 > Leu, Val177 > Met), and three splicing defects (IVS 5, 5'ss T+6 > A; IVS 10, 5'ss G+1 > A; IVS 10, 3'ss G-34 > A). Four of the mutations generated stop signals at codons 131, 321, 334, and 348; transcripts of all but the last, due to delta 1019-1020, were severely reduced. delta 1019-1020 (like delta 955-959, found in one patient and apparently recurrent) is at a short deletional hot spot. Arg156 > His, the product of which had detectable activity, was found in three patients whose second alleles were unlikely to yield active ADA. The oldest patient diagnosed was homozygous for a single base change in intron 10, which activates a cryptic splice acceptor, resulting in a protein with 100 extra amino acids. We speculate that this "macro ADA," as well as the Arg156 > His, Arg101 > Leu, Ser291 > Leu, and delta 1019-1020 products, may contribute to mild phenotype. Tissue-specific variation in splicing efficiency may also ameliorate disease severity in patients with splicing mutations.
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PMID:Novel splicing, missense, and deletion mutations in seven adenosine deaminase-deficient patients with late/delayed onset of combined immunodeficiency disease. Contribution of genotype to phenotype. 822 44

A promoter-selection vector (pKK232-8) was used to identify sequences with strong Escherichia coli promoter activity positioned near the start of the envelope-encoding genes (env) of two lentiviruses, simian immunodeficiency virus (SIV) and equine infectious anemia virus (EIAV). For EIAV, cloning the cryptic promoter sequences together with downstream sequences encoding the envelope glycoprotein (gp90) in moderate- to high-copy-number (hcn) plasmid vectors, such as pBR322 or pUC, resulted in rearrangements and point mutations in env when propagated in E. coli. To alleviate this problem, low-copy-number (lcn) cloning vectors, pLG338-30 and pLG339-SPORT, were constructed. The plasmids carry resistance markers for ampicillin (ApR) or kanamycin (KmR), the pSC101 origin of replication (ori) from plasmid pLG338 [Stoker et al., Gene 18 (1982) 335-341], and a multiple cloning site (MCS) from plasmids pIBI30 or pSPORT. Full-length env and genomic proviral sequences of EIAV were genetically stable when subcloned into these lcn vectors. Proviral sequences of an SIV clone (pBK28-SIV) that are genetically unstable in the hcn vector pUC18 were also stabilized and remained fully infectious when subcloned into the lcn vector pLG339-SPORT. These lcn vectors appear to be generally useful in stabilizing lentivirus genomic sequences for subcloning, propagation, and manipulation in E. coli, possibly as a result of reducing the level of toxic gene expression from cryptic promoter sequences.
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PMID:Lentivirus envelope sequences and proviral genomes are stabilized in Escherichia coli when cloned in low-copy-number plasmid vectors. 838 58

The splice donor and acceptor sequences for the subgenomic envelope messenger RNA of feline leukemia virus (FeLV) were determined. The splice junction was characterized for viral mRNA from a prototype subgroup A FelV and an immunodeficiency-inducing FeLV variant. Thirty-seven of 38 partial envelope cDNAs, cloned after PCR amplification from T cells infected with either virus, utilized the same splice donor and acceptor sites to generate a mRNA that would be predicted to encode envelope protein. One novel cDNA, which could also code for envelope protein, was generated from a cryptic splice acceptor 109 nucleotides downstream of the normal junction. No additional subgenomic FeLV gene products were detected using reverse transcription and polymerase chain reaction amplification of FeLV sequences from chronically infected cells.
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PMID:Nucleotide sequence of the splice junction of feline leukemia virus envelope mRNA. 839 48

Multiple RNA splicing sites exist within human immunodeficiency virus type 1 (HIV-1) genomic RNA, and these sites enable the synthesis of many mRNAs for each of several viral proteins. We evaluated the biological significance of the alternatively spliced mRNA species during productive HIV-1 infections of peripheral blood lymphocytes and human T-cell lines to determine the potential role of alternative RNA splicing in the regulation of HIV-1 replication and infection. First, we used a semiquantitative polymerase chain reaction of cDNAs that were radiolabeled for gel analysis to determine the relative abundance of the diverse array of alternatively spliced HIV-1 mRNAs. The predominant rev, tat, vpr, and env RNAs contained a minimum of noncoding sequence, but the predominant nef mRNAs were incompletely spliced and invariably included noncoding exons. Second, the effect of altered RNA processing was measured following mutagenesis of the major 5' splice donor and several cryptic, constitutive, and competing 3' splice acceptor motifs of HIV-1NL4-3. Mutations that ablated constitutive splice sites led to the activation of new cryptic sites; some of these preserved biological function. Mutations that ablated competing splice acceptor sites caused marked alterations in the pool of virus-derived mRNAs and, in some instances, in virus infectivity and/or the profile of virus proteins. The redundant RNA splicing signals in the HIV-1 genome and alternatively spliced mRNAs provides a mechanism for regulating the relative proportions of HIV-1 proteins and, in some cases, viral infectivity.
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PMID:Alternative splicing of human immunodeficiency virus type 1 mRNA modulates viral protein expression, replication, and infectivity. 841 38


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