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)

Polyomavirus BK (BKV) is a serious problem for immunocompromised patients, where latent virus can enter into the lytic cycle causing cytolytic destruction of host cells. BKV infects >80% of the population worldwide during childhood and then remains in a latent state in the kidney. In the context of immunosuppression in kidney transplant patients, reactivation of the viral early promoter (BKV(E)) results in production of T antigen, enabling virus replication and transition from latency to the lytic phase, causing polyomavirus-associated nephropathy. Reactivation of BKV can also cause complications such as nephritis, atypical retinitis and haemorrhagic cystitis in AIDS patients. Here, the effects of human immunodeficiency virus type 1 (HIV-1) proteins Tat and Vpr on BKV transcription were investigated and it was demonstrated that Tat dramatically stimulated BKV(E). Site-directed mutagenesis analysis of potential Tat-responsive transcriptional motifs complemented by an electrophoretic mobility shift assay (EMSA) showed that Tat activated BKV(E) by inducing binding of the NF-kappaB p65 subunit to a kappaB motif near the 3' end of BKV(E). In addition, a sequence within the 5' UTR of BKV(E) transcripts (BKV(E)-TAR) was identified that is identical to the HIV-1 transactivation response (TAR) element. The BKV(E)-TAR sequence bound TAT in RNA EMSA assays and deletion of the BKV(E)-TAR sequence eliminated Tat transactivation of BKV(E) transcription. Thus, Tat positively affected BKV(E) transcription by a dual mechanism and this may be important in diseases involving BKV reactivation in AIDS patients.
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PMID:Activation of early gene transcription in polyomavirus BK by human immunodeficiency virus type 1 Tat. 1669 Sep 19

The 5' untranslated region (5'UTR) of lentiviral genomic RNA is highly structured, and is the site of multiple RNA-RNA and RNA-protein interactions throughout the viral life cycle. The 5'UTR plays a critical role during transcription, translational regulation, genome dimerization, reverse transcription priming and encapsidation. The 5'UTR structures of human lentiviruses have been extensively studied, yet the respective role and conformation of each domain is still controversial. To gain insight into the structure-function relationship of lentiviral 5'UTRs, we modelled the RNA structure of the feline immunodeficiency virus (FIV), a virus that is evolutionarily distant from the primate viruses. Through combined chemical and enzymatic structure probing and a thorough phylogenetic study, we establish a model for the secondary structure of the 5'UTR and Gag coding region. This work highlights properties common to all lentiviruses, like the primer binding site structure and the presence of a stable stem-loop at the 5' extremity. We find that FIV has also evolved specific features, including a long stem loop overlapping the end of the 5'UTR and the beginning of the coding region. In addition, we observed footprints of Gag protein on each side of the initiation codon, this sheds light on the role of the sequences required for encapsidation.
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PMID:RNA secondary structure of the feline immunodeficiency virus 5'UTR and Gag coding region. 1862 13

The full-length genomic RNA of lentiviruses can be translated to produce proteins and incorporated as genomic RNA in the viral particle. Interestingly, both functions are driven by the genomic 5'-UTR (5'-untranslated region), which harbours structural RNA motifs for the replication cycle of the virus. Recent work has shown that this RNA architecture also functions as an IRES (internal ribosome entry site) in HIV-1 and -2, and in SIV (simian immunodeficiency virus). In addition, the IRES extends to the gag coding region for all these viruses and this leads to the synthesis of shorter isoforms of the Gag polyprotein from downstream initiation codons. In the present study, we have investigated how different members of the lentivirus family (namely HIV-1 and -2, and SIV) can initiate protein synthesis by distinct mechanisms. For this, we have used the competitive reticulocyte lysate that we have recently described. Our results show that HIV-1 is able to drive the synthesis of the Gag polyprotein both by a classical cap-dependent mechanism and an IRES, whereas HIV-2 and SIV appear to use exclusively an IRES mechanism.
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PMID:Lentiviral RNAs can use different mechanisms for translation initiation. 1863 Nov 41

Mutations in STAT3 (signal transducer and activator of transcription 3) have recently been found to cause the hyper-IgE syndrome (HIES) - a rare immunodeficiency syndrome including complex somatic features. We now tested whether STAT3 mutations or single-nucleotide polymorphisms (SNPs) within STAT3 may be responsible for increased IgE levels in asthmatic children. We genotyped DNA samples from 918 individuals of 217 core families by MALDI-TOF mass spectrometry. SNPs were selected from previous reports, by functional relevance and haplotype-tagging capacity. In 24 assays, including the recently described HIES mutations, no variant was detected. In another 27 SNP assays, there was no association of any STAT3 variant with asthma, allergic rhinitis or eczema. In addition, neither total and specific IgE and eosinophil count nor any lung function parameter showed any significant association. When combining high eosinophil counts and high total IgE levels to an HIES-like trait, four SNPs in the 5'-UTR of STAT3 were slightly overtransmitted. A minor fraction of asthmatic children may possibly have an alternate STAT3 promoter architecture influencing joined IgE and eosinophil upregulation. While an overall effect of STAT3 mutations on serum IgE is unlikely in asthma children.
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PMID:STAT3 single-nucleotide polymorphisms and STAT3 mutations associated with hyper-IgE syndrome are not responsible for increased serum IgE serum levels in asthma families. 1884 Nov 65

Feline immunodeficiency virus (FIV) is a lentivirus that infects cats and is related to human immunodeficiency virus (HIV). Although it is a common worldwide infection, and has potential uses as a human gene therapy vector and as a nonprimate model for HIV infection, little detail is known of the viral life cycle. Previous experiments have shown that its packaging signal includes two or more regions within the first 511 nucleotides of the genomic RNA. We have undertaken a secondary structural analysis of this RNA by minimal free-energy structural prediction, biochemical mapping, and phylogenetic analysis, and show that it contains five conserved stem-loops and a conserved long-range interaction between heptanucleotide sequences 5'-CCCUGUC-3' in R/U5 and 5'-GACAGGG-3' in gag. This long-range interaction is similar to that seen in primate lentiviruses where it is thought to be functionally important. Along with strains that infect domestic cats, this heptanucleotide interaction can also occur in species-specific FIV strains that infect pumas, lions, and Pallas' cats where the heptanucleotide sequences involved vary. We have analyzed spliced and genomic FIV RNAs and see little structural change or sequence conservation within single-stranded regions of the 5' UTR that are important for viral packaging, suggesting that FIV may employ a cotranslational packaging mechanism.
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PMID:The secondary structure of the 5' end of the FIV genome reveals a long-range interaction between R/U5 and gag sequences, and a large, stable stem-loop. 1897 79

The 5'-untranslated region (5'-UTR) of the human immunodeficiency virus type-1 (HIV-1) genome regulates multiple RNA-dependent functions during viral replication and has been proposed to adopt multiple secondary structures. Recent phylogenetic studies identified base pair complementarity between residues of the unique 5' element and those near the gag start codon (gag(AUG)) that is conserved among evolutionarily distant retroviruses, suggesting a potential long-range RNA-RNA interaction. However, nucleotide accessibility studies led to conflicting conclusions about the presence of such interactions in virions and in infected cells. Here, we show that an 11-nucleotide oligo-RNA spanning residues 105-115 of the 5'-UTR (U5) readily binds to oligoribonucleotides containing the gag start codon (AUG), disrupting a pre-existing stem loop and forming a heteroduplex stabilized by 11 Watson-Crick base pairs (K(d) = 0.47 +/- 0.16 microM). Addition of the HIV-1 nucleocapsid protein (NC), the trans-acting viral factor required for genome packaging, disrupts the heteroduplex by binding tightly to U5 (K(d) = 122 +/- 10 nM). The structure of the NC:U5 complex, determined by NMR, exhibits features similar to those observed in NC complexes with HIV-1 stem loop RNAs, including the insertion of guanosine nucleobases to hydrophobic clefts on the surface of the zinc fingers and a 3'-to-5' orientation of the RNA relative to protein. Our findings indicate that the previously proposed long-range U5-gag(AUG) interaction is feasible and suggest a potential NC-dependent mechanism for modulating the structure of the 5'-UTR.
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PMID:Potential intra- and intermolecular interactions involving the unique-5' region of the HIV-1 5'-UTR. 1900 24

Potent antiviral RNAi can be induced by intracellular expression of short hairpin RNAs (shRNAs) and artificial microRNAs (miRNAs). Expression of shRNA and miRNA results in target mRNA degradation (perfect base pairing) or translational repression (partial base pairing). Although efficient inhibition can be obtained, error-prone viruses such as human immunodeficiency virus type 1 (HIV-1) can escape from RNAi-mediated inhibition by mutating the target sequence. Recently, artificial miRNAs have been shown to be potent RNAi inducers due to their efficient processing by the RNAi machinery. Furthermore, miRNAs may be more proficient in suppressing imperfect targets than shRNAs. In this study, we tested the knockdown efficiency of miRNAs and shRNAs against wild-type and RNAi-escape HIV-1 variants with one or two mutations in the target sequence. ShRNAs and miRNAs can significantly inhibit the production of HIV-1 variants with mutated target sequences in the open reading frame. More pronounced mutation-tolerance was measured for targets in the 3' untranslated region (3' UTR). Partially complementary sequences within the 3' UTR of the HIV-1 RNA genome efficiently act as target sites for miRNAs and shRNAs. These data suggest that targeting imperfect target sites by antiviral miRNAs or shRNAs provides an alternative RNAi approach for inhibition of pathogenic viruses.
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PMID:RNAi-mediated inhibition of HIV-1 by targeting partially complementary viral sequences. 1965 54

Human leukocyte antigen (HLA)-G is a powerful modulator of the immune response. The aim of this study was to investigate whether soluble HLA-G (sHLA-G) expression is associated with human immunodeficiency virus type 1 (HIV-1) infection. HIV-1-infected female commercial sex workers (CSWs) had significantly lower levels of plasma sHLA-G compared with those in both the HIV-1-uninfected CSW and the non-CSW groups. The presence of HLA-G*010101, HLA-G*010404 alleles, and the 3'-untranslated region (3'UTR) genetic variant at position 3,952 were all significantly associated with lower plasma sHLA-G levels in the HIV-1-infected CSWs, whereas the HLA-G 3'UTR 14-bp sequence insertion was also associated with lower plasma sHLA-G levels in the overall population. When adjustment was made for all significant variables, the reduced expression of sHLA-G in the plasma remained significantly associated with HIV-1 infection and the HLA-G 3'UTR 14-bp insertion homozygote genotype. This study demonstrates that low levels of plasma sHLA-G are associated with HIV-1 infection.
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PMID:Blood soluble human leukocyte antigen G levels are associated with human immunodeficiency virus type 1 infection in Beninese commercial sex workers. 1991 87

As a retrovirus, the human immunodeficiency virus (HIV-1) packages two copies of the RNA genome as a dimer in the infectious virion. Dimerization is initiated at the dimer initiation site (DIS) which encompasses stem-loop 1 (SL1) in the 5'-UTR of the genome. Study of genomic dimerization has been facilitated by the discovery that short RNA fragments containing SL1 can dimerize spontaneously without any protein factors. On the basis of the palindromic nature of SL1, a kissing loop model has been proposed. First, a metastable kissing dimer is formed via standard Watson-Crick base pairs and then converted into a more stable extended dimer by the viral nucleocapsid protein (NCp7). This dimer maturation in vitro is believed to mimic initial steps in the RNA maturation in vivo, which is correlated with viral infectivity. We previously discovered a small molecule activator, Lys-Ala-7-amido-4-methylcoumarin (KA-AMC), which facilitates dimer maturation in vitro, and determined aspects of its structure-activity relationship. In this report, we present measurements of the binding affinity of the activators and characterization of their interactions with the SL1 RNA. Guanidinium groups and increasing positive charge on the side chain enhance affinity and activity, but features in the aromatic ring at least partially decouple affinity from activity. Although KA-AMC can bind to multiple structural motifs, the NMR study showed KA-AMC preferentially binds to unique structural motifs, such as the palindromic loop and the G-rich internal loop in the SL1 RNA. NCp7 binds to SL1 only 1 order of magnitude more tightly than the best small molecule ligand tested. This study provides guidelines for the design of superior small molecules that bind to the SL1 RNA that have the potential of being developed as an antiviral by interfering with SL1-NCp7 interaction at the packaging and/or maturation stages.
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PMID:Binding characteristics of small molecules that mimic nucleocapsid protein-induced maturation of stem-loop 1 of HIV-1 RNA. 2056 56

To identify hepatitis C virus (HCV) transmission routes among injection drug users in Northern Vietnam, plasma samples were collected from 486 drug users in Hai Phong. Plasma viral RNA was extracted from 323 (66.5%) samples that were positive for anti-HCV antibodies. Portions of the HCV 5'-untranslated (5'UTR)-Core and NS5B genes were amplified by reverse-transcriptase polymerase chain reaction, sequenced directly, and genotyped in 194 and 195 specimens, respectively. Both regions were genotyped in 137 specimens. In the 5'UTR-Core region, genotype 6a was predominant (32.5%), followed by genotype 1a (23.7%), genotype 1b (20.6%), and genotype 6e (14.4%). In the NS5B region, genotype 1a was predominant (42.6%), followed by genotype 1b (24.1%), genotype 6a (14.4%), genotype 3b (7.2%), and genotype 6e (5.1%). Of the 137 specimens with both regions genotyped, 23 (16.8%) showed discordant genotyping results between the two regions, suggesting possible recombination and/or dual infection. Phylogenetic analysis revealed close associations between Hai Phong strains and strains from Southern China: the Yunnan province for genotype 3b; the Guangxi province for genotype 6e; the USA for genotype 1a; and Southern Vietnam for genotypes 1a and 6e. The human immunodeficiency virus (HIV) infection rate among HCV-infected injection drug users was 52.6-55.4% and did not differ significantly by HCV genotype. Most drug users infected with HIV-1 [98.8% (171/173)] were co-infected with HCV. These results suggest multiple routes of HCV transmission among injection drug users in Northern Vietnam that may also be HIV transmission routes.
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PMID:Multiple routes of hepatitis C virus transmission among injection drug users in Hai Phong, Northern Vietnam. 2057 71


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