UMLS:C0021051 - FACTA Search

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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) integrase enzyme exhibits significant amino acid sequence conservation with integrase proteins of other retroviruses. We introduced specific amino acid substitutions at a number of the conserved residue positions of recombinant HIV-1 integrase. Some of these substitutions resulted in proteins which were not able to be purified in the same manner as the wild-type enzyme, and these were not studied further. The remaining mutant enzymes were assessed for their abilities to perform functions characteristic of the integrase protein. These included specific removal of the terminal dinucleotides from oligonucleotide substrates representative of the viral U5-long terminal repeat, nonspecific cleavage of oligonucleotide substrates, and mediation of the strand transfer (integration) reaction. Substitution at position 43, within the protein's zinc finger motif region, resulted in an enzyme with reduced specificity for cleavage of the terminal dinucleotide. In addition, a double substitution of aspartic acid and glutamine for valine and glutamic acid, respectively, at positions 151 and 152 within the D,D(35)E motif region rendered the integrase protein inactive for all of its functions. The introduction of this double substitution into an infectious HIV-1 provirus yielded a mutant virus that was incapable of productively infecting human T-lymphoid cells in culture.
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PMID:Requirement of active human immunodeficiency virus type 1 integrase enzyme for productive infection of human T-lymphoid cells. 143 23

The nucleocapsid protein NCp7 of human immunodeficiency virus type 1 (HIV-1), which has key functions in the virus life cycle, possesses two zinc fingers of the CX2CX4HX4C type characterized by three successive loops containing a tetrahedrally coordinated zinc atom. The replacement of any cysteine by a serine in either finger has been shown to result in the production of noninfectious viruses, probably by impairing the biological functions of NCp7. In order to more precisely elucidate the structural role of the zinc finger motif, His23 was replaced by Cys in the proximal finger of the peptide (13-64)NCp7 which retains NCp7 activities in vitro. The peptide Cys23(13-64)NCp7 was synthesized by solid phase and studied by 2D 1H NMR and molecular modeling. The His to Cys modification causes important structural modifications of the N-terminal zinc finger which impair the spatial proximity of the two zinc fingers as shown by the disappearance of several interresidue NOEs. The side chains of Val13, Lys14, Phe16, Thr24, Ala25, Trp37, Gln45, and Met46, which are thought to be involved in nucleic acid recognition, are no longer found clustered in the Cys23(13-64)NCp7 mutant as they are in the wild-type NCp7 structure. In vitro, Cys23(13-64)NCp7 is unable to tightly interact with the viral RNA or replication primer tRNA(Lys,3). The Cys23(NCp7) mutation was introduced into an infectious HIV-1 molecular clone, and virions produced upon DNA transfection into cells were analyzed for their viral protein and RNA compositions as well as for their infectivity. Results show that, while the Cys23(NCp7) mutation does not impair virion production, viruses contain a low amount of degraded viral RNA and are not infectious. These findings suggest that a bona fide conformation of the HIV-1 NCp7 is critical for the packaging of viral RNA, its stability in virions, and virus infectivity.
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PMID:1H NMR structure and biological studies of the His23-->Cys mutant nucleocapsid protein of HIV-1 indicate that the conformation of the first zinc finger is critical for virus infectivity. 791 87

The human cytomegalovirus (HCMV) immediate-early two (IE2) protein of 579 amino acids significantly activates expression from the human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter. Using a proviral HIV-1 genome with a mutated tat gene we demonstrate that the IE2 protein effects an increase in the steady-state level of viral RNA similar to a level as from a wild-type proviral genome. The regions of the HCMV IE2 protein required for transactivation of the HIV-1 LTR promoter were analyzed by mutagenizing the IE2 gene and determining the activity of the mutant protein in human fibroblast cells. The region between amino acids 169 and 194 is required to transactivate the HIV-1 LTR promoter, although we have previously shown that this region is not required to activate a representative HCMV early promoter (C. L. Malone, et al., J. Virol. 64, 1498, (1990)). A region downstream of amino acid 290, which is required to activate a representative HCMV early promoter, is also required to activate the HIV-1 LTR promoter. Three types of mutations within this region were shown to greatly decrease IE2 activity: (1) amino acid substitutions of the cysteine or histidine residues in a putative zinc finger motif between amino acids 428 and 452; (2) substitution of the acidic charged residues between amino acids 558 and 561; (3) substitution of the two prolines at residues 556 and 557 immediately upstream of these acidic residues. Substitution of the other acidic residues near the carboxyl terminus also diminished transactivation by IE2. These data indicate that acidic amino acids and the secondary structure in the carboxyl end of the IE2 protein have an important role in transactivation of the HIV-1 LTR promoter. The other regions of the IE2 protein required for transactivation of the HIV-1 LTR are discussed.
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PMID:Mutations of the human cytomegalovirus immediate-early 2 protein defines regions and amino acid motifs important in transactivation of transcription from the HIV-1 LTR promoter. 833 45

All retroviral nucleocapsid (NC) proteins, except those of spumaretroviruses, contain one or two copies of the conserved sequence motif C-X2-C-X4-H-X4-C. The conserved cysteine and histidine residues coordinate a zinc ion in each such motif. Rice et al. (W. G. Rice, J. G. Supko, L. Malspeis, R. W. Buckheit, Jr., D. Clanton, M. Bu, L. Graham, C. A. Schaeffer, J. A. Turpin, J. Domagala, R. Gogliotti, J. P. Bader, S. M. Halliday, L. Coren, R. C. Sowder II, L. 0. Arthur, and L. E. Henderson, Science 270:1194-1197, 1995) have described a series of compounds which inactivate human immunodeficiency virus type 1 (HIV-1) particles and oxidize the cysteine thiolates in the NC zinc finger. We have characterized the effects of three such compounds on Moloney murine leukemia virus (MuLV). We find that, as with HIV-1, the compounds inactivate cell-free MuLV particles and induce disulfide cross-linking of NC in these particles. The killed MuLV particles were found to be incapable of synthesizing full-length viral DNA upon infection of a new host cell. When MuLV particles are synthesized in the presence of one of these compounds, the normal maturational cleavage of the Gag polyprotein does not occur. The compounds have no effect on the infectivity of human foamy virus, a spumaretrovirus lacking zinc fingers in its NC protein. The resistance of foamy virus supports the hypothesis that the zinc fingers are the targets for inactivation of MuLV and HIV- I by the compounds. The absolute conservation of the zinc finger motif among oncoretroviruses and lentiviruses and the lethality of all known mutations altering the zinc-binding residues suggest that only the normal, wild-type structure can efficiently perform all of its functions. This possibility would make the zinc finger an ideal target for antiretroviral agents.
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PMID:Inactivation of murine leukemia virus by compounds that react with the zinc finger in the viral nucleocapsid protein. 876 2

The Gag proteins of Rous sarcoma virus (RSV) and human immunodeficiency virus (HIV) contain small interaction (I) domains within their nucleocapsid (NC) sequences. These overlap the zinc finger motifs and function to provide the proper density to viral particles. There are two zinc fingers and at least two I domains within these Gag proteins. To more thoroughly characterize the important sequence features and properties of I domains, we analyzed Gag proteins that contain one or no zinc finger motifs. Chimeric proteins containing the amino-terminal half of RSV Gag and various portions of the carboxy terminus of murine leukemia virus (MLV) (containing one zinc finger) Gag had only one I domain, whereas similar chimeras with human foamy virus (HFV) (containing no zinc fingers) Gag had at least two. Mutational analysis of the MLV NC sequence and inspection of I domain sequences within the zinc-fingerless C terminus of HFV Gag suggested that clusters of basic residues, but not the zinc finger motif residues themselves, are required for the formation of particles of proper density. In support of this, a simple string of strongly basic residues was found to be able to substitute for the RSV I domains. We also explored the possibility that differences in I domains (e.g., their number) account for differences in the ability of Gag proteins to be rescued into particles when they are unable to bind to membranes. Previously published experiments have shown that such membrane-binding mutants of RSV and HIV (two I domains) can be rescued but that those of MLV (one I domain) cannot. Complementation rescue experiments with RSV-MLV chimeras now map this difference to the NC sequence of MLV. Importantly, the same RSV-MLV chimeras could be rescued by complementation when the block to budding was after, rather than before, transport to the membrane. These results suggest that MLV Gag molecules begin to interact at a much later time after synthesis than those of RSV and HIV.
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PMID:Importance of basic residues in the nucleocapsid sequence for retrovirus Gag assembly and complementation rescue. 976 48

We report on a family with three stillborn males, three affected males who were small for gestational age and died within 8 months, and one male who died at age 5 years. This boy had cone-shaped teeth and oligoodontia. He had serious bacterial infections and inflammatory bowel disease. Mutations in the NF-kappaB essential modulator (NEMO) gene have recently been shown to be the cause of a group of ectodermal dysplasia and immunodeficiency disorders (EDA-ID). Analysis of the NEMO gene revealed a nucleotide change in the consensus sequence of the splicing donor site of exon 6 IVS6 + 5G --> A(1027 + 5G --> A), which has not previously been described in EDA-ID. RT-PCR analysis of fibroblast RNA from an aborted affected male fetus demonstrated a skipping of exons 4, 5, and 6 which resulted in a truncated protein of about 35 kDa revealed by NEMO antibody. The skipping of exons 4, 5, and 6 did not affect the ORF of the C-terminal of NEMO encoded by exons 7, 8, 9, and 10, which contains a coiled-coil motif (CC2), a leucin-zipper (LZ), and a zinc finger motif (ZF) sub-domains of NEMO. IkappaBalpha degradation was strongly impaired in the fetal fibroblasts, suggesting an impaired NF-kappaB signaling. One healthy carrier had a completely skewed X-inactivation pattern with the normal X active, whereas the two other carriers had a random X-inactivation pattern. This family may represent a new phenotype within the EDA-ID disorders. From the heterogeneity in X-inactivation phenotype, we conclude that this mutation is not deleterious enough to be lethal for peripheral blood cells.
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PMID:Novel splicing mutation in the NEMO (IKK-gamma) gene with severe immunodeficiency and heterogeneity of X-chromosome inactivation. 1633 36

Primate lentiviruses are composed of several distinct lineages, including human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus SIVagm. HIV-1 and HIV-2 have significant differences in the mechanisms of viral RNA encapsidation. Therefore, the RNA packaging mechanisms of SIVagm cannot be predicted from the studies of HIV-1 and HIV-2. We examined the roles of the nucleocapsid (NC) zinc finger motifs on RNA packaging by mutating the conserved zinc finger (CCHC) motifs, and whether SIVagm has a preference to package RNA in cis by comparing the RNA packaging efficiencies of gag mutants in the presence of a wild-type vector. Our results indicate that the SIVagm NC domain plays an important role in Gag-RNA recognition; furthermore SIVagm is distinct from the other currently known primate lentiviruses as destroying either zinc finger motif in the NC causes very drastic RNA packaging defects. Additionally, trans-packaging is a major mechanism for SIVagm RNA encapsidation.
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PMID:Molecular mechanisms of simian immunodeficiency virus SIV(agm) RNA encapsidation. 1732 60

Human immunodeficiency virus (HIV) virion infectivity factor (Vif) causes the proteasome-mediated destruction of human antiviral protein APOBEC3G by tethering it to a cellular E3 ubiquitin ligase composed of ElonginB, ElonginC, Cullin5, and Rbx2. It has been proposed that HIV Vif hijacks the E3 ligase through two regions within its C-terminal domain: a BC box region that interacts with ElonginC and a novel zinc finger motif that interacts with Cullin5. We have determined the crystal structure of the HIV Vif BC box in complex with human ElonginB and ElonginC. This complex presents direct structural evidence of the recruitment of a human ubiquitin ligase by a viral BC box protein that mimics the conserved interactions of cellular ubiquitin ligases. We further mutated conserved hydrophobic residues in a region downstream of the Vif BC box. These mutations demonstrate that this region, the Vif Cullin box, composes a third E3-ligase recruiting site critical for interaction between Vif and Cullin5. Furthermore, our homology modeling reveals that the Vif Cullin box and zinc finger motif may be positioned adjacent to the N terminus of Cullin5 for interaction with loop regions in the first cullin repeat of Cullin5.
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PMID:Structural insight into the human immunodeficiency virus Vif SOCS box and its role in human E3 ubiquitin ligase assembly. 1856 29

Lentiviruses contain accessory genes that have evolved to counteract the effects of host cellular defence proteins that inhibit productive infection. One such restriction factor, SAMHD1, inhibits human immunodeficiency virus (HIV)-1 infection of myeloid-lineage cells as well as resting CD4(+) T cells by reducing the cellular deoxynucleoside 5'-triphosphate (dNTP) concentration to a level at which the viral reverse transcriptase cannot function. In other lentiviruses, including HIV-2 and related simian immunodeficiency viruses (SIVs), SAMHD1 restriction is overcome by the action of viral accessory protein x (Vpx) or the related viral protein r (Vpr) that target and recruit SAMHD1 for proteasomal degradation. The molecular mechanism by which these viral proteins are able to usurp the host cell's ubiquitination machinery to destroy the cell's protection against these viruses has not been defined. Here we present the crystal structure of a ternary complex of Vpx with the human E3 ligase substrate adaptor DCAF1 and the carboxy-terminal region of human SAMHD1. Vpx is made up of a three-helical bundle stabilized by a zinc finger motif, and wraps tightly around the disc-shaped DCAF1 molecule to present a new molecular surface. This adapted surface is then able to recruit SAMHD1 via its C terminus, making it a competent substrate for the E3 ligase to mark for proteasomal degradation. The structure reported here provides a molecular description of how a lentiviral accessory protein is able to subvert the cell's normal protein degradation pathway to inactivate the cellular viral defence system.
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PMID:Structural basis of lentiviral subversion of a cellular protein degradation pathway. 2440 77

Although the RAG2 core domain is the minimal region required for V(D)J recombination, the noncore region also plays important roles in the regulation of recombination, and mutations in this region are often related to severe combined immunodeficiency. A complete understanding of the functions of the RAG2 noncore region and the potential contributions of its individual residues has not yet been achieved. Here, we show that the zinc finger motif within the noncore region of RAG2 is indispensable for maintaining the stability of the RAG2 protein. The zinc finger motif in the noncore region of RAG2 is highly conserved from zebrafish to humans. Knock-in mice carrying a zinc finger mutation (C478Y) exhibit decreased V(D)J recombination efficiency and serious impairment in T/B-cell development due to RAG2 instability. Further studies also reveal the importance of the zinc finger motif for RAG2 stability. Moreover, mice harboring a RAG2 noncore region mutation (N474S), which is located near C478 but is not zinc-binding, exhibit no impairment in either RAG2 stability or T/B-cell development. Taken together, our findings contribute to defining critical functions of the RAG2 zinc finger motif and provide insights into the relationships between the mutations within this motif and immunodeficiency diseases.
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PMID:Disruption of the RAG2 zinc finger motif impairs protein stability and causes immunodeficiency. 2669 6

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