Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human immunodeficiency virus type 2 gag precursor protein, pr41, self assembles as virus-like particles (VLP) when the gag gene is expressed in insect cells. To map the functional domains for HIV-2 gag VLP formation, a series of deletion mutants was constructed by removing sequentially the C-terminal region of HIV-2 gag precursor protein and expressing the truncated gag genes in SF9 insect cells by means of recombinant baculoviruses. We found that deletion of up to 143 amino acids at the C-terminus of HIV-2 gag, leaving 376 amino acids at the N-terminus of the protein, did not prevent VLP formation. However, an additional four amino acids deletion from the C-terminus, which represents 372 amino acids at the N-terminus, made gag protein fail to form VLP. There is a proline-rich region at amino acid positions 372 and 377 of HIV-2 gag. To analyze the role of these proline residues, we generated five mutants in which proline was changed sequentially into leucine. Our results showed that replacement of one or two prolines did not stop gag VLP formation, whereas replacement of all three prolines by leucine residues completely abolished VLP assembly. Our data demonstrate that the C-terminal p12 region of HIV-2 gag precursor protein and the zinc finger domain are dispensable for gag VLP assembly, but the presence of at least one of the three proline residues located between amino acid positions 372 and 377 of HIV-2NIH-Z is required.
 ...
PMID:Mapping of functional domains for HIV-2 gag assembly into virus-like particles. 797 51

T-cell-line-tropic human immunodeficiency virus type 1 cannot infect CD4-positive, brain-derived cells. We isolated several new variants that readily infected brain-derived cells. Mutation of proline to serine, to alanine, or to threonine in the well-conserved GPGR sequence in the V3 region of the envelope glycoprotein was found in all these variants. This indicates the importance of amino acid sequences at the tip of the V3 region for brain cell tropism of human immunodeficiency virus type 1.
 ...
PMID:Isolation and characterization of human immunodeficiency virus type 1 variants infectious to brain-derived cells: detection of common point mutations in the V3 region of the env gene of the variants. 798 Jul 82

A replication-defective virus (BM5d) of approximately 4.9 kb, is responsible for a retrovirus induced immunodeficiency syndrome in mice (MAIDS) that shares many features with AIDS. BM5d is characterized by deletions in env and pol genes, furthermore its gag gene differs markedly from gag of other BM5 ecotropic viruses, particularly in its p12 sequence. The p12 region of the gag gene has been shown to account for the pathogenicity of the BM5d retrovirus. During our studies of BM5d integration in mice we found that p12-like sequences are present in the mouse genome of uninfected healthy C57BL/6 mice. Cloning and sequencing of this p12 gag homologue has revealed a high (63% to 89%) amino acid derived sequence identity with other retroviruses and shown that the major differences among p12 of pathogenic viral strains compared to non-pathogenic ones consist of a four amino acids deletion and a high abundance of proline and basic amino acids in their p12 region.
 ...
PMID:A p12 gag gene homologue is present in the mouse genome. 803 19

Synthetic peptides derived from influenza virus and human immunodeficiency virus were tested for their ability to promote the assembly of HLA-A2 and HLA-B51 molecules in T2 cell lysates. Specific assembly was detected by an enzyme-linked immunosorbent assay. The most significant HLA-A2 assembly was obtained in the presence of peptides known to be targets for HLA-A2-restricted cytotoxic T lymphocytes (influenza matrix M.58-66 and HIV Pol 476-484). Three of a batch of Nef peptides corresponding to epitopic regions for cytotoxic T lymphocytes, caused significant assembly of HLA-A2 (Nef 83-91, 137-145 and 144-153), but only at high concentrations (100 microM). As these peptides bound relatively weakly, it is unlikely that they are good candidates for HLA-A2-restricted CTL epitopes. Peptides matrix M.60-68, Nef 186-194, and Plasmodium falciparum sh.77-85 produced the most significant assembly of HLA-B51. These peptides have a dominant hydrophobic anchor residue (V, L. I) at position 9 that could occupy pocket "F". Our results also suggest that another hydrophobic residue (V, L) at position 3 or 4 may anchor to hydrophobic pocket "D" of HLA-B51. Proline at position 2 greatly increases HLA-B51 anchoring.
 ...
PMID:A simple assay for detection of peptides promoting the assembly of HLA class I molecules. 812 45

Human immunodeficiency virus (HIV) dementia is a common clinical syndrome of uncertain pathogenesis in patients with AIDS. In several animal models of retrovirus-induced brain disease, specific viral envelope sequences have been found to influence the occurrence of central nervous system disease. Therefore, to search for unique envelope sequences correlated with HIV dementia, we studied 22 HIV-infected patients who were neurologically assessed premortem and classified into demented (HIVD) (n = 14) and nondemented (ND) (n = 8) groups. Using DNA from autopsied brain and spleen, we amplified, cloned, and sequenced a 430-nucleotide region including the V3 loop and flanking regions. All brain-derived clones in both clinical groups showed marked homology to the macrophage-tropic consensus sequence within the V3 loop. Two amino acid positions within (position 305) and outside (position 329) the V3 region showed significant divergence between the two clinical groups. At position 305, a histidine was predominant in the HIVD group and was not observed in the ND group, but a proline was predominant in the ND group and was not observed in the HIVD group. Similarly, at position 329, a leucine was predominant in the HIVD group but rarely observed in the ND group, whereas an isoleucine was predominant in the ND group at this position. In addition, the HIVD group had 21 amino acid residues at specific positions that were unique relative to the ND group, whereas only 2 residues at specific positions were unique to the ND group. These data suggest that distinct HIV envelope sequences are associated with the clinical expression of HIV dementia.
 ...
PMID:Demented and nondemented patients with AIDS differ in brain-derived human immunodeficiency virus type 1 envelope sequences. 820 38

Genetic deficiency of adenosine deaminase (ADA) results in varying degrees of immunodeficiency, including neonatal onset severe combined immunodeficiency (ADA- SCID) and milder, later onset immunodeficiency. We have determined the molecular basis of disease in a child from a consanguineous mating with ADA- SCID of clinically and biochemically reduced severity, diagnosed at 15 months of age and characterized by retention of more immunologic function than is typical of the fulminant neonatal onset type. The course was notable for an early predominance of bacterial infections and eosinophilia. In contrast to its absence in most ADA- SCIDs, residual ADA activity (1-2% of normal) could be detected in EBV-transformed B cells. Consistent with the increased residual ADA, excretion of the substrate deoxyadenosine and accumulation of the toxic metabolite deoxyATP were less than seen in ADA- SCID patients with fulminant disease. Sequence analysis of cDNA revealed a G853C transversion, predicting a substitution of proline for arginine at codon 253 (Arg253Pro). The parents were heterozygous and the child was homozygous for the mutation, as shown by sequence analysis of amplified genomic DNA. Transient expression of mutant cDNA in Cos cells revealed an electrophoretically abnormal, more negatively charged ADA with 1-2% of normal activity. These observations are consistent with replacement of positively charged arginine by proline, the lower accumulation of toxic metabolites, and the milder phenotype. By contrast, transient expression of a Gly216Arg mutant cDNA, associated, when homozygous, with neonatal onset ADA-SCID, did not reveal ADA activity. Mutations such as Arg253Pro, which retain residual activity of monomeric ADA, should be dominant for ameliorating the phenotype in patients carrying two different allelic mutations. Identification of additional similar mutations may be significant in evaluating the goals for and efficacy of current trials of gene and gene product replacement.
 ...
PMID:Severe combined immunodeficiency of reduced severity due to homozygosity for an adenosine deaminase missense mutation (Arg253Pro). 825 46

Patients with human immunodeficiency virus (HIV) infection are prone to the development of focal segmental glomerulosclerosis, a lesion in which increased mesangial cell proliferation and matrix synthesis may play a role. We undertook the present study to determine whether HIV sera may affect mesangial cell proliferation and matrix synthesis either directly or indirectly via effects on macrophage supernatants. Pooled HIV sera was found to significantly enhance (P < 0.01) mesangial cell proliferation in a concentration-related manner. Mesangial cell proliferation was significantly suppressed by two medications commonly utilized in HIV-infected patients, azidothymidine and trimethoprim/sulfamethoxazole, and was not significantly altered by lipopolysaccharide, suggesting that these medications as well as recurrent infection are unlikely to account for the proliferative effect of HIV sera. Supernatants from HIV sera-treated macrophages were found to significantly enhance (P < 0.01) mesangial cell incorporation of [3H]proline, a marker for synthesis of the matrix component collagen, compared to supernatants from control sera-treated macrophages. These results suggest that HIV sera may directly enhance mesangial cell proliferation and may indirectly increase mesangial cell matrix synthesis by altering macrophage secretory products. These effects may play a role in the development of glomerulosclerosis in patients with HIV infection.
 ...
PMID:Effects of human immunodeficiency virus sera and macrophage supernatants on mesangial cell proliferation and matrix synthesis. 836 79

In order to study the relationship between virus populations in a human immunodeficiency virus type 1 (HIV-1)-infected mother and her infant, we analysed a 276 bp fragment, including the V3 region, of genomic HIV-1 RNA purified from serum. Samples were collected from the mother 6, 4 and 2 months prior to delivery, during delivery and 10 months after childbirth (samples MA to ME, respectively) and from the infant at birth (cord blood) and the ages of 6 weeks and 9 months. A heterogeneous sequence population was observed in the maternal samples (mean nucleotide variation of 2.4 to 4.2%, range 0 to 8.3%). Until the age of 6 weeks the sequence population in the infant was highly homogeneous (mean nucleotide variation < or = 0.7%, range 0 to 2.5%). At 9 months of age, the infant's virus population showed more heterogeneity (mean nucleotide variation of 1.8%, range 0.4 to 3.6%) and a drift in the consensus sequence was observed. The evolution of the V3 region in the mother was characterized by accumulation of amino acid substitutions diverging from the virus population observed in the infant. The mean nucleotide distance between the maternal sequence populations and the sequence population of the child at birth was 2.8, 2.6, 3.7, 5.2 and 5.3% for the samples MA, MB, MC, MD and ME, respectively. Nearly complete replacement at position 308, previously described as antigenically important, from a proline to a histidine was observed during pregnancy, whereas all clones of the child's virus at birth and at 6 weeks contained a proline at that position. In conclusion, intra-uterine transmission is associated with a homogeneous sequence population in the child at birth, which is more closely related to the sequence population present in the mother during the first and second trimester of pregnancy than to the sequence population at delivery.
 ...
PMID:Genomic human immunodeficiency virus type 1 RNA variation in mother and child following intra-uterine virus transmission. 837 56

The third complementarity-determining region (CDR3) within domain 1 of the human CD4 molecule has been suggested to play a critical role in membrane fusion mediated by the interaction of CD4 with the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein. To analyze in detail the role of CDR3 and adjacent regions in the fusion process, we used cassette mutagenesis to construct a panel of 30 site-directed mutations between residues 79 and 96 of the full-length CD4 molecule. The mutant proteins were transiently expressed by using recombinant vaccinia virus vectors and were analyzed for cell surface expression, recombinant gp120-binding activity, and overall structural integrity as assessed by reactivity with a battery of anti-CD4 monoclonal antibodies. Cells expressing the CD4 mutants were assayed for their ability to form syncytia when mixed with cells expressing the HIV-1 envelope glycoprotein. Surprisingly in view of published data from others, most of the mutations had little effect on syncytium-forming activity. Normal fusion was observed in 21 mutants, including substitution of human residues 85 to 95 with the corresponding sequences from either chimpanzee, rhesus, or mouse CD4; a panel of Ser-Arg double insertions after each residue from 86 to 91; and a number of other charge, hydrophobic, and proline substitutions and insertions within this region. The nine mutants that showed impaired fusion all displayed defective gp120 binding and disruption of overall structural integrity. In further contrast with results of other workers, we observed that transformant human cell lines expressing native chimpanzee or rhesus CD4 efficiently formed syncytia when mixed with cells expressing the HIV-1 envelope glycoprotein. These data refute the conclusion that certain mutations in the CDR3 region of CD4 abolish cell fusion activity, and they suggest that a wide variety of sequences can be functionally tolerated in this region, including those from highly divergent mammalian species. Syncytium formation mediated by several of the CDR3 mutants was partially or completely resistant to inhibition by the CDR3-directed monoclonal antibody L71, suggesting that the corresponding epitope is not directly involved in the fusion process.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:CD4 molecules with a diversity of mutations encompassing the CDR3 region efficiently support human immunodeficiency virus type 1 envelope glycoprotein-mediated cell fusion. 841 49

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.
 ...
PMID:Mutational analysis of the leucine zipper-like motif of the human immunodeficiency virus type 1 envelope transmembrane glycoprotein. 849 69


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>