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)

Complete sequence-specific assignments of the 1H-NMR spectrum of a fusion protein of the alpha-amylase inhibitor tendamistat from Streptomyces tendae and the activation domain of Tat from human immunodeficiency virus type 1 (HIV-1) was obtained by homonuclear two-dimensional NMR methods. The protein behaves as expected for an ideal fusion protein: the flexible linker allows an almost completely decoupled motion of the subunits of the protein and the two subunits show almost no mutual interaction. In the tendamistat part, small structural distortions due to exchange of the carboxy-terminal leucine propagate mainly via the hydrogen bonds of the beta-sheet and the disulfide bond. The Tat part of the protein contains the seven cysteine residues of full-length Tat. The fusion protein was expressed in Streptomyces lividans and exported. During the export to the extracellular space disulfide bonds are created by the expressing cells, only one sulfhydryl group remains accessible for sulfhydryl reagents. Although a unique, dominant conformation with a specific disulfide bonding pattern exists, a significant conformational variation can be observed including cis-proline peptide bonds, which may indicate smaller populations with alternative disulfide bonding patterns.
 ...
PMID:Complete 1H nuclear magnetic resonance assignments and structural characterization of a fusion protein of the alpha-amylase inhibitor tendamistat with the activation domain of the human immunodeficiency virus type 1 Tat protein. 762 84

The human immunodeficiency virus type 1 strain MN (HIV-1MN) principal neutralizing determinant (PND, V3 loop) was introduced into infectious molecular clones HIV-2KR and simian immunodeficiency virus mm239 (SIVmm239) by hybridization PCR, replacing the corresponding HIV-2 or SIV envelope cysteine loops with the HIV-1 coding sequence. The HIV-2 chimera (HIV-2KR-MNV3) was found to be capable of infecting a number of T-cell lymphoblastic cell lines as well as primary peripheral blood mononuclear cells. In contrast, the SIV chimera (SIV239MNV3) was not replication competent. Envelope produced by HIV-2KR-MNV3 but not the parental HIV-2KR was recognized by V3-specific and HIV-1-specific polyclonal antisera in radioimmunoprecipitation assays. HIV-2-specific antisera recognized both the chimeric and parental virus but not HIV-1MN. The chimeric HIV-2KR-MNV3 virus proved to be exquisitely susceptible to neutralization by HIV-1-specific and V3-specific antisera, suggesting the potential for use in animal models designed to test HIV-1 vaccine candidates which target the PND.
 ...
PMID:An infectious chimeric human immunodeficiency virus type 2 (HIV-2) expressing the HIV-1 principal neutralizing determinant. 766 43

The human immunodeficiency virus-1 Tat protein can efficiently enter cells when added exogenously in tissue culture. Using the transactivation activity of Tat as a measure of intracellular delivery, we found that the addition of hydrophobic groups to Tat potentiated its uptake. Biotin was the most promising of the reagents tested and we characterized this effect in more detail. When coupled through a cysteine thiol, the addition of a single biotin to Tat increased activity by about six-fold. Increased activity was only seen with reducible biotin analogs, as modification with noncleavable analogs is known to block Tat transactivation activity. Biotin had no effect on Tat uptake when mixed with Tat without cross-linking. Recently, Tat was used as a carrier to direct the uptake of heterologous proteins into cells. We have used RNase as a model system for studying Tat-mediated uptake and found that biotin also increased the delivery of a Tat37-58-RNase conjugate. The increased uptake of Tat and Tat conjugates by addition of hydrophobic groups may significantly enhance the usefulness of Tat as a delivery vehicle, and the approach may be applicable to other systems.
 ...
PMID:Increased cellular uptake of the human immunodeficiency virus-1 Tat protein after modification with biotin. 766 78

The methylation and transsulfuration pathways are intimately linked and have been implicated in the progression of neurologic damage and immune cell depletion caused by human immunodeficiency virus (HIV) infection. We studied the following metabolites related to these pathways: S-adenosylmethionine (SAMe), homocysteine, cysteine, cysteinyl-glycine, and glutathione (GSH) in blood and CSF of 16 HIV-infected patients with neurologic complications and 20 HIV-negative control patients undergoing lumbar punctures for other medical reasons. We confirmed recent studies of decreased CSF SAMe concentrations in HIV infection and demonstrated that diastereomers of SAMe are present in CSF but not in plasma or erythrocytes from both HIV-infected and HIV-negative patients. In HIV-infected patients, CSF GSH and cysteinyl-glycine, but not homocysteine or cysteine, were significantly reduced. This is the first report of decreased CSF GSH induced by HIV infection. GSH has a regulatory effect on the synthesis of SAMe in hepatic tissue, and the same mechanism may also apply in the CNS. Administration of SAMe-butanedisulphonate, 800 mg/d intravenously for 14 days, was associated with significant increases in CSF SAMe and GSH. These findings have potentially important therapeutic implications for the use of SAMe in protecting against SAMe and GSH deficiency in the CNS of HIV-infected patients.
 ...
PMID:Cerebrospinal fluid S-adenosylmethionine (SAMe) and glutathione concentrations in HIV infection: effect of parenteral treatment with SAMe. 767 26

A sequence of four amino acid residues amino-terminal to the only intramolecular disulphide bond of the human immunodeficiency virus type 1 (HIV-1) transmembrane protein gp41 is recognized by an anti-idiotypic antibody (9G5A) raised against another monoclonal antibody (M38), which recognizes the C5 region of gp120. 9G5A is an Ab2 beta antibody (internal image of the M38 epitope) in that it inhibits the interaction of M38 to its antigen. The binding of 9G5A to gp41 can be inhibited by M38 showing that the two antibodies interact via their paratopes. 9G5A neutralizes HIV-1 infection and syncytia formation. Ab3 antibodies induced in mice and rabbits immunized with 9G5A also can neutralize virus in both assays. These data show that the M38-defined epitope of the carboxy-terminal region of gp120 interacts with the 9G5A-defined epitope of gp41, and that this interaction can be reproduced by the idiotypic mimicry of the two antibodies. The results are consistent with a proposed molecular model of the two env regions which predicts the presence, within the C5 region of gp120, of a large intramolecular pocket that is contacted by the gp41 cysteine loop.
 ...
PMID:Identification of human immunodeficiency virus type 1 glycoprotein gp120/gp41 interacting sites by the idiotypic mimicry of two monoclonal antibodies. 767 70

We investigated the effects of glutathione (GSH), the major naturally occurring thiol, and a pharmacologic thiol precursor of GSH, N-acetyl cysteine (NAC), on the expression of human immunodeficiency type 1 (HIV-1) in primary cord blood and adult donor monocyte-derived macrophages (MDM). HIV-1 infection of cord blood and adult MDM was accomplished after incubating 10-15-d-old cultures for 4 h with a monocyte-tropic strain of HIV-1 (Bal). After 1 wk in culture cell supernatants were tested for reverse transcriptase (RT) activity. MDM were exposed to 5, 10 and 20 mM concentrations of both GSH and NAC before infection, during infection, and after infection was established. GSH and NAC suppressed the replication of HIV-1 in both primary cord blood and adult donor MDM in a concentration dependent fashion. These suppressive effects were more pronounced in cord-derived cells than in adult-derived cells. In cells treated with GSH or NAC before infection, there was no significant rise in RT activity as compared with controls. Similarly, when cells were treated with GSH and NAC and simultaneously infected, there was also no significant rise in RT activity after 1 wk in culture. In cells treated after infection was established, RT values were suppressed 80-90% that of untreated controls. This effect persisted for 1-2 wk after exposure to GSH and NAC. Untreated controls demonstrated syncytium formation and lost characteristics of spreading and elongation 2 wk after HIV-1 infection, whereas most of the treated cells remained free of syncytium and retained cytoplasmic spreading, adherence, and elongation. These data are consistent with other studies of thiol suppression of HIV-1 replication and demonstrate a similar observation for primary cultured cord MDM. These results may offer new approaches toward cellular protection after infection with HIV-1.
 ...
PMID:Thiol suppression of human immunodeficiency virus type 1 replication in primary cord blood monocyte-derived macrophages in vitro. 767 9

Illimaquinone, a natural marine product, was shown by us to inhibit preferentially the ribonuclease H (RNase H) activity of the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1). We have also shown that illimaquinone inhibits the RNase H activity of HIV-2 RT in addition to that of HIV-1 RT, murine leukemia virus RT, and Escherichia coli RNase H. Chemical modifications of HIV-1 RT by sulfhydryl-specific reagents, such as N-ethylmaleimide (NEM) have been demonstrated to specifically inhibit the RNase H activity of the enzyme. Since our previous studies have suggested that cysteine 280 in HIV-1 RT interacts with the sulfhydryl reagents, we have examined the possibility that illimaquinone interacts with the RT molecules via amino acid residues located in the vicinity of cysteine 280 in both HIV-1 and HIV-2 RTs. In the combined effect studies of illimaquinone and NEM, the two structurally unrelated compounds were shown to be mutually exclusive, exhibiting an antagonistic interaction with both HIV-1 and murine leukemia virus-associated RNase H activities. This implicates cysteine 280, in both HIV-1 and HIV-2 RTs, to be in close proximity to the putative binding site of the enzyme to illimaquinone. The above conclusion is further supported by the fact that the RNase H activity of an enzymatically active mutant of HIV-1 RT, in which cysteine 280 was replaced by serine, was substantially more resistant to illimaquinone than the corresponding activity of the wild-type enzyme. The fact that NEM failed to inhibit E. coli RNase H as opposed to illimaquinone highlights a major difference between the retroviral and bacterial RNase H.
 ...
PMID:The interaction of illimaquinone, a selective inhibitor of the RNase H activity, with the reverse transcriptases of human immunodeficiency and murine leukemia retroviruses. 768 48

Bisheteroarylpiperazines are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). We describe a novel bisheteroarylpiperazine, U-90152 [1-(5-methanesulfonamido-1H-indol-2-yl-carbonyl)-4-[3-(1-methyl eth yl-amino)pyridinyl]piperazine], which inhibited recombinant HIV-1 RT at a 50% inhibitory concentration (IC50) of 0.26 microM (compared with IC50s of > 440 microM for DNA polymerases alpha and delta). U-90152 blocked the replication in peripheral blood lymphocytes of 25 primary HIV-1 isolates, including variants that were highly resistant to 3'-azido-2',3'-dideoxythymidine (AZT) or 2',3'-dideoxyinosine, with a mean 50% effective dose of 0.066 +/- 0.137 microM. U-90152 had low cellular cytotoxicity, causing less than 8% reduction in peripheral blood lymphocyte viability at 100 microM. In experiments assessing inhibition of the spread of HIV-1IIIB in cell cultures, U-90152 was much more effective than AZT. When approximately 500 HIV-1IIIB-infected MT-4 cells were mixed 1:1,000 with uninfected cells, 3 microM AZT delayed the evidence of rapid viral growth for 7 days. In contrast, 3 microM U-90152 totally prevented the spread of HIV-1, and death and/or dilution of the original inoculum of infected cells prevented renewed viral growth after U-90152 was removed at day 24. The combination of U-90152 and AZT, each at 0.5 microM, also totally prevented viral spread. Finally, although the RT amino acid substitutions K103N (lysine 103 to asparagine) and Y181C (tyrosine 181 to cysteine), which confer cross-resistance to several nonnucleoside inhibitors, also decrease the potency of U-90152, this drug retains significant activity against these mutant RTs in vitro (IC50s, approximately 8 microgramM).
 ...
PMID:U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication. 768 95

We have previously shown that IgM antibodies that react with human immunodeficiency virus (HIV) Tat, a regulatory protein essential for viral replication, are present in sera of all normal, HIV-negative individuals and deficient in sera of HIV-positive individuals at progressively greater frequency as diagnosis of AIDS nears. That IgM was designated as a set of natural antibodies, a repertoire of the normal humoral immune system believed to provide early defense against infectious invaders. In the prior study, by means of a series of synthetic peptides representing the amino acid sequence of HIV-1 Tat, one epitope for the IgM natural antibodies was defined within the cysteine-rich domain, shown in cell transfection studies to participate in Tat function. In this study we have defined another epitope, within the basic domain, with which the natural antibodies react. The specific sequence and amino acid residues required for that epitope are coincident with those required for the role of Tat in viral replication. The IgM antibodies reactive with the two epitopes of Tat make up two distinct sets, which, together, account for the total Tat reactivity of both HIV-negative and HIV-positive sera. The striking coincidence of the two epitopes with the two functional sequences of Tat suggests a potential role of those natural antibodies in control of HIV pathogenesis. By inference from the extensive evidence for the presence of extracellular Tat in cultures of HIV-infected cells, Tat may be expected to be present in the circulating plasma of infected people. We propose, therefore, that the Tat-reactive natural antibodies, documented in these studies to be present in the circulating plasma in the pre-AIDS stages of HIV infection, may inhibit cell entry of plasma-borne Tat and thereby curtail HIV propagation. Thus, those natural antibodies may be a host factor for delay in HIV pathogenetic progression.
 ...
PMID:Epitopes for natural antibodies of human immunodeficiency virus (HIV)-negative (normal) and HIV-positive sera are coincident with two key functional sequences of HIV Tat protein. 768 27

Tat (trans-activator) proteins are early RNA binding proteins regulating lentiviral transcription. These proteins are necessary components in the life cycle of all known lentiviruses, such as the human immunodeficiency viruses (HIV) or the equine infectious anemia virus (EIAV). Tat proteins are thus ideal targets for drugs intervening with lentiviral growth. The consensus RNA binding motif (TAR, trans-activation responsive element) of HIV-1 is well characterized. Structural features of the 86 amino acid HIV-1, Zaire 2 isolate (HV1Z2) Tat protein in solution were determined by two dimensional (2D) nuclear magnetic resonance (NMR) methods and molecular dynamics (MD) calculations. In general, sequence regions corresponded to structural domains of the protein. It exhibited a hydrophobic core of 16 amino acids and a glutamine-rich domain of 17 amino acids. Part of the NH2 terminus, Val4 to Pro14, was sandwiched between these domains. Two highly flexible domains corresponded to a cysteine-rich and a basic sequence region. The 16 amino acid sequence of the core region is strictly conserved among the known Tat proteins, and the three-dimensional fold of these amino acids of HV1Z2 Tat protein was highly similar to the structure of the corresponding EIAV Tat domain. HV1Z2 Tat protein contained a well defined COOH-terminal Arg-Gly-Asp (RGD) loop similar to the recently determined decorsin RGD loop.
 ...
PMID:Structural studies of HIV-1 Tat protein. 772 10


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