Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The third variable domain (V3 domain) of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 contains a substantial number of positively charged amino acid residues. We previously demonstrated that mutation of basic amino acid residues at position 303, 306, 309, 313, and 325 in the V3 domain of HIV-1 strain NL4-3 resulted in a dramatic elimination of both virus infectivity and syncytium-inducing ability. Mutations of arginine at position 302 to serine (R302S) or lysine at position 320 to glutamine (K320Q) had variable effects on infectivity for a panel of T cell lines tested. These mutations are located on opposite sides of the Gly-Pro-Gly-Arg-Ala sequence in the center of the V3 domain. The R302S and K320Q mutations allowed us to determine if these basic residues are important for virus neutralization by polyanionic compounds. Dextran sulfate and heparin inhibited the cytopathogenicities of both mutants for MT-4 cells, although their 50% antiviral effective doses were slightly higher than those required to achieve complete protection against wild-type HIV-1NL4-3 replication. This result emphasizes that the basic amino acids of Arg302 and Lys320 are not essential for the inhibitory effect of dextran sulfate and heparin on HIV-1 infection.
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PMID:Single basic amino acid substitutions at position 302 or 320 in the V3 domain of HIV type 1 are not sufficient to alter the antiviral activity of dextran sulfate and heparin. 757 13

Various sulfated cerebroside analogs, which are mimicks of cerebroside, have been prepared from per-O-acetylated D-glucose, per-O-acetylated D-galactose, and per-O-acetylated D-lactose with ethyleneglycol dodecyl ether, 3-docosyloxy-1-propanol, 2-hydroxymethyl-1,3-O-dimyristyl-1,3-propanediol, and L-serine diamide derivatives as ceramide moieties. The synthesized sulfated glycolipids showed anti-HIV-1 activities.
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PMID:Synthesis of sulfated cerebroside analogs having mimicks of ceramide and their anti-human immunodeficiency virus type 1 activities. 760 Jun 12

Many biologically important peptide sequences contain proline. It confers unique conformational constraints on the peptide chain in that the side-chain is cyclized back onto the backbone amide position. Inside an alpha-helix the possibility of making hydrogen bonds to the preceding turn is lost and a kink will be introduced. The conformational restrictions imposed by proline motifs in a peptide chain appear to imply important structural or biological functions as can be deduced from their often remarkably high degree of conservation as found in many proteins and peptides, especially cytokines, growth factors, G-protein-coupled receptors, V3 loops of the HIV envelope glycoprotein gp 120, and neuro- and vasoactive peptides. Only a limited number of peptidases are known to be able to hydrolyze proline adjacent bonds. Their activity is influenced by the isomeric state (cis-trans) as well as the position of proline in the peptide chain. The three proline specific metallo-peptidases (aminopeptidase P, carboxypeptidase P and prolidase) are activated by Mn2+, whereas the three serine type peptidases cleaving a post proline bond (prolyl oligopeptidase, dipeptidyl peptidase IV, and prolylcarboxypeptidase) share the sequential order of the catalytic Ser-Asp-His triade, which differentiates them from the chymotrypsin (His-Asp-Ser) and subtilisin (Asp-His-Ser) families. An endo or C terminal Pro-Pro bond and an endo pre-Pro peptide bond possess a high degree of resistance to any mammalian proteolytic enzyme.
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PMID:Proline motifs in peptides and their biological processing. 760 38

Vpr is one of the accessory proteins encoded by the HIV-1 genome. Several interesting features associated with Vpr include incorporation into virus particles, ability to oligomerize, localization in the nucleus, and positive effect on virus production and replication. In order to understand the structure-function relationship of Vpr, we have analyzed the role of the Gly75 and Cys76 (GC) residues which are highly conserved in HIV-1 Vpr and in Vpr and Vpx of HIV-2/SIV. We have generated several substitution mutants involving this dipeptide and have evaluated for expression, stability, nuclear localization, and virion incorporation of Vpr. Our data demonstrate that the GC residues are not essential for virion incorporation and nuclear localization of Vpr. Serine substitution for Cys, however, restricted the localization of Vpr in the cytoplasm without affecting the Gag-directed incorporation of Vpr into virus-like particles. Interestingly, the cysteine-substituted mutants showed altered stability in comparison to the wild type, and substitution mutants for glycine showed minimal effect on stability. These results indicate that the glycine and cysteine do not play a role in nuclear localization or virion incorporation properties of Vpr and further suggest that these two functions of Vpr may not be interdependent.
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PMID:Role of the conserved dipeptide Gly75 and Cys76 on HIV-1 Vpr function. 761 86

Viral variation has been proposed to play a role in the pathogenesis of human immunodeficiency virus type-1 (HIV-1) infection, and is an important consideration in vaccine design. During the course of an infection, isolates with sequence changes in CD8 T-cell and B-cell epitopes arise. To determine whether sequence variation within the V3 loop of HIV-1 gp120 affects HLA-DR beta 1*0101-restricted CD4 T-cell recognition, we have generated CD4 T-cell clones (TLC) specific to gp120 V3 loop peptides. Four HLA-DR beta 1*0101-restricted groups of TLC were defined by distinct patterns of responses to a panel of peptides, consistent with a highly diverse T-cell repertoire recognizing the 30 amino acid stretch (296-326) of the gp120 V3 loop. Nevertheless, a single residue change at position 311 was found to abolish the recognition of two of the four groups of TLC. This was not due to an effect of the residue at 311 on binding to major histocompatibility complex (MHC), because: (1) irrespective of the residue at 311, peptides competed well with the influenza haemagglutinin peptide 307-319 for binding to cell-bound DR1; and (2) R311-specific TLC were also HLA DR beta 1*0101 restricted. Instead, the substitution of arginine for serine at position 311 blocked the interaction of the peptide with the T-cell receptor. Thus, despite the diversity of the T-cell response to the V3 loop of HIV-1, a single amino acid change can have a considerable influence on the responding T-cell population. As residue 311 is one of the most variable of the V3 loop residues, these results suggest that CD4 recognition can also exert pressure on viral variation consistent with a role for these cells in antiviral immunity.
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PMID:The effect of a single amino acid substitution within the V3 loop of HIV-1 gp120 on HLA-DR1-restricted CD4 T-cell recognition. 764 8

Site-directed mutagenesis has been used to assess the importance of lysine 263 in substrate binding of human immunodeficiency virus-1 (HIV-1) reverse transcriptase. Previous studies have indicated that lysine 263 functions in the binding of 2'-deoxynucleoside 5'-triphosphate (dNTP) substrates (Basu, A., Tirumalai, R. S., and Modak, M. J. (1989) J. Biol. Chem. 264, 8746-8752). We studied this interaction directly by using site-specific mutagenesis to change lysine 263 to a serine. Highly purified mutant enzyme K263S bound natural dNTP substrates and primed polynucleic acid substrates with equal affinity when compared to the wild type reverse transcriptase. No difference was observed in the binding of 3'-azido-2',3'-dideoxythymidine 5'-triphosphate to the mutant reverse transcriptase on the basis of Km and Ki determinations. The serine substitution had no effect on RNase H activity. These results indicate that lysine 263 is not essential in the binding of substrates to HIV-1 reverse transcriptase.
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PMID:Biochemical analysis of human immunodeficiency virus-1 reverse transcriptase containing a mutation at position lysine 263. 767 98

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.
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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

Pentosan polysulfate, a polyanionic mucopolysaccharide, which has been shown to exert inhibitory effects on human immunodeficiency virus (HIV-I) replication, inhibited the activities of protein tyrosine kinases from lymphocytes (Jurkat cells) and rat lung in a concentration dependent manner. In addition, the autophosphorylation of p56lck, a lymphocyte associated protein tyrosine kinase from Jurkat cells was also inhibited by pentosan polysulfate (100 micrograms/ml). Furthermore, the activities of protein serine/threonine kinases such as Ca2+, phospholipid-dependent protein kinase (protein kinase C) from human platelets and the catalytic subunit of cAMP-dependent protein kinase from skeletal muscle were also inhibited by this mucopolysaccharide. However, the activity of phosphorylase kinase was not altered. The inhibition of rat lung protein tyrosine kinase was rapid and competitive with respect to ATP with an apparent Ki value of 5-20 micrograms/ml. These results suggest that the ability of pentosan polysulfate to inhibit various protein serine/threonine and tyrosine kinases may be one of the mechanisms by which this compound exerts its inhibitory effect of HIV-I replication.
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PMID:Pentosan polysulfate, a potent anti HIV and anti tumor agent, inhibits protein serine/threonine and tyrosine kinases. 768 45

The human immunodeficiency virus type 2 (HIV-2) Nef protein expressed in Escherichia coli forms highly stable homooligomeric complexes in vitro. Similarly, the native protein synthesized in the persistently infected H9 T cell line also forms stable homooligomers in vivo. To determine whether homooligomer formation is mediated by the leucine zipper-type sequence located in the middle region of the protein, site-directed mutagenesis was used to introduce double and triple point mutations at heptad leucine positions L1, L2, and L4 within the HIV-2NIHZ Nef protein sequence. Here, we show that substitution of a serine residue for the L1 (residue 108) and L2 (residue 115) heptad leucines, and a glutamine residue for the L4 (residue 129) heptad leucine, did not prevent Nef homooligomer formation in vitro. However, a more drastic substitution of alpha-helix-breaking proline residue for the L2 and L4 heptad leucines significantly abrogated ability of the protein to form stable homooligomers. In addition, because significantly higher levels of the Nef oligomers were consistently observed under the nonreducing SDS-PAGE condition, site-specific mutagenesis was also used to examine the role of cysteine residues in generating disulfide-linked Nef dimers in vitro. Here, we also show that single cysteine-to-glycine substitutions at positions 28, 32, or 55 drastically reduced covalent Nef dimer formation and thermal stability of the Nef protein in vitro. Therefore, these results demonstrate that the leucine zipper-type motif in the HIV-2 Nef protein mediates stable homooligomer formation in vitro, and also establish a role for covalent disulfide bonds in the formation of linked Nef dimers and thermal stability of the monomer Nef in vitro.
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PMID:Oligomerization of the HIV type 2 Nef protein: mutational analysis of the heptad leucine repeat motif and cysteine residues. 773 98

The multiple roles of the viral proteinase 2A in poliovirus replication have been difficult to assess because, to date, it has not been possible to isolate and characterize a viral genome with an inactive 2Apro. We have previously reported that a poliovirus replicon containing an inactive 2Apro by virtue of a change at amino acid 109 from a cysteine to a serine (C109S) was replication competent when transfected into cells previously infected with vaccinia virus (R. Pal-Ghosh and C. D. Morrow, J. Virol. 67:4621-4629, 1993). To further develop this system, we have used a poliovirus replicon which contains the human immunodeficiency virus type 1 (HIV-1) gag gene positioned between nucleotides 1174 and 2470 of the poliovirus genome and have engineered a second mutation within this replicon to change the codon for amino acid 109 of the 2Apro from cysteine to serine (2AC109S). Transfection of this replicon into cells previously infected with vaccinia virus results in the replication and expression of a protein with a molecular mass consistent with that of a P1-HIV-1 Gag-2A fusion protein. Using a recently described complementation system which relies on the capacity of a recombinant vaccinia virus (VV-P1) to provide the capsid precursor (P1) in trans (D. C. Ansardi, D. C. Porter, and C. D. Morrow, J. Virol. 67:3684-3690, 1993; and D. C. Porter, D. C. Ansardi, W. S. Choi, and C. D. Morrow, J. Virol. 67:3712-3719, 1993), we have encapsidated this replicon containing the 2AC109S mutation. By using reverse transcription PCR, we demonstrated that after 15 serial passages the encapsidated replicon still contained the 2AC109S mutation. Infection of cells with a stock of encapsidated replicon, either in the presence or in the absence of vaccinia virus, resulted in the expression of the P1-HIV-1 Gag-2A fusion protein. Expression of the P1-HIV-1 Gag fusion protein in cells infected with the encapsidated replicon containing the 2AC109S mutation was reduced compared with the expression of P1-HIV-1 Gag in those cells infected with a replicon containing a wild type 2A gene. The protein expression and replication of the replicon RNA in cells containing the 2AC109S mutation was maintained for a longer period of time than for the replicons containing the wild-type 2A gene, possibly because of a reduced cytopathic effect.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Encapsidation and serial passage of a poliovirus replicon which expresses an inactive 2A proteinase. 781 22


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