Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The Vpr gene product of human immunodeficiency virus type 1 is a virion-associated protein that is important for efficient viral replication in nondividing cells such as macrophages. At the cellular level, Vpr is primarily localized in the nucleus when expressed in the absence of other viral proteins. Incorporation of Vpr into viral particles requires a determinant within the p6 domain of the Gag precursor polyprotein Pr55gag. In the present study, we have used site-directed mutagenesis to identify a domain(s) of Vpr involved in virion incorporation and nuclear localization. Truncations of the carboxyl (C)-terminal domain, rich in basic residues, resulted in a less stable Vpr protein and in the impairment of both virion incorporation and nuclear localization. However, introduction of individual substitution mutations in this region did not impair Vpr nuclear localization and virion incorporation, suggesting that this region is necessary for the stability and/or optimal protein conformation relevant to these Vpr functions. In contrast, the substitution mutations within the amino (N)-terminal region of Vpr that is predicted to adopt an alpha-helical structure (extending from amino acids 16 to 34) impaired both virion incorporation and nuclear localization, suggesting that this structure may play a pivotal role in modulating both of these biological properties. These results are in agreement with a recent study showing that the introduction of proline residues in this predicted alpha-helical region abolished Vpr virion incorporation, presumably by disrupting this secondary structure (S. Mahalingam, S. A. Khan, R. Murali, M. A. Jabbar, C. E. Monken, R. G. Collman, and A. Srinivasan, Proc. Natl. Acad. Sci. USA 92:3794-3798, 1995). Interestingly, our results show that two Vpr mutants harboring single amino acid substitutions (L to F at position 23 [L23F] and A30F) on the hydrophobic face of the predicted helix coded for relatively stable proteins that retained their ability to translocate to the nucleus but exhibited dramatic reduction in Vpr incorporation, suggesting that this hydrophobic face might mediate protein-protein interactions required for Vpr virion incorporation but not nuclear localization. Furthermore, a single mutation (E25K) located on the hydrophilic face of this predicted alpha-helical structure affected not only virion incorporation but also nuclear localization of Vpr. The differential impairment of Vpr nuclear localization and virion incorporation by mutations in the predicted N-terminal alpha-helical region suggests that this region of Vpr plays a role in both of these biological functions of Vpr.
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PMID:Mutagenic analysis of human immunodeficiency virus type 1 Vpr: role of a predicted N-terminal alpha-helical structure in Vpr nuclear localization and virion incorporation. 747 23

The duration of human immunodeficiency virus (HIV-1) infection prior to the development of AIDS is variable, and for most patients the exact time of infection is not known. A group of 38 HIV-1-infected subjects was tested while asymptomatic for comparative cytotoxic lymphocyte responses to the Gag and envelope antigens of HIV-1. Twenty of the 38 patients had no detectable primary cytotoxic T lymphocyte (CTL) response to Gag, and this was associated with a relative risk of 1.89 for progression to ARC or AIDS during the subsequent 3 to 40 months of observation when compared with patients who had Gag-specific CTL activity at the beginning of the observation period. In contrast, no significant association was observed between envelope-specific cytotoxic activity and disease progression. Other patient characteristics, including CD4+ T lymphocyte counts and antibody levels to the p24gag protein, measured at the start of observation, did not correlate with disease progression during the observation period. This suggests that the anti-Gag CTL response may be protective during HIV-1 infection.
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PMID:Gag-specific cytotoxic responses to HIV type 1 are associated with a decreased risk of progression to AIDS-related complex or AIDS. 749 37

Human immunodeficiency virus type 1 Vpr is a virion-associated, regulatory protein that is required for efficient viral replication in monocytes/macrophages. The protein is believed to act in conjunction with the Gag matrix protein to allow import of the viral preintegration complex in nondividing cells. In cells, Vpr localizes to the nucleus. Recently, we showed that Vpr prevents the activation of p34cdc2-cyclin B. This results in arrest of Vpr-expressing cells in the G2/M phase of the cell cycle. Here, we use a panel of expression vectors encoding Vpr molecules mutated in the amino-terminal alpha-helical region, the central hydrophobic region, or the carboxy-terminal basic region to define the functional domains of the protein. The results showed cell cycle arrest was largely controlled by the carboxy-terminal basic domain of the protein. In contrast, the amino-terminal alpha-helical region of Vpr was required for nuclear localization and packaging into virions. The carboxy terminus appeared to be unnecessary for nuclear localization. In the alpha-helical region, mutation of Ala-30 to Pro resulted in a protein that localized to the cytoplasm. Surprisingly, fusion of Vpr to luciferase resulted in a molecule that failed to localize to the nucleus. In addition, we show that simian immunodeficiency virus Vpr, but not Vpx, induces G2 arrest. We speculate that Vpr has two sites for interaction with cellular factors: one in the alpha-helical region that specifies nuclear localization and one in the carboxy-terminal domain that is required for Cdc2 inhibition.
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PMID:Mutational analysis of cell cycle arrest, nuclear localization and virion packaging of human immunodeficiency virus type 1 Vpr. 749 3

To use Env proteins as antigens for detection of the human immunodeficiency virus type-1 (HIV-1) antibodies, we attempted to overexpress the Env proteins in Escherichia coli. To study the epitopes in the Env proteins recognized by the sera of HIV carriers, various regions of the proviral DNA encoding the Env region were fused to the 3' end of the lacZ gene. The immunoblotting analysis of the LacZ-Env(512-611) and LacZ-Env(721-826) proteins with the 41 positive sera revealed that the former and the latter immunologically reacted with 100 and 78% of the sera, respectively. To avoid rare false-positive reactions due to the LacZ moiety of the fusion protein, we attempted to express the Env(512-611) alone or Gag-Env(512-611) under the control of bacteriophage T7 promoter. Although we could express only a low level of the Env(512-611) peptide in E. coli, we succeeded in producing large amounts of the Gag(121-406)-Env(512-611) and Gag(308-406)-Env(512-611) proteins as chimeric proteins. Both of these chimera proteins strongly reacted with the 41 positive sera. We purified these proteins and analyzed the immunological reactivity by dot blot with the 60 positive sera and the 84 normal sera. As little as 20 ng of the dotted proteins was enough for the reaction with the positive sera, whereas as much as 320 ng of them did not show false-positive reactions with the normal sera. We obtained highly purified Gag-Env proteins with highly specific seroreactivity, which should be useful for diagnosis and prognosis.
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PMID:Use of the recombinant chimera proteins, LacZ-Env and Gag-Env, for immunological studies on HIV-1 infection. 750 55

Lentiviruses, such as human immunodeficiency virus type 1 (HIV-1), assemble at and bud through the cytoplasmic membrane. Both the matrix (MA) domain of Gag and its amino-terminal myristylation have been implicated in these processes. We have created HIV-1 proviruses lacking the entire matrix domain of gag which either lack or contain an amino-terminal myristate addition sequence at the beginning of the capsid domain. Myristate- and matrix-deficient [myr(-)MA(-)] viruses produced after transient transfection are still able to assemble into particles, although the majority do not form at the plasma membrane or bud efficiently. Myristylation of the amino terminus of the truncated Gag precursor permits a much more efficient release of the mutant virions. While myr(-)MA(-) particles were inefficient in proteolytic processing of the Gag precursor, myristylation enabled efficient proteolysis of the mutant Gag. All matrix-deficient viruses are noninfectious. Particles produced by matrix-deficient mutants contain low levels of glycoproteins, indicating the importance of matrix in either incorporation or stable retention of Env. Since matrix-deficient viruses contain a normal complement of viral genomic RNA, a role for MA in genomic incorporation can be excluded. Contrary to previous reports, the HIV-1 genome does not require sequences between the 5' splice donor site and the gag start codon for efficient packaging.
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PMID:Efficient particle formation can occur if the matrix domain of human immunodeficiency virus type 1 Gag is substituted by a myristylation signal. 752 19

U-75875 inhibits human immunodeficiency virus types 1 and 2 and simian immunodeficiency virus (SIV) proteases and blocks Gag-Pol protein processing and viral maturation and replication in vitro. Rhesus monkeys were treated with vehicle alone or with formulated U-75875 at doses of 7 or 20 mg/kg of body weight per day for 26 days by continuous intravenous infusion beginning 6 h prior to intravenous inoculation with 10 monkey 50% infectious doses of SIV Delta B670, and the monkeys were monitored until death. The effects of treatment on the level of SIV p26 antigenemia, the infectious virus titer in serum, and the level of proviral DNA in blood mononuclear cells evaluated by PCR were assessed. SIV infection of the controls resulted in an initial viral antigenemia that began 5 to 10 days postinoculation (p.i.), reached peak values on days 10 to 14 p.i., and lasted for more than 15 days. Proviral DNA was detectable in peripheral blood mononuclear cells by 7 to 11 days p.i., reached the mean peak level by 11 days p.i., and remained at high levels through day 24 p.i. Infectious virus was detected in serum from all of the infected controls by 24 days p.i. Treatment with U-75875 for 26 days resulted in a dose-related delay in the day of the peak level of antigenemia (P = 0.034). The level of proviral DNA in peripheral blood mononuclear cells at 11 days p.i. was significantly decreased in a dose-related fashion in the treated monkeys ( P </- 0.048), with a delay in the attainment of the peak level of proviral DNA in the treated groups. The titer of infectious virus in the serum of the group treated with 20 mg/kg/day was significantly decreased on day 24 p.i. compared with that in the serum of controls ( P = 0.046). Treatment with formulated U-75875 was well tolerated in rhesus monkeys and resulted in an inhibitory effect of SIV in vivo.
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PMID:Effects of U-75875, a peptidomimetic inhibitor of retroviral proteases, on simian immunodeficiency virus infection in rhesus monkeys. 752 27

The structural proteins of human immunodeficiency virus type 1, for example, Gag and Env, are encoded by unspliced and incompletely spliced viral transcripts. The expression of these mRNAs in the cytoplasm, along with their commensurate translation, is absolutely dependent on the virally encoded Rev trans activator. Previous studies have demonstrated that Rev binds directly to its substrate mRNAs via an arginine-rich element that also serves as its nuclear localization sequence. In an attempt to define the specific amino acid residues that are important for in vivo activity, we have constructed a series of missense mutations that scan across this region. Our data demonstrate that all eight arginine residues within this element can, individually, be substituted for either leucine or lysine with no apparent loss of function. Importantly, these findings suggest that no single amino acid within the arginine-rich domain of Rev is, by itself, essential for activity and that considerable functional redundancy is therefore likely to exist within this region. Interestingly, one mutant in which a tryptophan had been substituted for a serine failed to accumulate exclusively in the nucleus but still bound RNA in a manner that was indistinguishable from that of the wild-type protein. This observation indicates that features of the arginine-rich region that are additional to those required for RNA binding are important for Rev's correct accumulation in the nucleus.
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PMID:Scanning mutagenesis of the arginine-rich region of the human immunodeficiency virus type 1 Rev trans activator. 752 98

T epitope mapping in human immunodeficiency virus proteins provides a useful tool for AIDS vaccine design. We have previously shown that four peptides selected from the Gag polyprotein of HIV-1 were able to prime mice for in vitro lymphoproliferative responses. These responses were shown to be MHC restricted, and a pool of these peptides was able to prime mice for a subsequent humoral response to HIV-1 Gag proteins. Here we show that two of these Gag peptides are able to prime the anti-HIV-1 IgG response to heat-inactivated HIV-1 in B10Sc.Cr mice. Furthermore, we extended this study in the nonhuman primate model, and show efficient priming of the IgG response to heat-inactivated HIV-1 using the pool of four Gag peptides in baboons. Further mapping of "nonself" peptides is extended to the HIV-1 Nef protein. Three potential Nef T epitopes located at positions 137-145, 98-107, and 81-95 are also shown to prime the IgG response to HIV-1 in the mouse model, although T cell proliferation to recall peptides in vitro was not detectable. Although they have not yet been defined as major helper T epitopes in humans, using classic in vitro stimulation assays, the fact that most of them are able to prime IgG responses in animals without detectable in vitro proliferative responses does not rule out their functional helper capacity in humans.
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PMID:Nef and Gag synthetic peptide priming of antibody responses to HIV type 1 antigens in mice and primates. 753 60

The human immunodeficiency virus type 1 (HIV-1) protease is the enzyme required for processing of the Gag and Gag-Pol polyproteins to yield mature, infectious virions. Although the complete absence of proteolytic activity prevents maturation, the level of activity sufficient for maturation and subsequent infectivity has not been determined. Amino acid substitutions that reduce catalytic activity without affecting substrate recognition have been engineered into the active site of the HIV-1 protease. The catalytic efficiency (kcat) of the HIV-1 protease is decreased 4-fold when threonine 26 is replaced by serine (T26S) and approximately 50-fold when alanine 28 is replaced by serine (A28S). Genes containing these mutations were cloned into a proviral vector for analysis of their effects on virion maturation and infectivity. The results show that virions containing the T26S protease variant, in which only 25% of the protease is active, are very similar to wild-type virions, although slight reductions in infectivity are observed. Virions containing the A28S protease variant are not infectious, even though a limited amount of polyprotein processing does occur. There appears to be a linear correlation between the level of protease activity and particle infectivity. Our observations suggest that a threshold of protease activity exists between a 4-fold and 50-fold reduction, below which processing is insufficient to yield infectious particles. Our data also suggest that a reduction of protease activity by 50-fold or greater is sufficient to prevent the formation of infectious particles.
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PMID:Defining the level of human immunodeficiency virus type 1 (HIV-1) protease activity required for HIV-1 particle maturation and infectivity. 753 64

The human immunodeficiency virus type-1 (HIV-1) integrase protein (IN) mediates the insertion of linear double-stranded viral DNA into the host genome. Mutations in IN can have different effects on the virus life cycle. In this study, Gag-Pol polyprotein processing, Tat synthesis, and viral replication were investigated in integrase-defective HIV-1 mutants. In the absence of IN synthesis, the Gag-Pol polyprotein stability, packaging, and/or processing was reduced. There was limited expression of Tat observed in IN mutants, but no viral replication.
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PMID:Analysis of human immunodeficiency virus type 1 integrase mutants. 749 94


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