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)

Earlier findings indicate that peptides can affect the expression of major histocompatibility complex (MHC) class I molecules on the surface of cells with defective peptide loading mechanism. We have used peptide induced increase of class I antigen expression to assess peptide interaction with MHC class I molecules. A panel of 41 overlapping synthetic peptides derived from the human immunodeficiency virus-1 (HIV-1) gag protein and 33 nonoverlapping peptides from Epstein-Barr virus (EBV) proteins EBNA-1, 2, 3, 4, 5, 6, LMP, BZLF2, BILF2, BSLF2, BALF4 and BcLF1 was assessed for the ability to enhance the expression of HLA-A2.1, H-2Db, Kb and Dd on the murine RMA-S and human 721.174/T2 (.174/T2) lines by indirect immunofluorescence. Considering doubling of the fluorescence intensity in the peptide-treated samples as positivity, 6 of 39 HIV and 1 of 32 EBV peptides were found to bind to A2.1, 6 of 39 HIV gag and 7 of 16 EBV peptides to Db, 8 of 39 HIV gag and 5 of 16 EBV peptides to Kb and 2 of 39 HIV gag and 1 of 17 EBV peptides to Dd. The sensitivity of the method is comparable to the in vitro class I assembly assay with conformation-dependent monoclonal antibody and is more discriminating than the solid-phase assay. Due to its simplicity this method can also serve for testing large peptide panels for binding capacity to various class I molecules. Moreover, the method provides information about the relevance of in vitro tests for class I assembly in living cells.
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PMID:Assessment of major histocompatibility complex class I interaction with Epstein-Barr virus and human immunodeficiency virus peptides by elevation of membrane H-2 and HLA in peptide loading-deficient cells. 132 2

To identify the target proteins of CD8+ T lymphocytes we have explored the cytolytic immune responses of 12 rhesus macaques experimentally infected with the simian immunodeficiency virus (SIVmac). Target cells were autologous B cell lines presenting SIVmac proteins after infection with recombinant vaccinia viruses. The eight following proteins were studied: ENV, POL, GAG, NEF, VIF, REV, TAT, and VPX. Macaque PBMC stimulated with Con A and expanded in T cell growth factor-containing medium produced cell lines with cytolytic activity in the majority of infected animals (9/12). The structural proteins ENV, POL, and GAG were recognized by cell lines derived from nine, eight, and six macaques, respectively. The small regulatory proteins also represented efficient CTL targets, a specific activity being detected against NEF (8/12), REV (7/12), VPX (7/12), TAT (6/12), and VIF (5/12). Most cytotoxic responses (except those directed against ENV) were mediated by CD8 cells and were MHC class I restricted. Limiting dilution analysis allowed us to quantify the frequency of CTL precursors and confirmed the high immunogenicity of multiple SIV proteins. Three different patterns of response could be defined: six animals were able to recognize at least six of the eight tested target proteins, two of them reacting with all eight target proteins. The other three responder macaques reacted only against a few SIV proteins, whereas no cytotoxic activity was detected in the three remaining infected macaques and in the nine negative controls. The six animals responding against multiple proteins were still healthy 12 to 22 mo after infection with two of them presenting a decrease in circulating CD4 cells concurrently to the disappearance of the CTL response. Conversely, three nonresponder or low responder macaques developed an overt disease after 4 to 12 mo, and two other presented a very low level of CD4 cells, suggesting that the pattern of response may be of prognostic value.
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PMID:Cytotoxic T lymphocyte response against multiple simian immunodeficiency virusA (SIV) proteins in SIV-infected macaques. 134 22

Studies to date assessing HIV escape from CTL in vivo have yielded conflicting results. Previous studies have demonstrated that simian immunodeficiency virus of macaques (SIVmac)-infected rhesus monkeys expressing the MHC class I allele Mamu-A*01 reproducibly develop a gag-specific CTL response limited to a 9-amino acid epitope of the SIVmac gag protein (residues 182-190 within peptide 11C). To determine whether CTL have a role in selecting for AIDS virus mutants, we examined mutations in SIVmac proviral DNA encoding this gag CTL epitope in PBL of infected rhesus monkeys. Three Mamu-A*01+ rhesus monkeys were infected with SIVmac and assessed for gag- and peptide 11C-specific CTL responses. This specific CTL response was maintained in two monkeys, but lost in the third animal 2 yr after infection. The generation of proviral gag mutations was then determined by sequencing 500-bp proviral fragments amplified from fresh PBL obtained from the monkeys more than 2.5 yr after infection. Although numerous point mutations were characterized in 131 polymerase chain reaction-generated clones of SIVmac gag, only four mutations within the gag CTL epitope-coding region of the genome were identified. Comparison of synonymous and nonsynonymous nucleotide substitutions in the regions encoding peptide 11C (p11C) and the flanking gag protein indicated a lack of selective pressure for viral mutations in the CTL epitope coding region. Interestingly, a predominant gag mutant encoding a single amino acid change in p11C was found in a monkey which lost its CTL activity. However, even in this setting there was no evidence for selection of mutations in the CTL epitope coding region when compared with the flanking region. Furthermore, synthetic peptides corresponding to all naturally occurring variants in the gag epitope-coding region were recognized by cloned and bulk cultured effector cells of the infected monkeys with persistent CTL. These results indicate that SIVmac gag- and p11C-specific CTL do not select for mutations in the immunodominant epitope-coding region and that the naturally occurring mutants do not appear to escape CTL recognition.
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PMID:Cytotoxic T lymphocytes do not appear to select for mutations in an immunodominant epitope of simian immunodeficiency virus gag. 146 Feb 91

An effective vaccine against the human immunodeficiency virus should be capable of eliciting both an antibody and a cytotoxic T lymphocyte (CTL) response. However, when viral proteins and peptides are formulated with traditional immunological adjuvants and inoculated via a route acceptable for use in humans, they have not been successful at eliciting virus-specific, major histocompatibility complex (MHC) class I-restricted CTL. We have designed a novel viral subunit vaccine by encapsulating a previously defined synthetic peptide CTL epitope of the simian immunodeficiency virus (SIV) gag protein within a proteoliposome capable of attaching to and fusing with plasma membranes. Upon fusing, the encapsulated contents of this proteoliposome can enter the MHC class I processing pathway through the cytoplasm. In this report, we show that after a single intramuscular vaccination, rhesus monkeys develop a CD8+ cell-mediated, MHC class I-restricted CTL response that recognizes the synthetic peptide immunogen. The induced CTL also demonstrate antiviral immunity by recognizing SIV gag protein endogenously processed by target cells infected with SIV/vaccinia recombinant virus. These results demonstrate that virus-specific, MHC class I-restricted, CD8+ CTL can be elicited by a safe, nonreplicating viral subunit vaccine in a primate model for acquired immune deficiency syndrome. Moreover, the proteoliposome vaccine formation described can include multiple synthetic peptide epitopes, and, thus, offers a simple means of generating antiviral cell-mediated immunity in a genetically heterogeneous population.
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PMID:Vaccination of rhesus monkeys with synthetic peptide in a fusogenic proteoliposome elicits simian immunodeficiency virus-specific CD8+ cytotoxic T lymphocytes. 146 Apr 29

Antigenic peptides bound to class I molecules of the major histocompatibility complex (MHC) are recognized by T-cell receptors during development of an antiviral immune response. T cells respond to peptides derived from cytoplasmic viral proteins as well as viral membrane proteins, indicating that a pathway exists for the transport of proteins or peptides from the cytosol into the compartment(s) where the MHC class I molecules assemble. To investigate this pathway, we have developed an in vitro assay for the transport of peptides into microsomal vesicles. This assay provides evidence for the transport of chemically synthesized peptides (13-21 amino acids) containing N-linked glycosylation acceptor sequences, which serve as glycosylation substrates. Their transport results in depletion of the pool of available dolichol high-mannose oligosaccharides in the lumen of the microsomal vesicles. We have observed transport of peptides derived from antigenic human immunodeficiency virus gag and influenza B nucleoprotein sequences, but transport of a third randomly selected peptide was not detected, suggesting specificity of the transport process. We were not able to demonstrate ATP dependence of this peptide transport process by using apyrase and an ATPase inhibitor. This result was unexpected in light of the recent identification of MHC-linked genes with homology to ATP-binding cassette transporters, which have been proposed to mediate peptide transport.
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PMID:Evidence for peptide transport across microsomal membranes. 157 Mar 12

Progressive multifocal leukoencephalopathy (PML) is caused by JC virus (JCV) infection of the central nervous system (CNS) in immunosuppressed patients. The immunopathogenesis of this chronic encephalitis is unknown. Because major histocompatibility (MHC) class I and class II antigens are important in modulating the immune response and viral clearance, we examined the tissue expression of MHC molecules in relation to CNS damage and presence of virus. By immunocytochemical staining, both MHC class I and class II antigens were expressed at high levels within PML lesions. Beta-2 microglobulin (beta-2m) was present on endothelial cells and JCV-infected oligodendroglia within the lesions. Also, many astrocytes with bizarre morphology expressed MHC class I antigens. In histologically normal regions of PML brains expression of beta-2m was noted only on endothelial cells. Expression of MHC class II also was focused within demyelinating lesions and was restricted to macrophages/microglia and occasional endothelial cells. When compared to other viral encephalitides (e.g. human immunodeficiency virus) these findings suggest that intra-CNS immune response to JCV is appropriate for antigenic presentation; however, the absence of responsive systemic T-cells may lead to chronic viral infection with progressive neuropathology.
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PMID:Expression of major histocompatibility complex antigens in the brains of patients with progressive multifocal leukoencephalopathy. 158 32

An antigen-specific feline T-lymphocyte cell line (Q201) was generated and infected in vitro with the feline immunodeficiency virus (FIV). Syncytium formation and the release of the viral core protein p24 into culture fluid were accompanied by a reduction in expression of the CD4 surface antigen. The reduction in CD4 expression was transient, the resulting persistently infected population of cells expressing levels of CD4 comparable to those observed prior to infection. Persistently infected cells gradually lost expression of major histocompatibility antigen (MHC) class II while maintaining pre-infection levels of expression of CD4, MHC class I, CD18 or CD29.
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PMID:Productive infection of T-helper lymphocytes with feline immunodeficiency virus is accompanied by reduced expression of CD4. 168 47

CD8+ CTL inhibit the replication of HIV and simian immunodeficiency virus of macaques (SIVmac) in PBL and, therefore, are likely to play an important role in containing the spread of the AIDS virus in infected individuals. We have generated a series of gag-specific lytic T lymphocyte clones from PBL: of an SIVmac-infected rhesus monkey. These T cell clones are CD3+CD8+ and are MHC class I-restricted in their target specificity. They are, therefore, CTL. Interestingly, all gag-specific CTL clones, as well as the gag-specific lytic activity of PBL of this monkey, demonstrated specificity for a single 25 amino acid fragment of the SIVmac gag protein. Moreover, they were restricted in their lytic function by a single MHC class I allele. These findings illustrate a powerful method for cloning AIDS virus-specific T lymphocytes and demonstrate a remarkably restricted epitope specificity of this AIDS virus-specific CTL response.
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PMID:Studies of cloned simian immunodeficiency virus-specific T lymphocytes. gag-specific cytotoxic T lymphocytes exhibit a restricted epitope specificity. 169 57

We have shown by site-directed mutagenesis that the sequence between positions -69 and -40 of the mouse alpha A-crystallin gene is crucial for tissue-specific gene expression in a transfected mouse lens epithelial cell line transformed with the early region of simian virus 40. Gel retardation experiments with synthetic oligodeoxynucleotides revealed a mouse lens nuclear protein which bound specifically to the palindromic sequence 5'-GGGAAATCCC-3' at positions -66 to -57 in the alpha A-crystallin promoter. By screening a bacteriophage lambda gt11 expression library of the transformed lens cells, we isolated a 2.5-kilobase-pair cDNA encoding a fusion protein which bound to this sequence and to the regulatory element of the major histocompatibility complex (MHC) class I gene. This cDNA hybridized to a 10-kilobase-pair polyadenylated RNA present in many different tissues, including lens. It encoded a protein, tentatively called alpha A-CRYBP1, containing at least two zinc fingers. alpha A-CRYBP1 is either homologous or very similar to the human nuclear proteins MBP-1 (Baldwin et al., Mol. Cell. Biol. 10:1406-1414, 1990), PRDII-BFI (Fan and Maniatis, Genes Dev. 4:29-42, 1990), and HIV-EP1 (Maekawa et al., J. Biol. Chem. 264:14591-14593, 1989), which bind to regulatory elements of the MHC class I, beta interferon, and human immunodeficiency virus genes, respectively. Our results suggest that the lens-specific alpha A-crystallin, MHC class I, beta interferon and other genes have a similar cis-acting DNA regulatory motif that shares alpha A-CRYBPI, MBP-1, PRDII-BF1, HIV-EP1, or other closely related proteins as trans-acting factors.
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PMID:Regulation of the mouse alpha A-crystallin gene: isolation of a cDNA encoding a protein that binds to a cis sequence motif shared with the major histocompatibility complex class I gene and other genes. 169 16

Evidence indicates that cytotoxic T lymphocytes (CTLs) may be important in containing the spread of the human immunodeficiency virus (HIV) in the infected host. Although the use of recombinant viruses has been proposed as an approach to elicit protective immunity against HIV, the ability of recombinant viral constructs to elicit CD8+ CTL responses in higher primates has never been demonstrated. A live recombinant virus, vaccinia-simian immunodeficiency virus of macaques (SIVmac), was used to determine whether such a genetically restricted, T lymphocyte-mediated antiviral response could be generated in a primate. Vaccinia-SIVmac vaccination elicited an SIVmac Gag-specific, CD8+ CTL response in rhesus monkeys. These CTLs recognized a peptide fragment that spans residues 171 to 195 of the Gag protein. The rhesus monkey major histocompatibility complex (MHC) class I gene product restricting this CTL response was defined. Both the vaccinated and SIVmac-infected monkeys that shared this MHC class I gene product developed CTLs with the same Gag epitope specificity. These findings support the use of recombinant virus vaccines for the prevention of HIV infections in humans.
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PMID:Recombinant virus vaccine-induced SIV-specific CD8+ cytotoxic T lymphocytes. 170 68


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