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 immunologic and genetic analysis of a 14-week-old-male cardigan Welsh corgi puppy that presented with failure to thrive, diarrhea, and intermittent vomiting are described. The lack of palpable lymph nodes, the premature death of a male sibling, and similar clinical signs in a male cousin suggested that a primary immunodeficiency disease might be responsible for his poor clinical condition. Quantitation of serum immunoglobulins revealed low concentrations of IgG and undetectable IgA, yet normal concentrations of IgM. A complete blood cell count showed a slight anemia and lymphopenia. Although the peripheral blood contained a normal percentage of T cells, with an increased CD4:CD8 ratio, they were unable to proliferate in response to phytohemagglutinin (PHA) and/or interleukin 2 (IL-2). Furthermore, following PHA activation, the peripheral blood lymphocytes (PBL) demonstrated a nearly complete lack of IL-2 binding. All of these laboratory findings were identical with our previous findings from dogs with X-linked severe combined immunodeficiency (XSCID) that is due to a mutation in their IL-2 receptor gamma (IL-2R gamma) chain. Examination of the corgi's IL-2R gamma cDNA revealed an insertion of a cytosine following nucleotide 582, resulting in a premature stop codon prior to the transmembrane domain. The insertion also created an EcoO109 restriction enzyme site that enabled us to detect the mutation in the patient's genomic DNA. This new mutation in the IL-2R gamma chain discovered in a cardigan Welsh corgi puppy results in XSCID with similar immunologic abnormalities as observed in dogs with the same disease resulting from a different IL-2R gamma chain mutation.
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PMID:A single nucleotide insertion in the canine interleukin-2 receptor gamma chain results in X-linked severe combined immunodeficiency disease. 857 41

The mechanisms of immune suppression by the human immunodeficiency virus, HIV-1, are more complex than simple helper T cell deletion via infection and viral-induced lysis. Since the recent description of cellular proteins associated with HIV suggests that these proteins may be active in viral pathogenesis, the nature of HLA class II gene product carried on HIV, one of the most abundant of the human components carried with the virus, was examined. HIV bearing HLA-DR was shown to act with bacterial superantigen, staphylococcal enterotoxin A (SEA), to stimulate highly purified human T lymphocytes. T cell stimulation by wild-type HIV was shown by both induction of proliferation and by production of the cytokine interleukin 2 (IL-2). In contrast, HIV produced from mutant cells lacking class II genes were unable to cooperate with SEA to activate T cells. Neither whole HIV nor several proteins purified from HIV (gp120, gp41, p24, p7, and p6) exhibited superantigen-like activity in this system. HLA-DR-bearing HIV could, in the continued presence of SEA, induce T cell apoptosis, as detected by nuclear fragmentation and morphological criteria. These data indicate that human cellular proteins associated with HIV may be biologically active, and these proteins should be considered in mechanisms of viral pathogenicity and immunogenicity.
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PMID:HLA class II on HIV particles is functional in superantigen presentation to human T cells: implications for HIV pathogenesis. 867 86

When administered in high doses to HIV positive (HIV+) individuals, interleukin 2 (IL-2) causes extreme toxicity and markedly increases plasma HIV levels. Integration of the information from the structure-activity relationships of the IL-2 receptor interaction, the cellular distribution of the different classes of IL-2 receptors, and the pharmacokinetics of IL-2 provides for the rationale that low IL-2 doses should circumvent toxicity. Therefore, to identify a nontoxic, but effective and safe IL-2 treatment regimen that does not stimulate viral replication, doses of IL-2 from 62,500 to 250,000 IU/m2/day were administered subcutaneously for 6 months to 16 HIV+ individuals with 200-500 CD4+ T cells/mm3. IL-2 was already detectable in the plasma of most HIV+ individuals even before therapy. Peak plasma IL-2 levels were near saturating for high affinity IL-2 receptors in 10 individuals who received the maximum nontoxic dose, which ranged from 187,500 to 250,000 IU/m2/day. During the 6 months of treatment at this dose range, plasma levels of proinflammatory cytokines remained undetectable, and plasma HIV RNA levels did not change significantly. However, delayed type hypersensitivity responses to common recall antigens were markedly augmented, and there were IL-2 dose-dependent increases in circulating Natural Killer cells, eosinophils, monocytes, and CD4+ T cells. Expanded clinical trials of low dose IL-2 are now warranted, especially in combination with effective antivirals to test for the prevention of immunodeficiency and the emergence of drug-resistant mutants and for the eradication of residual virions.
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PMID:Rational interleukin 2 therapy for HIV positive individuals: daily low doses enhance immune function without toxicity. 881 13

Correlates of progression of human immunodeficiency virus (HIV) infection to AIDS include the reduction in CD4+ T cells and the emergence of syncytium-inducing (SI) HIV variants. It has been suggested that progressive defects in interleukin 2 (IL-2), IL-12, and IFN- gamma production (type 1 cytokines), and increased production of IL-4 (and of IL-4-driven hyper-IgE), IL-6, and IL-10 (type 2 cytokines), could provide another correlate of disease progression. To determine the possible association among these markers, viral phenotype, cytokine production, IgE serum concentration, and rate of CD4 depletion were analyzed in a cohort of vertically HIV-infected children. We report that significantly higher production of type 2 cytokines and augmented IgE concentration are observed in children in whom HIV SI is isolated. In addition, we observed that the isolation of HIV SI and the production of high quantities of type 2 cytokines are correlated with increased loss of CD4 T cells in the 12 months preceding the determinations. These data suggest that the virologic and immunologic parameters characteristic of advanced HIV infection may be associated in pediatric HIV infection, and indicate a virologic-immunologic pathogenesis leading to the appearance of AIDS.
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PMID:Virologic and immunologic markers of disease progression in pediatric HIV infection. 887 Aug 47

The role of cytokines in the regulation and function of the immune system is of great importance. In human immunodeficiency virus (HIV) infection, with progressive deterioration of cell-mediated immune response, cytokines are dysregulated. We have therefore investigated cytokine mRNA expression in type-1 and type-2 helper T cells of HIV-seropositive (HIV+) individuals, stimulated with mitogen (leukoagglutinin) and HIV-1 Tat and Rev peptides, previously found to induce proliferative T-cell responses in these individuals. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect interleukin 2 (IL-2), interferon gamma (IFN-gamma), IL-4, and IL-10 mRNAs. There was no difference in the mRNA expression of these cytokines when the cells of HIV-infected or noninfected individuals were polyclonally stimulated with the mitogen, as all cytokine mRNAs were detected in both groups. Baseline cytokine expression of unstimulated cells was, however, different in these two groups: the cells of HIV+ persons did not show comparable expression of mRNAs to HIV-seronegative (HIV+) individuals. When the cells of HIV+ individuals were stimulated with the peptides, 70% of the cases showed IL-10 mRNA expression, 20% IFN-gamma, and 10% IL-2, with no detection of IL-4 mRNA in any of the cases. Our results thus show that HIV-specific T-cell antigens induce production of IL-10 in HIV-infected individuals. The increase in IL-10 demonstrated here may have a role in hyperactivation of B cells, as well as in immunosuppression of T cells often seen in HIV-infected individuals.
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PMID:Interleukin-10 gene expression induced by HIV-1 Tat and Rev in the cells of HIV-1 infected individuals. 889 65

Profound cellular immunodeficiency occurs as the result of mutations in proteins involved in both the differentiation and function of mature lymphoid cells. We describe here a novel human immune aberration arising from a truncation mutation of the interleukin-2 receptor alpha chain (CD25), a subunit of the tripartite high-affinity receptor for interleukin 2. This immunodeficiency is characterized by decreased numbers of peripheral T cells displaying abnormal proliferation but normal B cell development. Extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone, is observed, accompanied by tissue atrophy and inflammation. Although mature T cells are present, the absence of CD25 does affect the differentiation of thymocytes. While displaying normal development of CD2, CD3, CD4, and CD8 expression, CD25-deficient cortical thymocytes do not express CD1, and furthermore they fail to normally down-regulate levels of the anti-apoptotic protein bcl-2.
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PMID:Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. 909 64

Live attenuated simian immunodeficiency virus (SIV) vaccines, like nef deletion mutants, have been the most effective vaccines tested in the SIV/macaque model so far. The efficacy of live attenuated SIV vaccines in therapeutic vaccination and postexposure prophylaxis has not been determined. Inoculation of macaques with a pathogenic challenge virus and an attenuated SIV vaccine at the same time mimics postexposure vaccination, whereby vaccination with the attenuated virus is performed as rapidly as possible after exposure to pathogenic SIV. In the study presented here, four rhesus macaques were coinfected with pathogenic SIV and a nearly 3000-fold excess of a nef deletion mutant of SIV. Four macaques received pathogenic SIV and an approximately 200-fold excess of a nef deletion mutant expressing interleukin 2 (IL-2). The IL-2-expressing SIV had been previously constructed to enhance the immunogenicity of live attenuated SIV vaccines. All coinfected macaques had a high viral load, and some of them developed AIDS-like symptoms and pathological alterations rapidly. In the presence of pathogenic SIV, both live attenuated SIV vaccines did not protect from disease in this postexposure vaccination model.
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PMID:Live attenuated SIV vaccines are not effective in a postexposure vaccination model. 913 77

The proliferative responses to four gag peptides were examined in 24 HIV-seropositive patients whose CD4 counts ranged between 500 and 1400 cells/mm3. To overcome some of the limitations imposed by HIV infection on the T-cell proliferative assay, recombinant interleukin 2 (rIL-2) was added to the cultures, and the culture time of the cells was increased from the standard 6 to 8 or 10 days. Four of 24 patients responded to one or more core peptides, aa180-194, 208-217, 267-286, and 287-306 by the standard 6-day culture: this increased to 13 of 24 using the optimized culture approach. The greatest number and magnitude of responses occurred after cells were in culture for 8 days. Eight patients responded to gag 180-194, which has not been identified previously as a TH epitope in humans but has considerable homology with a TH epitope recognized by cloned T cells from macaques immunized with simian immunodeficiency virus (SIV). We have identified four T-cell epitopes on the HIV core protein p24, using synthetic peptides as immunogens. Three of the peptides would not have been considered immunogenic had the standard assay system been used to detect T-cell responsiveness. We have also shown that a region of the core protein encompassed by aa180-194 is recognized by TH cells in humans.
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PMID:T-cell response to HIV in natural infection: optimized culture conditions for detecting responses to gag peptides. 929 83

SIVsmmPBj14 is a highly pathogenic lentivirus which causes acute diarrhea, rash, massive lymphocyte proliferation predominantly in the gastrointestinal tract, and death within 7 to 14 days. In cell culture, the virus has mitogenic effects on resting macaque T lymphocytes. In contrast, SIVmac239 causes AIDS in rhesus macaques, generally within 2 years after inoculation. In a previous study, replacement of amino acid residues 17 and 18 of the Nef protein of SIVmac239 with the corresponding amino acid residues of the Nef protein of SIVsmmPBj14 yielded a PBj-like virus that caused extensive activation of resting T lymphocytes in cultures and acute PBj-like disease when inoculated into pig-tailed macaques. This study suggested that nef played a major role in both processes. In this study, we replaced the nef/long terminal repeat (LTR) region of a nonpathogenic simian-human immunodeficiency virus (SHIV), SHIVPPc, with the corresponding region from SIVsmmPBj14 and examined the biological properties of the resultant virus. Like SIVsmmPBj14, SHIVPPcPBjnef caused massive stimulation of resting peripheral blood mononuclear cells (PBMC), which then produced virus in the absence of extraneous interleukin 2. However, when inoculated into macaques, the virus failed to replicate productively or cause disease. Thus, while these results confirmed that the nef/LTR region of SIVsmmPBj14 played a major role in the activation of resting PBMC, duplication of the cellular activation process in macaques may require a further interaction between nef and the envelope glycoprotein of simian immunodeficiency virus because SHIV, containing the envelope of human immunodeficiency virus type 1, failed to cause activation in vivo.
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PMID:Simian-human immunodeficiency virus (SHIV) containing the nef/long terminal repeat region of the highly virulent SIVsmmPBj14 causes PBj-like activation of cultured resting peripheral blood mononuclear cells, but the chimera showed No increase in virulence. 957 93

Live attenuated simian immunodeficiency viruses (SIV), such as nef deletion mutants, are the most effective vaccines tested in the SIV-macaque model so far. To modulate the antiviral immune response induced by live attenuated SIV vaccines, we had previously infected rhesus monkeys with a nef deletion mutant of SIV expressing interleukin 2 (SIV-IL2) (B. R. Gundlach, H. Linhart, U. Dittmer, S. Sopper, S. Reiprich, D. Fuchs, B. Fleckenstein, G. Hunsmann, S. Stahl-Hennig, and K. Uberla, J. Virol. 71:2225-2232, 1997). In the present study, SIV-IL2-infected macaques and macaques infected with the nef deletion mutant SIVDeltaNU were challenged with pathogenic SIV 9 to 11 months postvaccination. In contrast to the results with naive control monkeys, no challenge virus could be isolated from the SIV-IL2- and SIVDeltaNU-infected macaques. However, challenge virus sequences could be detected by nested PCR in some of the vaccinated macaques. To determine the role of immune responses directed against Env of SIV, four vaccinated macaques were rechallenged with an SIV-murine leukemia virus (MLV) hybrid in which the env gene of SIV had been functionally replaced by the env gene of amphotropic MLV. All vaccinated macaques were protected from productive infection with the SIV-MLV hybrid in the absence of measurable neutralizing antibodies, while two naive control monkeys were readily infected. Since the SIV-MLV hybrid uses the MLV Env receptor Pit2 and not CD4 and a coreceptor for virus entry, chemokine inhibition and receptor interference phenomena were not involved in protection. These results indicate that the protective responses induced by live attenuated SIV vaccines can be independent of host immune reactions directed against Env.
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PMID:Env-independent protection induced by live, attenuated simian immunodeficiency virus vaccines. 973 21


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