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)

CD4 is the predominant cell membrane protein that binds human immunodeficiency virus type 1 (HIV-1) gp120 and facilitates HIV-1 infection, but other membrane-associated molecules may be involved in determining HIV-1 cellular infection. Our prior work had suggested that CD44, the transmembrane receptor for hyaluronan, might play a role in the infection of mononuclear phagocytes with HIV-1. In the present work, we have used cells of the CD4-positive, CD44-negative human T-lymphoblast cell line Jurkat to study the role of CD44 in HIV-1 infection and tropism. Cells were transfected with cDNA for the standard (S, or hematopoietic) CD44 isoform CD44S or the epithelial isoform CD44E. The resultant lines expressed appropriate CD44S or CD44E mRNA and protein. While the parent Jurkat cells, those transfected with vector alone, and those transfected with CD44E could be productively infected with only the lymphocytotropic strain HIV-1-LAI, cells transfected with CD44S were rendered susceptible to productive infection with the monocytotropic strains HIV-1-BaL and HIV-1-ADA. Also, CD44S-transfected cells displayed higher levels of infection with HIV-1-LAI than did the other transfected Jurkat cells. The transfected cell line cells all had comparable growth rates and expressed similar levels of the membrane antigens CD4, CD7, major histocompatibility complex (MHC) class I, MHC class II, and CD11a, while levels of CD3 were slightly higher in cells transfected with vector alone and in one of the clones transfected with CD44S. Hyaluronan binding was increased in cells transfected with either CD44S or CD44E. Mouse NIH 3T3 fibroblasts transfected with human CD4, human CD44S, or both human CD4 and CD44S displayed the appropriate antigens, but they could not be productively infected with lymphocytotropic or monocytotropic strains of HIV-1. The results indicate that in human leukocytes, CD44S is an important determinant of HIV-1 productive infection and may be involved in viral cellular tropism.
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PMID:Cellular CD44S as a determinant of human immunodeficiency virus type 1 infection and cellular tropism. 753 3

Polyethylene glycol-modified adenosine deaminase (PEG-ADA) has now been used for 8.5 years as enzyme replacement therapy for immunodeficiency due to ADA deficiency. PEG-ADA restores a metabolic environment necessary for recovery of immune function. In most cases, the level of function achieved has been sufficient to protect against opportunistic and life-threatening infections. To date, mortality and morbidity with PEG-ADA have been less than for haploidentical bone marrow transplantation. As a true "orphan drug" used to treat a very small patient population, the cost per patient of PEG-ADA is very high, but it has been well tolerated, free of adverse reactions, and effective as an alternative for patients who lack an HLA-identical marrow donor, but are considered too ill to undergo haploidentical marrow transplantation. Concomitant treatment with PEG-ADA has also permitted investigation of gene therapy to be carried out safely.
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PMID:PEG-ADA replacement therapy for adenosine deaminase deficiency: an update after 8.5 years. 755 73

We investigated the relationship between the fusion selectivity of the envelope glycoprotein (env) and the tropism of different human immunodeficiency virus type 1 (HIV-1) isolates for CD4+ human T-cell lines vs. primary macrophages. Recombinant vaccinia viruses were prepared encoding the envs from several well-characterized HIV-1 isolates with distinct cytotropisms. Cells expressing the recombinant envs were mixed with various CD4+ partner cell types; cell fusion was monitored by a quantitative reporter gene assay and by syncytia formation. With CD4+ continuous cell lines as partners (T-cell lines, HeLa cells expressing recombinant CD4), efficient fusion occurred with the envs from T-cell line-tropic isolates (IIIB, LAV, SF2, and RF) but not with the envs from macrophage-tropic isolates (JR-FL, SF162, ADA, and Ba-L). The opposite selectivity pattern was observed with primary macrophages as cell partners; stronger fusion occurred with the envs from the macrophage-tropic than from the T-cell line-tropic isolates. All the envs showed fusion activity with peripheral blood mononuclear cells as partners, consistent with the ability of this cell population to support replication of all the corresponding HIV-1 isolates. These fusion selectivities were maintained irrespective of the cell type used to express env, thereby excluding a role for differential host cell modification. We conclude that the intrinsic fusion selectivity of env plays a major role in the tropism of a HIV-1 isolate for infection of CD4+ T-cell lines vs. primary macrophages, presumably by determining the selectivity of virus entry and cell fusion.
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PMID:Fusogenic selectivity of the envelope glycoprotein is a major determinant of human immunodeficiency virus type 1 tropism for CD4+ T-cell lines vs. primary macrophages. 756 61

Various cobalamins act as important enzyme cofactors and modulate cellular function. We investigated cobalamins for their abilities to modify productive human immunodeficiency virus-1 (HIV-1) infection of hematopoietic cells in vitro. We show that hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl), and adenosylcobalamin Ado-Cbl (Ado-Cbl) inhibit HIV-1 infection of normal human blood monocytes and lymphocytes. The inhibitory effects were noted when analyzing the monocytotropic strains HIV-1-BaL and HIV-1-ADA as well as the lymphocytotropic strain HIV-1-LAI. Cobalamins did not modify binding of gp120 to CD4 or block early steps in viral life cycle, inhibit reverse transcriptase, inhibit induction of HIV-1 expression from cells with established or latent infection, or modify monocyte interferon-alpha production. Because of the ability to achieve high blood and tissue levels of cobalamins in vivo and the general lack of toxicity, cobalamins should be considered as potentially useful agents for the treatment of HIV-1 infection.
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PMID:Inhibition of productive human immunodeficiency virus-1 infection by cobalamins. 763 33

Adenosine deaminase (ADA, EC 3.5.4.4) is a ubiquitous enzyme in the purine catabolic pathway. In contrast to the widespread tissue distribution of this enzyme, inherited ADA deficiency in human results in a tissue-specific severe combined immunodeficiency. To explain the molecular basis for this remarkable tissue specificity, we have used a genetic approach to study ADA deficiency. We demonstrate that ADA deficiency causes depletion of CD8low transitional and CD4+CD8+ double-positive thymocytes by an apoptotic mechanism. This effect is mediated by a p53-dependent pathway, since p53-deficient mice are resistant to the apoptosis induced by ADA deficiency. DNA damage, known to be caused by the abnormal accumulation of dATP in ADA deficiency, is therefore responsible for the ablation of T-cell development and for the immunodeficiency. The two thymocyte subsets most susceptible to apoptosis induced by ADA deficiency are also the two thymocyte subsets with the lowest levels of bcl-2 expression. We show that thymocytes from transgenic mice that overexpress bcl-2 in the thymus are rescued from apoptosis induced by ADA deficiency. Thus, the tissue specificity of the pathological effects of ADA deficiency is due to the low bcl-2 expression in CD8low transitional and CD4+CD8+ double-positive thymocytes.
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PMID:p53 expression is required for thymocyte apoptosis induced by adenosine deaminase deficiency. 766 98

The recent discovery of molecular defects in three forms of X-linked immunodeficiency has quickly transformed the study of immunodeficiency into one of the most exciting in basic and clinical immunology. The identification of defects in the IL-2R gamma chain in the etiology of X-linked SCID has suggested a heretofore unanticipated functional role of the gamma chain in immunologic development. While new and novel cytokines and cytokine receptors continue to be identified, it has become clear that our knowledge of IL-2, one of the best understood cytokine/receptor systems, is far from complete. Clarifying the molecular interactions between IL-2 and its receptor complex will improve the sophistication with which these interactions are manipulated in the clinic for the treatment of autoimmune disorders and allograft rejection, treatment of lymphoid malignancies, and cytokine-based therapies for immunotherapeutic treatment of nonlymphoid cancers. Recent gene therapy approaches to the treatment of children with the ADA-deficient form of SCID offers yet another exciting path for investigation. The use of retrovirally infected cord blood hematopoietic progenitor cells in attempts to reconstitute the immune system of ADA-deficient SCID children with ADA-producing cells raises the possibility of similarly "correcting" the defect in X-linked SCID. Such approaches almost certainly loom on the near horizon for other diseases. However, in view of the complexity and potentially pleiomorphic nature of defects in the IL-2R gamma chain, both in terms of their identification and correction, gene therapy for treatment of X-linked SCID will require a thorough understanding of the molecular nature of the respective defects. Effective therapy will require precise knowledge of the defects, in terms of their influence on the ligand, receptor, and signaling apparatus, as well as their potential effects on cells of multiple lineages. However, these caveats aside, the potential for understanding and correcting a disease that robs infants at so early an age of the potential for a normal life will continue to make these exciting and extraordinarily rewarding pursuits.
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PMID:Severe combined immunodeficiency, interleukin-2 (IL-2), and the IL-2 receptor: experiments of nature continue to point the way. 802 93

Lymphotropic strains of human immunodeficiency virus type 1 (HIV-1), including HTLV-IIIB, replicate poorly in macrophages. We have shown previously that lymphotropic HIV-1 fuses equally well with T lymphocytes and macrophages (M. J. Potash, M. Zeira, Z.-B. Huang, T. Pearce, E. Eden, H. Gendelman, and D. J. Volsky, Virology 188:864-868, 1992), suggesting that events in the virus life cycle following virus-cell fusion limit virus replication. We report here that HIV-1 DNA is synthesized efficiently in either ADA or HTLV-IIIB infected alveolar macrophages or monocyte-derived macrophages within 24 h of virus infection, as observed by polymerase chain reaction for amplification of viral DNA sequences from the gag gene. Infection by a cloned lymphotropic HIV-1 strain, N1T-A, also leads to viral DNA synthesis. However, circular viral DNA was detected during strain ADA infection but not during HTLV-IIIB or N1T-A infection of monocyte-derived macrophages. These findings indicate that during replication of lymphotropic HIV-1 in macrophages, all steps of the virus life cycle up to and including reverse transcription take place and that defects in later events, including DNA migration to the nucleus, may account for the limited production of viral proteins.
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PMID:Infection of macrophages with lymphotropic human immunodeficiency virus type 1 can be arrested after viral DNA synthesis. 841 94

The outer membrane glycoprotein gp120 and the transmembrane glycoprotein gp41 are predominant targets of the humoral immune response to infection by human immunodeficiency virus type 1. The third hypervariable region (V3 loop) is the principal neutralizing domain and is the primary target of neutralizing antibodies directed against the envelope proteins of HIV-1. The V3 loop is also the major determinant for HIV-1 cell-specific tropism. To further characterize the humoral immune response directed against the gp120 envelope proteins, we expressed two prototypic gp120 envelope proteins (LAI/HXB2 and ADA) and chimeric gp120 envelope proteins in stable transfected Drosophila melanogaster Schneider 2 cells. Sera from four infected adults over the course of infection [McNearney et al. (1992) Proc. natn. Acad. Sci. U.S.A. 89, p. 10,242] were assayed for reactivity with the respective envelope proteins. Sera obtained at early stages preferentially recognized the gp120 envelope protein ADA, whereas in later stages of infection the sera showed diminished reactivity with both gp120 LAI/HXB2 and gp120 ADA. Chimeric envelope proteins revealed that the humoral response was directed primarily against the V3 loop of gp120 ADA. Furthermore, 22 sera from HIV-1 infected individuals in different stages of the disease were tested. Reactivity of sera with the gp120 envelope protein ADA was seven-fold higher than with the gp120 envelope protein LAI/HXB2. Our results suggest that the humoral immune response is preferentially elicited against the V3 loop of the prototypic macrophage-tropic gp120 envelope protein ADA.
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PMID:Sera from HIV-1 infected individuals in all stages of disease preferentially recognize the V3 loop of the prototypic macrophage-tropic glycoprotein gp120 ADA. 854 53

Genetic manipulation of somatic cells may be of therapeutic value in a variety of infectious diseases, particularly in human immunodeficiency virus (HIV) infection. Stable insertion of "resistance genes" into cells, susceptible to HIV, could reduce the viral burden in infected individuals and potentially retard the characteristic progressive immune dysfunction. Alternatively, ectopic expression of genes that encode viral antigens, might induce potent antiviral immune responses and form the basis for novel prophylactic and therapeutic vaccines. While laboratory studies have proved that the approach works in principle, preclinical and clinical studies will be necessary to evaluate the therapeutic benefits of such gene-based therapies. Currently, more than 400 patients have already been treated by this innovative therapeutic strategy in the US. In Japan, the Expert Committee on Gene therapy was set up in the council on Science and the Public Health and Welfare in 1991. Recently, gene therapy for ADA has been approved. It is thought that the first gene therapy against HIV infection in Japan is not far away.
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PMID:[Gene therapy for AIDS: current trends]. 858 96

Adenosine deaminase (ADA; EC 3.5.4.4) deficiency in humans is an autosomal recessive genetic disorder that results in severe combined immunodeficiency disease. ADA-deficient mice generated by targeted gene disruption die perinatally, preventing postnatal analysis of ADA deficiency. We have recently rescued ADA-deficient fetuses from perinatal lethality by expression of an ADA minigene in the placentas of ADA-deficient fetuses, thus generating postnatal mice admissible to analysis of ADA deficiency. The minigene used also directed ADA expression to the forestomach postnatally, producing adult animals that lacked ADA enzymatic activity in all tissues outside the gastrointestinal tract. Mice with limited ADA expression exhibited profound disturbances in purine metabolism, including thymus-specific accumulations of deoxyadenosine and dATP, and inhibition of S-adenosylhomocysteine hydrolase in the thymus, spleen, and, to a lesser extent, the liver. Lymphopenia and mild immunodeficiency were associated with these tissue-specific metabolic disturbances. These mice represent the first genetic animal model for ADA deficiency and provide insight into the tissue-specific requirements of ADA.
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PMID:Metabolic and immunologic consequences of limited adenosine deaminase expression in mice. 866 40


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