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)

Eventually, gene therapy may be a valid option for chronic viral infections, including retroviral infections. Human retroviral diseases fit two categories: (1) those that result from a monoclonal outgrowth of a human T-cell leukemia virus type I (HTLV-I)-infected cell, as in the case of adult T cell leukemia (ATL); and (2) those that appear to result directly from virus load rather than monoclonal outgrowth--such as tropical spastic paraparesis/HTLV-I associated myelopathy (TSP/HAM) and human immunodeficiency virus (HIV)-associated acquired immune deficiency syndrome (AIDS). For ATL gene therapy, corrective mechanisms directed at regulatory sequences rather than viral sequences may be most important, though perhaps anti-tax therapy would be useful. For TSP/HAM and AIDS, gene therapy directed to control virus replication may be most useful. For anti-retroviral therapy, one may use dominant negative mutants and a variety of other approaches that direct toxins or compete out viral regulatory gene signal sequences. For maximum benefit, such therapy should be directed to different essential genes (eg gag, pol, env, tat or rev) involved in the virus replication cycle and utilize different toxic approaches. A major impediment to the use of gene therapy for AIDS is our inability to transfect a significant fraction of target cells in vivo. Except for reconstituted mice, retroviral systems of animals have been under-utilized as models for gene therapy. Naturally occurring retroviral diseases of cats, goats, horses, and other species provide models for future development.
Leukemia 1995 Oct
PMID:Gene therapy against retroviral diseases. 747 20

Current thrust in controlling the Acquired Immune Deficiency Syndrome (AIDS) focuses on antiviral drug development targeting the infection and replication of the human immunodeficiency virus (HIV), the causative agent of AIDS. To date, treatment of AIDS has relied on nucleoside reverse transcriptase inhibitors such as AZT, ddI, and ddC, which eventually become ineffective upon the emergence of resistant mutants bearing specific nucleotide substitutions. The Anti-AIDS Drug Screening Program of the NCI conducts and coordinates a high-capacity semi-robotic in vitro screening of synthetic or natural compounds submitted by academic, research and pharmaceutical institutions world-wide. About 10,000 synthetic compounds are screened annually for anti-HIV activity. Confirmed active agents are subjected to in-depth studies on range and mechanism of action. Emerging from this intense screening activity were a number of potentially promising categories of nonnucleoside reverse transcriptase inhibitors (NNRTI) with structural diversity but strong and reproducible anti-HIV activity. Over 2500 active compounds were evaluated for their inhibitory activity against a panel of both laboratory and clinical virus isolates in the appropriate established cell line or fresh human peripheral blood leukocyte and macrophage preparations. Out of these, 40 agents could be placed structurally in nine categories with an additional 16 unique compounds that share the characteristics of NNRTI. These NNRTIs were shown to inhibit reverse transcriptase enzymatically using homopolymeric or ribosomal RNA as templates. NNRTIs demonstrated similarity in their inhibitory pattern against the HIV-1 laboratory strains IIIB and RF, and an AZT-resistant strain; all were inactive against HIV-2. These compounds were further tested against NNRTI-resistant HIV-1 isolates. NNRTI-resistant HIV-1 isolates were selected and characterized with respect to the change(s) in the viral reverse transcriptase nucleotide sequence. Also, differential cross-resistance or sensitivity patterns to NNRTIs were studied in detail among NNRTI-resistant mutants. When tested in combination with AZT, all of the NNRTI's uniformly exhibited synergistic inhibition of HIV-1, suggesting that combination antiviral therapy of NNRTIs with AZT may be therapeutically promising for AIDS treatment.
Leukemia 1995 Oct
PMID:Characteristics of a group of nonnucleoside reverse transcriptase inhibitors with structural diversity and potent anti-human immunodeficiency virus activity. 747 21

We generated variants of the human immunodeficiency virus type 1 (HIV-1) that are resistant to 2',3'-dideoxycytidine (ddC) and 2',3'-didehydro-3'-deoxythymidine (d4T) by in vitro selection in MT-4 cells. Portions of flanking protease and integrase sequences as well as the complete reverse transcriptase (RT) open-reading frame of these viruses were cloned and sequenced, using polymerase chain reaction (PCR)-based methods. Mutations were observed at amino acid position 65 (Lys-->Arg; AAA-->AGA) when ddC was employed in the selection procedure and at site 50 (Ile-->Thr; ATT-->ACT) when d4T was used. We confirmed the ability of these mutations to confer diminished sensitivity for these compounds by site-directed mutagenesis, in which these mutations were inserted into the pol gene of infectious recombinant HXB2-D DNA. Viruses that contained the site 65 mutation possessed approximately 5-10 fold resistance against ddC when compared with wild-type HXB2-D. The site 50 mutation conferred approximately 30-fold resistance to d4T in these same assays. Similar results were obtained using primary cord blood lymphocytes in drug resistance assays, indicating that these mutations could confer drug resistance in more than one cell type and that the respective mutations could be expressed in cells of primary origin. No cross-resistance against 3'-azido-3'-deoxythymidine (AZT) was noted for either the site 65 or 50 mutations.
Leukemia 1994 Apr
PMID:Identification of novel mutations that confer drug resistance in the human immunodeficiency virus polymerase gene. 751 78

We studied a series of 18 patients with CD3- lymphoproliferative disease of granular lymphocytes (LDGL) for evidence of chronic viral infection, including Epstein-Barr (EBV), hepatitis B (HBV), hepatitis C (HCV), human T lymphotropic virus (HTLV), and human immunodeficiency virus (HIV). Although all patients tested had serologic evidence for past infection with EBV, polymerase chain reaction (PCR) analysis of peripheral blood mononuclear cell (PBMC) DNA utilizing specific EBV primers demonstrated the presence of EBV-DNA in only six of 17 CD3- LDGL cases. A previous history of HBV infection, as defined by the presence of circulating IgG anti-HBc antibodies associated with either HBsAg positivity or negativity, was documented in seven cases; however, viral DNA was not detected in PBMC of these patients using PCR with specific HBV primers. Specific anti-HCV antibodies, confirmed by recombinant immunoblot assay, were detected in five CD3- LDGL patients; PCR analysis demonstrated the presence of viral RNA in PBMC of two of these cases. No patient had antibodies to HTLV-I/II or HIV-1/2. Five patients were infected by more than one virus (two with HBV and EBV and three with HBV and HCV). Our results provide serologic evidence for past viral infection in the large majority of CD3- NK-type LDGL patients. These data suggest that viral infection may have played a role early in disease pathogenesis and may no longer be necessary in sustaining GL proliferation in CD3- NK-type LDGL.
Leukemia 1995 Jul
PMID:Serologic and molecular evidence for a possible pathogenetic role of viral infection in CD3-negative natural killer-type lymphoproliferative disease of granular lymphocytes. 763 Jan 96

Tumor-infiltrating T-lymphocytes (T-TIL) are putative mediators of tumor containment that exhibit unique specificity for autologous tumor cells. The magnitude of T-TIL response in biopsy specimens from patients with B-cell lymphoma has been suggested as an independent predictor of clinical outcome. Since recognition of tumor antigens may occur in association with major histocompatibility complex (MHC) molecules, effective T-TIL tumor immunosurveillance may be limited by either failure to express MHC-encoded recognition structures and/or host T-cell immunocompetence. To further delineate T-cell immunoregulation in B-cell lymphoma, we assessed T-TIL fraction and tumor expression of invariant class I and class II HLA determinants by immunohistochemistry in biopsy specimens. Two distinct clinical cohorts of B-cell lymphoma were investigated to delineate pathogenetic differences in T-TIL response. One group, representing immunodeficient and transplant-related lymphomas, comprised 18 patients with AIDS- or allograft-related lymphoma. The second group comprised 83 consecutive cases of sporadic diffuse large cell (DLCL) lymphoma. Median CD8+ T-TIL was significantly lower (4.9% versus 12.7%) among immunodeficiency-associated lymphoma and the frequency of cases with low (< 6%) CD8+ T-TIL greater (76% versus 23%) (p < 0.0001). None of the immunodeficiency-associated lymphomas demonstrated non-polymorphic HLA loss. Absence of one or more class I or II HLA determinants was found in 13 out of 19 (68%) sporadic DLCL specimens with low CD8+ T-TIL, compared to 20% of cases with higher T-TIL fraction (p = 0.0004). These findings implicate impaired host immunosurveillance in deficient T-TIL response in immunodeficiency-associated B-cell lymphoma, whereas low T-TIL in sporadic cases of DLCL relates to tumor loss of HLA determinants. Strategies to modulate tumor HLA expression or augment antitumor response merit investigation in patients with B-cell lymphoma.
Leukemia 1993 Mar
PMID:Deficient tumor-infiltrating T-lymphocyte response in malignant lymphoma: relationship to HLA expression and host immunocompetence. 768 Apr

We have investigated the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and several potent vitamin D3 analogs [1,25(OH)2-16-ene-23-yne-D3; 1,25(OH)2-16-ene-23-yne-26,27-F6-D3] on productive infection by human immunodeficiency virus (HIV) in human macrophages. Macrophages derived from the peripheral blood were either pretreated with the vitamin D3 analogs, washed, and exposed to HIV (pre-infection treatment) or were infected with HIV, washed, and cultured with the vitamin D3 compounds (post-infection treatment). After three days of HIV-infection, levels of p24 antigen were measured. Pretreatment of macrophages with either 1,25(OH)2D3 or 1,25(OH)2-16-ene-23-yne-26,27-F6-D3 (pre-infection treatment) increased productive HIV infection about 3.5-fold; 1,25(OH)2-16-ene-23-yne-D3 increased levels about 4.7-fold. In contrast, exposure of HIV infected macrophages to the vitamin D3 compounds (post-infection treatment) did not affect levels of HIV production compared to untreated controls. Soluble CD4 completely inhibited productive HIV infection of macrophages pretreated with vitamin D3 analogs. Also, the vitamin D3 compounds slightly decreased CD4 expression on macrophages. The mechanism of enhanced productive HIV infection by the vitamin D3 compounds is unclear, but can not be explained by either alteration of CD4 expression or entry into cells by a CD4-independent route. These studies may have implications for both the basic biology of HIV infectious production and possibly clinical treatment of AIDS patients.
Leukemia 1993 Oct
PMID:Effect of 1,25-dihydroxyvitamin D3 and its analogs on human immunodeficiency virus infection in monocytes/macrophages. 769 90

The human immunodeficiency virus type-1 (HIV-1) encoded Vpu protein facilitates the release of budding virions from the surface of infected cells and delays the rate of syncytium formation of the virus. Furthermore, Vpu induces rapid degradation of nascent CD4 molecules that are retained in the endoplasmic reticulum by the formation of gp160-CD4 complexes. Currently, little is known of the precise mechanism(s) by which Vpu function. Whether or not these different events are related remain unclear. In this report, we describe our recent structure/function studies on vpu suggesting that the protein may have independent biological activities during the HIV-1 infection.
Leukemia 1994 Apr
PMID:Mutational analysis of the HIV-1 Vpu protein. 815 84

Zidovudine (3'-azido-2',3'-dideoxythymidine) resistant isolates of human immunodeficiency virus type I (HIV-1) were previously demonstrated in zidovudine-treated AIDS patients. The genetic linkage of multiple mutations characteristic of zidovudine-resistance as well as dideoxyinosine-resistance were demonstrated by examining clones of viral reverse transcriptase after polymerase chain reaction (PCR) amplification of plasma culture DNA. The zidovudine-resistance mutations persisted in seven timepoints from four patients for 5 to 22 months despite cessation of zidovudine therapy (and while patients underwent ddI therapy). One patient's plasma virus isolate at 14 months possessed a genotype doubly resistant to ZDV and ddI. Virus recovered from four timepoints showed Intermediate to high levels of zidovudine-resistance. As these genotypes were mainly derived from plasma culture, the zidovudine resistant virus appears to persist and replicate well in vivo after cessation of zidovudine therapy.
Leukemia 1994 Apr
PMID:Long-term persistence of AZT-resistance mutations in the plasma HIV-1 of patients removed from AZT therapy. 815 87

Recent evidence of cell membrane expression of interleukin-2 receptors (IL-2R) by malignant B cells in hairy cell leukemia (HCL) and B-chronic lymphocytic leukemia (B-CLL) has lead to speculation that growth factors, such as IL-2, may play a role in the pathophysiology of these diseases. However, to date, it is not clear that IL-2 is a consistent growth factor in vitro or in vivo for malignant B cells. What then is the potential significance of membrane IL-2R on the malignant B-cell membrane? Laboratory analysis indicates that the malignant cells are the source of elevated serum levels of soluble Tac protein (sIL-2r alpha) in both diseases. Indeed, these cells spontaneously secrete sIL-2R alpha into culture medium. We speculate that the presence of an expanding mass of malignant B cells possessing high and low affinity membrane IL-2R may contribute significantly to the associated immunodeficiency seen in B-CLL. In particular, it is the cell associated high affinity IL-2R that have the greatest potential for reducing the levels of free IL-2 available to normal immune cells.
Leukemia 1994 Jan
PMID:Does IL-2 receptor expression and secretion in chronic B-cell leukemia have a role in down-regulation of the immune system? 828 5

We have analyzed the expression of the zeta chain of the T cell receptor/CD3 complex and the co-stimulatory molecule CD28 by dual colour immunofluorescence on T lymphocytes from patients with B cell chronic lymphocytic leukemia (CLL). Zeta chain was significantly reduced on CD3-positive lymphocytes from 33 patients compared with normal controls (P<0.0001). The values were lower in stages B and C than in stage A. In five patients tested in partial remission the values were normal. CD28, investigated in CD3, CD4 and CD8 positive T cells from 18 CLL patients appeared to be reduced in the three subsets but more marked in CD8-positive lymphocytes. The loss of zeta chain and CD28 in a proportion of circulating T lymphocytes from CLL may underlie some of the known functional abnormalities of these cells and the immunodeficiency associated with the disease.
Leukemia 1996 Mar
PMID:Zeta chain and CD28 are poorly expressed on T lymphocytes from chronic lymphocytic leukemia. 864 68


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