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: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human immunodeficiency virus is a member of the lentivirus subfamily of the retrovirus family. Retroviruses are RNA viruses which code for an RNA-dependent DNA polymerase (reverse transcriptase), which transcribes the RNA genome into a DNA provirus which, on integration with the host DNA, directs the synthesis of new virions. The RNA genome consists of a gag gene, which codes for the viral core proteins, a pol gene, which codes for the reverse transcriptase, an env gene, which codes for the glycoproteins of the viral envelope, and several genes (tat, rev, vif, vpr, and nef), that code for regulatory proteins. At each end of the genome are long terminal repeats, that contain regulatory elements for transcription. There are 3 subfamilies of Retroviridae (Oncovirinae, Spumavirinae, and Lentiverinae). The Lentiverinae ("slow viruses") include the bovine immunodeficiency virus (BIV), the feline immunodeficiency virus (FIV), the human immunodeficiency viruses (HIV), and the simian immunodeficiency viruses (SIV). SIV has been isolated from macaques (mac), African green monkeys (agm), sooty mangabeys (sm), and mandrills (mnd). Only SIVmac causes an AIDS-like disease in its natural host, but it is genetically closer to HIV-2 than to HIV-1. SIVsm causes an AIDS-like disease in macaques, but not in the sooty mangabey. Monkeys infected with SIV develop diarrhea, wasting, decrease in T4 lymphocytes, lymphadenopathy, development of giant cells, and encephalitis, as well as opportunistic infections. Kaposi's sarcoma, however, has not been found in SIV-infected primates. Virus is recovered from peripheral blood mononuclear cells and the brain. SIV models are useful for understanding the natural history of primate lentiviruses, for defining the pathogenesis of AIDS, and for developing vaccines. The ideal model would be one in which HIV causes AIDS, but so far only chimpanzees and gibbons have successfully been infected with HIV-1, and although virus, is recovered from peripheral blood mononuclear cells of chimpanzees within 2 weeks of infection, and 2 animals have lost antibodies to the p24 protein, none has so far developed clinical AIDS. Attempts to develop vaccines to immunize chimpanzees are continuing. Nonprimate lentiviruses include the visna virus, the feline immunodeficiency virus, and the bovine immunodeficiency virus. The visna virus infects fibroblasts by fusion of the viral envelope with the plasma membrane of the fibroblast; it infects macrophages by endocytosis. Infected macrophages regulate the production and dissemination of viral particles. The feline immunodeficiency virus infects T-lymphocytes of cats and produces oral, gastrointestinal and respiratory pathology as well as lymphadenopathy and opportunistic infections. Bovine immunodeficiency-like virus causes a generalized lymphadenopathy similar to that seen in AIDS-related complex.
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PMID:Animal models for HIV infection and AIDS: memorandum from a WHO meeting. 285 Jan 18

A wasting disease in moose (Alces alces) has killed more than one thousand animals in a densely populated, limited geographical area in Sweden. To investigate the cause, local environmental conditions were studied and infectious agents, mainly viruses, were looked for. A virus, identified as a retrovirus, has repeatedly been isolated from diseased animals by cocultivation of their leukocytes with fetal moose kidney cells. The virus has the characteristics of a member of the Oncovirinae subfamily, as deduced from its morphology from EM studies, reverse transcriptase activity, cell transforming properties, and serological cross-reactivity with other oncoviruses. Striking features of the disease are the poor and transient capacity of affected moose to respond serologically in addition to the frequent presence of high levels of reverse transcriptase activity in their sera.
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PMID:Association of a retrovirus with a wasting condition in the Swedish moose. 751 66

Severe combined immunodeficient (SCID) mice injected with co-isogenic CD4+/CD45RBhigh lymph node T cells from normal donors develop a wasting disease that is caused by hyperplasia of the intestinal epithelium. SCID mice injected with purified lymph node CD4+ T cells or CD4+/CD45RBlow T cells do not develop the disease. The IEL compartment from SCID mice injected with highly purified CD4+/CD45RBhigh T cells or CD4+ T cells contained significant numbers of T cells that expressed both CD4 and CD8 alpha, but not CD8 beta. The CDr+/CD8 alpha + T cells were unique to the IEL compartment of the small intestine and were not observed in significant numbers in the lamina propria, mesenteric lymph node, nor IEL compartment of the large intestine. By using Ly-5 mismatched donors and recipients, we determined that the CD4+/CD8 alpha + T cells were derived from the donor T cells. The expression of CD8 alpha was stable in vitro, and CD8 alpha mRNA was detected in sorted CD4+/CD8 alpha + T cells by reverse transcriptase-PCR (RT-PCR). Recombinase-activating gene (RAG)-1 and -2 mRNA was not detected in the intra-epithelial lymphocyte CD4+/CD8 alpha + T cell population. Thus, it appears that under conditions unique to the epithelial layer of the small intestine, mature post-thymic CD4+ T cells can be induced to express CD8 alpha.
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PMID:Analysis of the intra-epithelial lymphocyte compartment in SCID mice that received co-isogenic CD4+ T cells. Evidence that mature post-thymic CD4+ T cells can be induced to express CD8 alpha in vivo. 787 40

Mineralocorticoid resistance (pseudohypoaldosteronism) is a rare condition first described in 1958 and associated with failure to thrive, salt wasting, and dehydration in infancy. In the index case it has previously been shown that binding of aldosterone to mineralocorticoid receptors in peripheral blood lymphocytes is absent; here, we report results of the molecular characterization of the mineralocorticoid receptor in this patient. Genomic DNA extracted from peripheral blood lymphocytes was subjected to Southern blot analysis after digestion with various restriction enzymes. There was no evidence of a major gene rearrangement or deletion. Oligonucleotide primers were designed on the basis of the published human complementary DNA sequence to cover the entire open reading frame of the mineralocorticoid receptor (MR). Total messenger ribonucleic acid (RNA) from lymphocytes was subjected to reverse transcription and amplification using the reverse transcriptase-polymerase chain reaction; the resulting fragments were then purified, subcloned, and sequenced. The patient showed no abnormality in the complementary DNA sequence corresponding to the open reading frame of the MR molecule compared with the published sequence. In addition, semiquantitative assessment of the patient's MR messenger RNA based on the reverse transcriptase-polymerase chain reaction technique suggested that he was producing MR RNA in roughly normal quantities. The mechanism of mineralocorticoid resistance in this case, therefore, remains uncertain, and the possibility must be considered that the underlying abnormality is not in the MR gene, but in an independent gene acting through yet to be characterized processes.
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PMID:Pseudohypoaldosteronism: molecular characterization of the mineralocorticoid receptor. 802 37

Johne's disease is a chronic enteritis of cattle and other ruminant species that is of worldwide economic importance. The cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) have been associated with granuloma formation and wasting in other disease syndromes. The potential role of these cytokines in the development and progression of Johne's disease has not been investigated. Using reverse transcriptase polymerase chain reaction (RT-PCR) and specific bovine oligonucleotide cytokine primers and probes for bovine TNF-alpha and IL-6, we examined the ex vivo expression of mRNA for these inflammatory cytokines in whole blood from healthy cattle. Cytokine mRNA levels increased after a brief incubation of bovine whole blood with Mycobacterium paratuberculosis or its lipoarabinomannan (LAM). Muramyl dipeptide (MDP) and Escherichia coli LPS also stimulated TNF-alpha and IL-6 mRNA expression. Several strains of M. paratuberculosis were tested and found to have similar abilities to stimulate TNF-alpha and IL-6 mRNA expression. Several strains of the closely related Mycobacterium avium, and the unrelated saprophyte, Mycobacterium phlei, had somewhat less ability to stimulate TNF-alpha and IL-6 mRNA expression.
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PMID:Ex vivo induction of TNF-alpha and IL-6 mRNA in bovine whole blood by Mycobacterium paratuberculosis and mycobacterial cell wall components. 855 37

Infection with the human immunodeficiency virus (HIV) can lead to global alterations in metabolism as well as immunodeficiency. There is dysregulation of endocrine function in adults and children, the extent and magnitude correlating with disease progression. Some of the more prominent abnormalities occur in the thyroid, gonadal, and somatomedin axes. Clinical manifestations of these abnormalities are growth failure in children, which is one of the most sensitive indicators of disease progression, and a wasting syndrome in adults and children. Although there are case reports of growth hormone (GH) deficiency in HIV-infected children, most patients with growth failure have normal serum levels of GH and normal to low levels of insulin-like growth factor-I (IGF-I). Antiretrovial therapy can improve the growth rate in children for a period of time if there is a drop in viral titer, but as the viral load increases, the growth rate decreases again. Administration of GH or IGF-I to these patients can improve the growth rate and lean body mass, and in some patients improve immune function. Although studies on resting energy expenditure in HIV-infected patients have shown increases, these are not proportional to disease progression, but may be dependent upon cytokine activation and other abnormalities. Adult patients with wasting have been shown to have relatively normal total energy expenditure, but decreased intake. Appetite stimulants have been shown to have some benefit, but do not increase lean body mass. The most significant clinical benefit has come from administration of GH in short-term trials. GH and IGF-I are both able to inhibit apoptosis and reconstitute the immune system in rodents treated with ablative therapy. In addition, GH can modulate the marrow suppressive effects of zidovudine and may enhance its ability to inhibit viral reverse transcriptase. Current clinical trials are ongoing in both adults and children. GH and IGF-I may have a role in regimens intended for immune reconstruction, and could be useful as adjuvant therapy in selected patients with HIV infection.
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PMID:Use of human recombinant growth hormone and human recombinant insulin-like growth factor-I in patients with human immunodeficiency virus infection. 895 Jun 24

Fat redistribution in the setting of protease inhibitor use is increasingly common and is associated with insulin resistance in human immunodeficiency virus (HIV)-infected patients. However, little is known regarding the factors that may contribute to abnormal insulin regulation in this population. We assessed fasting insulin levels in HIV-infected men and determined the relationship among insulin, body composition, endogenous gonadal steroid concentrations, and antiviral therapy in this population. We also determined the effects of exogenous testosterone administration using the homeostatic model for insulin resistance (HOMA IR) in hypogonadal HIV-infected men with the acquired immunodeficiency syndrome wasting syndrome. Fifty HIV-infected men with acquired immunodeficiency syndrome wasting were compared with 20 age- and body mass index (BMI)-matched healthy control subjects. Insulin concentrations were significantly increased in HIV-infected patients compared to those in control patients (16.6+/-1.8 vs. 10.4+/-0.8 microU/mL; P<0.05) and were increased in nucleoside reverse transcriptase (NRTI)-treated patients who did not receive a protease inhibitor (PI; 21.7+/-4.3 vs. 10.4+/-0.8 microU/mL; P<0.05). Insulin concentrations and HOMA IR were inversely correlated with the serum free testosterone concentration (r = -0.36; P = 0.01 for insulin level; r = -0.30; P = 0.03 for HOMA), but not to body composition parameters, age, or BMI. In a multivariate regression analysis, free testosterone (P = 0.05), BMI (P<0.01), and lean body mass (P = 0.04) were significant. Lower lean body mass and higher BMI predicted increased insulin resistance. The HIV-infected patients demonstrated an increased trunk fat to total fat ratio (0.49+/-0.02 vs. 0.45+/-0.02; P<0.05) and an increased trunk fat to extremity fat ratio (1.27+/-0.09 vs. 0.95+/-0.06, P = 0.01), but a reduced extremity fat to total fat ratio (0.44+/-0.01 vs. 0.49 + 0.01; P = 0.02) and reduced overall total body fat (13.8+/-0.7 vs. 17.2+/-0.9 kg; P<0.01) compared to the control subjects. Increased truncal fat and reduced extremity fat were seen among NRTI-treated patients, but this pattern was most severe among patients receiving combined NRTI and PI therapy [trunk fat to extremity ratio, 1.47+/-0.15 vs. 0.95+/-0.06 (P<0.01); extremity fat to total fat ratio, 0.40+/-0.02 vs. 0.49+/-0.01 (P<0.05)]. Insulin responses to testosterone administration were investigated among 52 HIV-infected men with hypogonadism and wasting (weight <90% ideal body weight and/or weight loss >10%) randomized to either testosterone (300 mg, im, every 3 weeks) or placebo for 6 months. Testosterone administration reduced HOMA IR in the HIV-infected men (-0.6+/-0.7 vs. +1.41+/-0.8, testosterone vs. placebo, P = 0.05) in association with increased lean body mass (P = 0.02). These data demonstrate significant hyperinsulinemia in HIV-infected patients, which can occur in the absence of PI use. In NRTI-treated patients not receiving PI, a precursor phenotype is apparent, with increased truncal fat, reduced extremity fat, and increased insulin concentrations. This phenotype is exaggerated in patients receiving PI therapy, with further increased truncal fat and reduced extremity fat, although hyperinsulinemia per se is not worse. Endogenous gonadal steroid levels are inversely related to hyperinsulinemia in HIV-infected men, but reduced lean body mass and increased weight are the primary independent predictors of hyperinsulinemia. Indexes of insulin sensitivity improve in response to physiological androgen administration among hypogonadal HIV-infected patients, and this change is again related primarily to increased lean body mass in response to testosterone administration.
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PMID:Fasting hyperinsulinemia in human immunodeficiency virus-infected men: relationship to body composition, gonadal function, and protease inhibitor use. 1063 60

Lipodystrophies, characterized by reduction of subcutaneous fat over part or all of the body surface, are uncommon. Their causes are unknown. Recently, lipodystrophy has been reported in human immunodeficiency virus (HIV)-infected patients taking protease inhibitors, which have been recommended since 1996 as standard therapy for HIV disease in combination with nucleoside analogues. In these cases, lipodystrophy consists of an association of peripheral lipoatrophy with central adiposity. We report four HIV-infected men on protease inhibitors who developed a disfiguring lipodystrophy. In three of them, the protease inhibitor was administered for a mean duration of 21.5 months (range 19-23) with good immunological and virological responses. Patient 4 had been treated for 2 years with successive combinations of protease inhibitors with nucleoside analogues without success. The four patients progressively developed an increase in abdominal girth associated with fat wasting of the face and legs. Two of them had recurrent paronychia of the great toes. Triglyceride levels were moderately increased in all patients, and one had a slightly increased cholesterol level. One patient had elevated glucose and insulin plasma levels during a glucose tolerance test. In two patients, a deep biopsy taken from the thigh showed thinning of the subcutaneous fat without other morphological changes. Computed tomographic scans of the face and abdomen confirmed the loss of almost all subcutaneous fat of the cheek and temporal regions, and abdominal perivisceral fat accumulation. For patients 1-3, the protease inhibitor was replaced by a non-nucleoside reverse transcriptase inhibitor. Nine months later, dysmorphic changes had not regressed, but lipid abnormalities had returned to normal and the paronychia had disappeared.
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PMID:Lipodystrophy associated with protease inhibitors. 1073 57

Lipodystrophy is one of the most common and distressing side effects associated with combination therapy. Some aspects of the phenomenon were reported several years ago, but the frequency of reports has greatly increased with the introduction of protease inhibitors in 1996. Lipodystrophy is a redistribution of fat, and the cause of the change is uncertain. It is not known if it is a signal of disease progression, or a result of anti-HIV therapy. A report on three separate cases conveys success in treating lipodystrophy associated with the use of protease inhibitors. All cases switched people from protease inhibitors to non-nucleoside reverse transcriptase inhibitors (NNRTI), however 10 percent of the group had increases in HIV levels. Serostim, a human growth hormone, has also had some effect in reducing central obesity and buffalo hump, but does not seem to be effective on facial and limb wasting or on decreasing lipid levels. To date, most studies on lipodystropy have been driven by AIDS activists, with pharmaceutical companies and the research community being slow to follow. There is very little information on treating this syndrome, and it is unclear how widespread its effects are. Reports on incidence levels range from 15 percent to 75 percent.
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PMID:Lipodystrophy. 1136 31

Human disuse muscle atrophy frequently accompanies orthopedic injury, arthritis, or bed rest, and recovery is often incomplete despite current rehabilitation programs. We have studied the vastus lateralis muscle in 12 patients with chronic disuse atrophy associated with chronic osteoarthritis of the hip both preoperatively and after total hip arthroplasty. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated an increase in the level of expression of myostatin, insulin-like growth factor-1 (IGF-1) and leukemia inhibitory factor (LIF) mRNAs compared to healthy control muscle. In all patients there was a significant correlation preoperatively between increasing myostatin mRNA expression and reduction in type 2A and 2B fiber area. In the 8 female patients there was a significant correlation between increased myostatin mRNA expression and the atrophy factor calculated for 2A and 2B fiber types preoperatively. We hypothesize that a complex interaction occurs between muscle growth regulating factors in the genesis of muscle wasting. Our results indicate that myostatin is a muscle-wasting factor contributing to type 2B and 2A atrophy. Other muscle growth factors, such as IGF-1 and LIF, may be upregulated in a counterregulatory fashion or may be involved in the fiber type switching seen in disuse muscle wasting.
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PMID:Myostatin, insulin-like growth factor-1, and leukemia inhibitory factor mRNAs are upregulated in chronic human disuse muscle atrophy. 1141 Sep 16


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