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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenesis of neuropsychological abnormalities in patients with human immunodeficiency virus type 1 (HIV-1) encephalitis is obscure because neurons are not the target of infection and severe neuronal loss occurs only late during the disease. Moreover, there is evidence indicating that HIV dementia is not a homogeneous entity and could partially reverse after treatment with zidovudine. The finding that impaired axonal flow, evidenced by beta-amyloid precursor protein immunoreactivity, could contribute to the neuropsychological deficits prompted the present study. Brains of patients with full-blown acquired immunodeficiency syndrome (AIDS) were studied and findings compared with those of normal and abnormal control subjects. The presence of HIV-1 DNA was investigated by nested polymerase chain reaction; axonal abnormalities were detected by beta-amyloid precursor protein, ubiquitin immunohistochemistry, and silver staining. Accumulation of beta-amyloid precursor protein was observed in all the HIV encephalitis brains studied; the appearance of the immunostaining varied from globular structures to bundles of parallel formations. In 2 AIDS brains without pathological abnormalities, only the latter pattern was detected. The brains with trauma were strongly reactive with beta-amyloid precursor protein antibody and the different reactivity within them correlated with posttrauma survival, only globular structures being detected in the older cases. No correlation was found between the different pattern of beta-amyloid precursor protein reactivity and dementia in AIDS patients. These results show that widespread axonal injury is a constant feature in AIDS brains and suggest that it could play a role in the pathogenesis of the neuropsychological abnormalities of these patients.
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PMID:Accumulation of beta-amyloid precursor protein in HIV encephalitis: relationship with neuropsychological abnormalities. 922 83

Lymphoproliferation, chronic B-cell activation resulting in hypergammaglobulinemia, and profound immunodeficiency are prominent features of retrovirus-induced murine acquired immunodeficiency syndrome (murine AIDS). Here we demonstrate that in murine AIDS the ATP-dependent and ubiquitin-dependent proteolytic system is strongly affected, at least in the lymph nodes of infected mice. Solid-phase immunochemical assays show that the ubiquitin-conjugate pools increase by about threefold 10 weeks after infection, then decline slightly 15 weeks after infection to a twofold increase. Accumulation of ubiquitin conjugates is accompanied by induction of the ubiquitin-conjugating pathway, involving several carrier-protein isozymes (E2), mainly 14-kDa E2 and 17-kDa E2. Furthermore, accumulation of ubiquitin conjugates and induction of the conjugating system are coincident with an increase in the proteolytic activity supported by the 26S proteolytic complex. However, 15 weeks after infection, when the conjugation rate and levels of ubiquitin conjugates decrease, proteasome activity returns to values similar to those of the control, suggesting that a higher proteosomal activity is no longer needed. The concerted induction of the ubiquitin-conjugating and proteolytic systems in murine AIDS apparently does not involve the breakdown of viral products nor is it supported by virus-coded events, but probably arises as a cellular response to viral infection.
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PMID:Up-regulation of the ubiquitin-conjugating and proteolytic systems in murine acquired immunodeficiency syndrome. 924 13

It has been proposed that oxidative stress is the common mediator of apoptotic cell death in AIDS. However, mechanistic relationships between oxidative damage and cell death are far from clear. It is reported here that the mitogenic activation of T lymphocytes from human immunodeficiency virus-positive subjects involves perturbation of redox balance, as indicated by the increase in hydroethydine intracellular oxidation and manganese superoxide dismutase adaptive induction. Principal molecular targets of oxidative injury are cellular proteins whose content in carbonyl groups increases together with a dramatic increase in degradation of newly synthesized proteins catalyzed by the ATP- and ubiquitin-dependent proteolytic system. The major consequence of this metabolic anomaly is the decrease in protein cell mass leading to cells that are smaller than normal at lethal mitosis.
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PMID:Oxidative protein damage and degradation in lymphocytes from patients infected with human immunodeficiency virus. 929 12

The presence of neuropsychological disturbances in HIV-positive, pre-symptomatic individuals is a controversial issue. Neuroimaging studies have not shown brain atrophy or hyperintensity in the white matter, whereas proton magnetic resonance spectroscopy has revealed some abnormality of cerebral biochemistry. Using an antibody to beta-amyloid precursor protein (beta-APP), we previously demonstrated frequent and widespread axonal changes in the brains of AIDS patients. In this study, we extended the use of beta-APP to asymptomatic patients in order to establish a possible morphological correlation with neuropsychological disorders. Brain samples from 29 patients were examined. Results showed bundles of beta-APP-positive axons in 8/29 cases (27%). The changes, seen in both superficial and deep white matter, were either focal or diffuse, could not be visualized by silver or ubiquitin stains, and did not coexist with any change in distribution or morphology of astrocytes and microglial cells. We conclude that in HIV-positive asymptomatic individuals, axonal changes: (a) may be related to the state of immune activation with consequent presence of toxic substances, including cytokines, observed in these patients; (b) may represent mild changes that could undergo repair, unless other pathological events, such as the supervening of the AIDS stage and the specific encephalitis, make them permanent.
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PMID:Axonal damage revealed by accumulation of beta-APP in HIV-positive individuals without AIDS. 937 Feb 37

Human biopsies obtained from skeletal muscle of cachectic AIDS patients clearly showed an increased expression (in relation to that of healthy subjects) of the genes encoding for the ubiquitin-ATP-dependent proteolytic system. Increases of 120% and 42% were observed for the 2.4 and 1.2 kb ubiquitin transcripts, respectively. The expression of the C8 proteasome subunit was also increased by 60% in the cachectic AIDS patients in relation to the healthy control subjects. It is suggested that the activation of this proteolytic system (possibly via changes in circulating cytokines, such as TNF) may be responsible for the skeletal muscle waste that often accompanies AIDS.
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PMID:Ubiquitin and proteasome gene expression is increased in skeletal muscle of slim AIDS patients. 985 46

The movement of a cell through the sequential phases of apoptosis is accompanied by a progressive decrease in cell size with loss in protein mass. In lymphocytes from Hiv-infected persons, protein loss during apoptosis is due to increased protein degradation rather than decreased synthesis. To identify and characterize the proteolytic enzymes or enzyme systems involved in this process, we studied several features of protein turnover in lymphocytes from peripheral blood and lymph nodes during the natural and experimental infection by feline immunodeficiency virus (Fiv). This animal model allowed us to integrate in vivo results with in vitro observations of protein damage. Here we report that protein breakdown in apoptotic cells is concomitant with the activation of the ATP and ubiquitin-dependent multicatalytic system (proteasome). We suggest that proteasome activation is part of the proteolytic cascade in the execution phases of apoptosis in AIDS.
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PMID:Protein degradation and apoptotic death in lymphocytes during Fiv infection: activation of the ubiquitin-proteasome proteolytic system. 1022 30

The development of pharmacological approaches for preventing the loss of muscle proteins would be extremely valuable for cachectic patients. For example, severe wasting in cancer patients correlates with a reduced efficacy of chemotherapy and radiotherapy. Pentoxifylline (PTX) is a very inexpensive xanthine derivative, which is widely used in humans as a haemorheological agent, and inhibits tumor necrosis factor transcription. We have shown here that a daily administration of PTX prevents muscle atrophy and suppresses increased protein breakdown in Yoshida sarcoma-bearing rats by inhibiting the activation of a nonlysosomal, Ca(2+)-independent proteolytic pathway. PTX blocked the ubiquitin pathway, apparently by suppressing the enhanced expression of ubiquitin, the 14-kDa ubiquitin conjugating enzyme E2, and the C2 20S proteasome subunit in muscle from cancer rats. The 19S complex and 11S regulator associate with the 20S proteasome and regulate its peptidase activities. The mRNA levels for the ATPase subunit MSS1 of the 19S complex increased in cancer cachexia, in contrast with mRNAs of other regulatory subunits. This adaptation was suppressed by PTX, suggesting that the drug inhibited the activation of the 26S proteasome. This is the first demonstration of a pharmacological manipulation of the ubiquitin-proteasome pathway in cachexia with a drug which is well tolerated in humans. Overall, the data suggest that PTX can prevent muscle wasting in situations where tumor necrosis factor production rises, including cancer, sepsis, AIDS and trauma.
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PMID:Manipulation of the ubiquitin-proteasome pathway in cachexia: pentoxifylline suppresses the activation of 20S and 26S proteasomes in muscles from tumor-bearing rats. 1036 54

Murine acquired immunodeficiency syndrome (MAIDS) is a complex immunopathology caused by a defective murine leukemia virus (LP-BM5) that mainly targets B-lymphocytes. Lymphadenophathy, splenomegaly, hypergammaglobulinemia and progressive immunodeficiency are prominent features of MAIDS. Previously, we showed that the ubiquitin proteolytic system was upregulated in infected lymph nodes [Crinelli, R., Fraternale, A., Casabianca, A. & Magnani, M. (1997) Eur. J. Biochem. 247, 91-97]. In this report, we demonstrate that increased 26S proteasome activity is responsible for accelerated turnover of the IkappaBalpha inhibitor in lymph node extracts derived from animals with MAIDS. The molecular mechanisms mediating IkappaBalpha proteolysis involved constitutive phosphorylation of IkappaBalpha at Ser32 and Ser36 and subsequent ubiquitination, suggesting persistent activation of an NF-kappaB inducing pathway. Interestingly, enhanced IkappaBalpha degradation did not result in enhanced NF-kappaB DNA binding activity, but rather in a different subunit composition. The modulation of NF-kappaB/IkappaB system may affect multiple immunoregulatory pathways and may in part explain the mechanisms leading to the profound immune dysregulation involved in MAIDS pathogenesis.
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PMID:Activation of the ubiquitin proteolytic system in murine acquired immunodeficiency syndrome affects IkappaBalpha turnover. 1042 5

Tyrosine kinase A (TrkA), a high affinity receptor for nerve growth factor (NGF), is activated during differentiation and regeneration of selective neuronal population. We investigated presence, distribution and expression of TrkA in frontal cortex from cases with Alzheimer's disease (AD), normal aging and a variety of conditions (AIDS, cystic fibrosis, cerebral infarcts) in which neuroaxonal dystrophy occurs. TrkA was immunocytochemically detected in 90% of dystrophic neurites surrounding amyloid deposits in normal aging, as well as in all not amyloid-related dystrophic neurites identified by ubiquitin immunoreactivity. Conversely, the amyloid associated dystrophic neurites were not TrkA reactive in AD tissue. The levels of TrkA protein and mRNA in AD frontal cortex did not significantly differ from those of non-demented aged controls. The absence of TrkA activation in amyloid associated neurites in AD, but not in normal aging, indicates a different reaction of neuronal tissue to amyloid (protein (Abeta) deposition, and suggests that other factors, besides Abeta, mediate neuronal degeneration in AD.
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PMID:Tyrosine kinase A-nerve growth factor receptor is antigenically present in dystrophic neurites from a variety of conditions but not in Alzheimer's disease. 1050 54

The authors examined multiple brain sections from 15 autopsy cases of AIDS for the vascular changes, presence of amyloid plaques and signs of axonal damage. The mean patients age was 33.8 years (range 24-48 years). Neuropathological findings included: HIV-specific changes (5), opportunistic infections (7), lymphoma (1) and two cases with nonspecific changes. All sections were stained with hematoxylin-eosin (H-E), selected sections were stained with Masson trichrome, Gomori reticulin, Congo red and thioflavine S method. Two sections from each case were immunostained for the presence of beta-amyloid (4G8). ubiquitin, alpha-smooth muscle actin and CD31. The different forms of vascular changes were found in all cases. The common changes were: lymphocytic perivascular or transmural infiltrations and hyalinization, thickening or fibrosis of the arterial and arteriolar wall. The perivascular space widening up to status lacunaris was a frequent phenomenon in the basal ganglia and deep white matter. Some of the cortical arterioles formed little multiluminal structures. Immunohistochemical examination revealed features of hypertrophy of the vascular muscular layer and signs of the slight endothelial cells proliferation. In three cases 4G8 immunopositive. Congo red and thioflavine S-negative, diffuse beta-amyloid deposits were present in the gray matter, focally their localization was perivascular. Ubiquitin immunoreactivity presented as numerous dot-like structures or focal bundles of positive widened axons in the white matter, spheroids and scattered positive neurons were also found. The authors suggest that some of morphological changes within the brain and consecutive neuropsychological symptoms in AIDS are of the vascular origin. Presence of amyloid plaques and axonal damage are the elements of the complex degenerative and inflammatory process in the brain caused by chronic inflammatory stimulation in HIV infection.
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PMID:Vasculopathy and amyloid beta reactivity in brains of patients with acquired immune deficiency (AIDS). 1169 22


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