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: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurologic manifestations of human immunodeficiency virus (HIV) infection, rather than being a late complication of the disease, are principally correlated with the early central nervous system (CNS) localization of HIV. The CNS may be infected in the early stages of acquired immunodeficiency syndrome (AIDS) without evidence of neurologic disorders. Evoked potentials (visual, auditory, and somatosensory) and electronystagmographic test batteries have proven to be very sensitive in showing subclinical CNS disorders due to HIV. In this study, auditory brain stem response (ABR) and electronystagmographic test battery findings (smooth pursuit, saccades, caloric test) were performed in 29 neurologically asymptomatic, HIV-positive subjects at different stages of the disease. Compared to results of a control group, the ABR latencies of waves V, I, and III and interpeaks I-V and III-V were significantly increased in HIV patients. The same parameters did not differ significantly among the stages of the disease. In HIV-positive subjects, the accuracy of saccades was significantly reduced, while latency was normal. The velocity and the gain of pursuit were significantly reduced in HIV-positive patients, and 15 of 29 patients showed corrective saccades. Caloric tests revealed qualitative nystagmus abnormalities in 82% of HIV patients, while quantitative parameters were normal. The present results confirm that CNS involvement by HIV occurs early in the course of the disease. In particular, HIV does not seem to affect the labyrinth or the eighth cranial nerve, as demonstrated by the normality of the I-III value of the ABR and of the quantitative parameters of the caloric responses, but it does appear to involve the brain stem acoustic pathways, pontocerebellar pathways, and supratentorial areas.
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PMID:Neurotological auditory brain stem response findings in human immunodeficiency virus-positive patients without neurologic manifestations. 986 37

Feline immunodeficiency virus (FIV) is a lentivirus causing immune suppression and neurological disease in cats. Like primate lentiviruses, FIV utilizes the chemokine receptor CXCR4 for infection. In addition, FIV gene expression has been demonstrated in immortalized human cell lines. To investigate the extent and mechanism by which FIV infected primary and immortalized human cell lines, we compared the infectivity of two FIV strains, V1CSF and Petaluma, after cell-free infection. FIV genome was detected in infected human peripheral blood mononuclear cells (PBMC) and macrophages at 21 and 14 days postinfection, respectively. Flow cytometry analysis of FIV-infected human PBMC indicated that antibodies to FIV p24 recognized 12% of the cells. Antibodies binding the CCR3 chemokine receptor maximally inhibited infection of human PBMC by both FIV strains compared to antibodies to CXCR4 or CCR5. Reverse transcriptase levels increased in FIV-infected human PBMC, with detection of viral titers of 10(1.3) to 10(2.1) 50% tissue culture infective doses/10(6) cells depending on the FIV strain examined. Cell death in human PBMC infected with either FIV strain was significantly elevated relative to uninfected control cultures. These findings indicate that FIV can productively infect primary human cell lines and that viral strain specificity should be considered in the development of an FIV vector for gene therapy.
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PMID:Productive infection of human peripheral blood mononuclear cells by feline immunodeficiency virus: implications for vector development. 997 34

Nitric oxide (NO) plays an important role in normal neural cell function. Dysregulated or overexpression of NO contributes to neurologic damage associated with various pathologies, including human immunodeficiency virus (HIV)-associated neurological disease. Previous studies suggest that HIV-infected monocyte-derived macrophages (MDM) produce low levels of NO in vitro and that inducible nitric oxide synthase (iNOS) is expressed in the brain of patients with neurologic disease. However, the levels of NO could not account for the degree of neural toxicity observed. In this study, we found that induction of iNOS with concomitant production of NO occurred in primary human astrocytes, but not in MDM, when astrocytes were cocultured with HIV-1-infected MDM. This coincided with decreased HIV replication in infected MDM. Supernatants from cocultures of infected MDM and astrocytes also stimulated iNOS/NO expression in astrocytes, but cytokines known to induce iNOS expression (interferon-gamma, interleukin-1beta, and tumor necrosis factor-alpha) were not detected. In addition, the recombinant HIV-1 envelope protein gp41, but not rgp120, induced iNOS in cocultures of uninfected MDM and astrocytes. This suggests that astrocytes may be an important source of NO production due to dysregulated iNOS expression and may constitute one arm of the host response resulting in suppression of HIV-1 replication in the brain. It also leads us to speculate that neurologic damage observed in HIV disease may ensue from prolonged, high level production of NO.
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PMID:Human immunodeficiency virus-1-infected macrophages induce inducible nitric oxide synthase and nitric oxide (NO) production in astrocytes: astrocytic NO as a possible mediator of neural damage in acquired immunodeficiency syndrome. 1006 56

The immunobiology of human immunodeficiency virus (HIV) and the role of laboratory testing in the diagnosis and management of HIV infection are reviewed. HIV is one of a family of RNA viruses called retroviruses. HIV has three structural genes (one of which codes for reverse transcriptase) and six regulatory and maturation genes. Upon infection in humans, HIV commandeers the immune system by infecting and lysing T-helper lymphocytes. Since these cells are key to directing the body's immune defenses, the person becomes susceptible to a variety of opportunistic infections, neoplasias, and neurologic disorders. Laboratory tests for HIV are used for three purposes: screening of large populations (such blood donors), diagnosis of current or latent infection, and monitoring of disease progression. Diagnosis of HIV infection relies on HIV antibody detection, viral cultures, antigen detection, or polymerase chain reaction viral genome detection. Disease progression can be estimated using immunophenotyping with flow cytometry or using other immunologic markers. The immunologic variables associated with HIV infection disclose a growing spectrum of immune deficits. New tests for diagnosing and monitoring patients infected with HIV have been quickly incorporated into clinical practice.
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PMID:HIV infection: immunobiology and laboratory diagnosis. 1017 56

Cerebrospinal fluid (CSF) samples were collected from 24 uninfected and 24 SIV251 MPBMC-infected rhesus monkeys during early infection and from 6 animals in a longitudinal design up to 7 months postinfection to investigate excitatory and inhibitory amino acid neurotransmitter levels. During the early infection period CSF amino acid concentrations of infected animals were not significantly different from those of uninfected animals. However, long-term studies demonstrated that gamma-aminobutyric acid (GABA) concentrations were decreased while glutamate concentrations were increased late in infection compared with the preinfection values of the same animals. Moreover, we showed that the source of increased glutamate in animals with AIDS is, at least partially, microglial cells. Our data support the hypothesis that excitotoxicity is involved in immunodeficiency virus-induced neurological disease and propose microglia as a contributor to excitotoxic damage.
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PMID:Involvement of microglia in cerebrospinal fluid glutamate increase in SIV-infected rhesus monkeys (Macaca mulatta). 1019 57

Glutamic acid is the principal excitatory neurotransmitter in the mammalian central nervous system. Glutamic acid binds to a variety of excitatory amino acid receptors, which are ligand-gated ion channels. It is activation of these receptors that leads to depolarisation and neuronal excitation. In normal synaptic functioning, activation of excitatory amino acid receptors is transitory. However, if, for any reason, receptor activation becomes excessive or prolonged, the target neurones become damaged and eventually die. This process of neuronal death is called excitotoxicity and appears to involve sustained elevations of intracellular calcium levels. Impairment of neuronal energy metabolism may sensitise neurones to excitotoxic cell death. The principle of excitotoxicity has been well-established experimentally, both in in vitro systems and in vivo, following administration of excitatory amino acids into the nervous system. A role for excitotoxicity in the aetiology or progression of several human neurodegenerative diseases has been proposed, which has stimulated much research recently. This has led to the hope that compounds that interfere with glutamatergic neurotransmission may be of clinical benefit in treating such diseases. However, except in the case of a few very rare conditions, direct evidence for a pathogenic role for excitotoxicity in neurological disease is missing. Much attention has been directed at obtaining evidence for a role for excitotoxicity in the neurological sequelae of stroke, and there now seems to be little doubt that such a process is indeed a determining factor in the extent of the lesions observed. Several clinical trials have evaluated the potential of antiglutamate drugs to improve outcome following acute ischaemic stroke, but to date, the results of these have been disappointing. In amyotrophic lateral sclerosis, neurolathyrism, and human immunodeficiency virus dementia complex, several lines of circumstantial evidence suggest that excitotoxicity may contribute to the pathogenic process. An antiglutamate drug, riluzole, recently has been shown to provide some therapeutic benefit in the treatment of amyotrophic lateral sclerosis. Parkinson's disease and Huntington's disease are examples of neurodegenerative diseases where mitochondrial dysfunction may sensitise specific populations of neurones to excitotoxicity from synaptic glutamic acid. The first clinical trials aimed at providing neuroprotection with antiglutamate drugs are currently in progress for these two diseases.
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PMID:The role of excitotoxicity in neurodegenerative disease: implications for therapy. 1033 61

Central nervous system (CNS) involvement is a prominent feature of human immunodeficiency virus (HIV-1) infection. Monocytes and CD4+ T cells traverse the blood brain barrier (BBB), and serve as vehicles for the virus and perpetrators for brain pathology by their production of neurotoxins. In the present study cerebrospinal fluid (CSF) samples from HIV-1-infected patients were analyzed for the presence of chemotactic factors. All 36 CSF samples from the patients were positive for the CXC chemokine interferon-gamma inducible protein (IP-10), which was not detected in CSF samples of 14 controls. The IP-10 concentrations were higher in HIV-1-infected patients with HIV-1 associated neurologic disorders than in those without neurological deficits. In contrast to IP-10, other chemotactic factors including the CC chemokines MCP-1, MIP-1alpha, MIP-1beta and RANTES and the cytokines IL-15 and IL-16 were either not detected or increased in only less than 30% of the patients. Unlike the CSF samples of controls, all CSF samples from HIV-1-infected patients induced chemotaxis of T cells activated with IL-2. The significance of IP-10 as a T cell chemotactic cytokine in HIV-1-infected CSF is shown by (1) the correlation of the IP-10 levels with the extent of T cell chemotaxis, (2) the neutralization of T cell chemotaxis by anti-IP-10 antibodies and (3) the correlation of the chemotactic response of CSF samples on activated T cells and the CSF white cell count in the patients. Our data provide evidence that IP-10 contributes to the accumulation of activated T cells in the CSF compartment in HIV-1-infected individuals.
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PMID:Identification of a T cell chemotactic factor in the cerebrospinal fluid of HIV-1-infected individuals as interferon-gamma inducible protein 10. 1037 81

Previously, we described the derivation of a pathogenic strain of simian-human immunodeficiency virus (SHIV(KU-2)) consisting of the tat, rev, vpu, and env genes of HIV-1 (strain HXB2) in a genetic background of SIV(mac)239 that causes AIDS and productive infection of the CNS in rhesus macaques (Macca mulatta) (Raghavan et al., 1997, Brain Pathol. 7, 851-861). We report here on the characterization of a molecular clone of SHIV(KU-2), designated SHIV(KU-2MC4), that caused CD4(+) T cell loss as well as neurological and renal disease in macaques. DNA sequence analysis of selected SIV regions of SHIV(KU-2MC4) revealed 10 nucleotide changes in the LTR, whereas Gag, Vif, Vpr, Vpx, and Nef had 1, 1, 1, 2, and 13 predicted amino acid substitutions, respectively, compared to SIV(mac)239. DNA sequence analysis of HIV-1 derived regions of SHIV(KU-2MC4) revealed 2, 1, 2, and 18 predicted amino acid substitutions in the Tat, Rev, Vpu, and Env proteins, respectively, when compared to SHIV-4. Unlike the parental SHIV-4, which is not tropic for macrophages, SHIV(KU-2MC4) replicated efficiently in macrophage cultures as determined by p27 assays. However, despite the numerous changes in the Env protein and newly acquired tropism for macrophages, SHIV(KU-2MC4), like the parental SHIV-4, used CXCR4 exclusively as its coreceptor for entry into susceptible cells. Inoculation of SHIV(KU-2MC4) into two rhesus macaques resulted in severe infection in which the numbers of circulating CD4(+) T cells in the blood declined rapidly by 2 weeks postinoculation and virus producing cells in the peripheral blood mononuclear cells were identified throughout the course of infection. At the time of euthanasia (20 and 22 weeks), both macaques had lost a significant amount of weight and had no circulating CD4(+) T cells. In addition, one macaque developed intension tremors and uncoordinated movements. Virological examination of tissues at necropsy revealed active virus replication in both lymphoid and nonlymphoid tissues such as the lung and brain. Histological examination revealed that the induced immunodeficiency was associated with lymphoid depletion of the lymph nodes and spleen, opportunistic infections, lentiviral encephalitis, and severe glomerulosclerosis of the kidney. This molecular clone will serve as the basis for analyzing the molecular determinants through which SHIV(KU-2) causes severe CD4(+) T cell loss, neurological disease, and SHIV nephropathy in rhesus macaques.
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PMID:Derivation and biological characterization of a molecular clone of SHIV(KU-2) that causes AIDS, neurological disease, and renal disease in rhesus macaques. 1041 64

The use of magnetism in medicine has a long and colorful history since its legendary discovery in the Western world by the shepherd Magnes. More recent use of magnetism has centered on nuclear magnetic resonance. Magnetic resonance spectroscopy (MRS) provides chemical information on tissue metabolites. Both hydrogen 1 (1H) and phosphorus 31 resonances have been used to study brain tissue, but the magnetic resonance sensitivity for protons is far greater than it is for phosphorus. One of the most important contributions of 1H-MRS to clinical neurology is its ability to quantify neuronal loss and to demonstrate reversible neuronal damage. 1H-magnetic resonance spectroscopy has been found to be a useful research tool in elucidating the pathophysiology underlying certain diseases. This review focuses on the use of proton MRS to study various neurologic diseases, including epilepsy, multiple sclerosis, brain tumors, human immunodeficiency virus 1-associated neurologic disorders, as well as cerebrovascular, neurodegenerative, and metabolic diseases. It highlights the contributions of 1H-MRS to the diagnosis and the monitoring of these neurologic diseases that make it a useful adjunct in patient management.
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PMID:Proton magnetic resonance spectroscopy for the diagnosis and management of cerebral disorders. 1044 96

The pattern of neurological disease caused by human immunodeficiency virus (HIV) infection of the central nervous system (CNS) was investigated using a macaque model of acquired immune defiency syndrome (AIDS). Seven of nine macaques inoculated with neurovirulent simian imunodeficiency virus (SIVmac ) developed AIDS within 3 months. Four of these had clinically obvious neurological disease and extensive conduction defects in the form of latency increases in evoked potential (EP) responses. Neuropathologically, all four animals had disseminated white matter disease in the form of multifocal, perivascular and nodular parenchymal mononuclear cell infiltrates, along with extensive involvement of the cortical grey matter, leptomeninges and intracranial portions of cranial nerves. A brisk multinucleated giant cell (MGC) response was a frequent accompaniment in the affected areas. Three of the animals in this group also showed spongiform vacuolation in the occipital grey matter, a lesion described only rarely in HIV encephalitis. In the remaining three animals, there was only minimal evidence of overt neurological impairment or conduction defects. These animals had only mild to moderate neuropathological changes and lesions were virtually confined to the white matter regions of the brain. MGC responses were rare or absent in the CNS of these animals. Neuropathological findings in this SIVmac model have therefore shown good correlation with the severity of clinical and neurophysiological changes, and are reminiscent of HIV-1 encephalitis. More importantly, white matter involvement was a consistent finding in the affected macaques, regardless of the duration and severity of disease, or type of virus inoculated, suggesting an unusual susceptibility for lentiviral infection in these regions of the macaque CNS.
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PMID:Morphological correlates of neurological dysfunction in macaques infected with neurovirulent simian immunodeficiency virus. 1047 45


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