Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine intracisternal A-type particles (IAPs) are endogenous retroviruses showing sequence homologies to B/D- and avian C-type retroviruses and a gene expression strategy similar to that of D-type retroviruses. These viruses form immature particles in the endoplasmic reticulum and do not release extracellular virions, but are competent for retrotransposition within the virus-producing cell. It had been assumed that lack of polyprotein processing and maturation is due to a defect in the viral proteinase (PR), but recent experiments have shown that polyprotein processing occurs when assembly of the mouse IAP MIA14 is artificially directed to the plasma membrane. We have expressed and purified recombinant MIA14 PR and show that it undergoes N- and C-terminal autoprocessing at defined sites. Using peptide cleavage and inhibition assays and in vitro cleavage of recombinant HIV-1 and MIA14 Gag polyproteins, we show that MIA14 PR is a catalytically competent enzyme comparable in its efficiency to PRs from type D exogenous retroviruses. MIA14 PR is related to the PR of Mason-Pfizer monkey virus both functionally and with respect to its expression strategy, and is distinct from HIV-1 PR with respect to substrate specificity and catalytic efficiency. These findings reveal a functional and possibly evolutionary relationship between MIA14 and D-type retroviruses and imply that a functional PR may be relevant for intracellular retrotransposition even in the case of an endogenous retrovirus that does not produce extracellular virus.
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PMID:The murine endogenous retrovirus MIA14 encodes an active aspartic proteinase that is functionally similar to proteinases from D-type retroviruses. 1183 58

HIV-1 pathogenicity factor Nef has been shown to modulate calcium signaling in host cells, but the underlying molecular mechanisms have remained unclear. Here we show that calcium/calcineurin-dependent activation of nuclear factor of activated T cells (NFAT) by Nef in Jurkat T cells requires the endoplasmic reticulum-resident inositol trisphosphate receptor (IP(3)R), but yet does not involve increase in phospholipase-C gamma 1 (PLC gamma 1)-catalyzed production of IP(3) or depletion of IP(3)-regulated intracellular calcium stores. Nef could be coprecipitated with endogenous IP(3)R type-1 (IP(3)R1) from Nef-transfected Jurkat T cells as well as from HIV-infected primary human peripheral mononuclear cells. Thus, the Nef/IP(3)R1-interaction defines a novel T cell receptor-independent mechanism by which Nef can promote T cell activation, and appears to involve atypical IP(3)R-triggered activation of plasma membrane calcium influx channels in a manner that is uncoupled from depletion of intracellular calcium stores.
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PMID:HIV-1 Nef interacts with inositol trisphosphate receptor to activate calcium signaling in T cells. 1195 93

Patients with AIDS often develop cognitive and motor dysfunction that results from damage to synapses and death of neurons in brain regions such as the hippocampus and basal ganglia. This brain syndrome, called AIDS dementia or HIV encephalitis, is believed to result from the infection of one or more populations of mitotic brain cells with HIV-1, which then release viral proteins that are toxic to neurons. Two neurotoxic HIV-1 proteins have been identified, the viral coat protein gp120 and the transcription regulator Tat. Each of these proteins can induce apoptosis of cultured neurons and can render neurons vulnerable to excitotoxicity and oxidative stress. Gp120 and Tat also cause neuronal dysfunction and death in rodents in vivo. Both gp120 and Tat disrupt neuronal calcium homeostasis by perturbing calcium-regulating systems in the plasma membrane and endoplasmic reticulum. Accordingly, drugs that stabilize cellular calcium homeostasis can protect neurons against the toxic effects of gp120 and Tat. By altering voltage-dependent calcium channels, glutamate receptor channels, and membrane transporters, the HIV-1 proteins promote calcium overload, oxyradical production, and mitochondrial dysfunction. A better understanding of how gp120 and Tat disrupt neuronal calcium homeostasis may lead to the development of novel treatments for AIDS patients.
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PMID:Calcium dysregulation and neuronal apoptosis by the HIV-1 proteins Tat and gp120. 1239 83

Tissue from an extirpated cervical lymph node of an African AIDS patient with tuberculosis was investigated with the electron microscope. A peculiar cytoplasmic structure was found in histiocytic cells of the lymph node tissue. This structure consisted of a loose aggregation of convoluted, folded curvilinear membranes, demonstrating C-shaped, U-shaped, and S-shaped profiles according to the plane of section. These curvilinear membranous formations (CMF) were formed by 2 parallel-running unit membranes separated by a narrow electron-lucent space. Continuities of CMF with rough-surfaced endoplasmic reticulum were sometimes observed. Occasionally, an electron-dense, blurred cytoplasmic area was seen between 2 neighboring CMF. Several CMF also formed a seastar-like configuration by mergence in such an area. It is unknown whether the HIV infection of the patient was the primary cause of the CMF.
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PMID:Curvilinear membranous formations in lymph node cells of an African AIDS patient with tuberculosis. 1255 36

Mannose-binding lectin (MBL), a C-type lectin component of the human innate immune system, binds to the gp120 envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1). The objective of this study was to assess the effects of inhibitors of endoplasmic reticulum glucosidases and Golgi mannosidase as well as neuraminidase (NA) on the interaction between HIV and MBL. Production of HIV in the presence of the mannosidase I inhibitor deoxymannojirimycin (dMM) significantly enhanced binding of HIV to MBL and increased MBL neutralization of an M-tropic HIV primary isolate. In contrast, culturing HIV in the presence of alpha-glucosidase I and II inhibitors castanospermine and deoxynojirimycin only slightly affected virus binding and neutralization by MBL. Removal of sialic acid from HIV by NA also significantly enhanced virus binding and neutralization by MBL. Treatment of virus grown in the presence of dMM with endoglycosidase F1 substantially reduced binding to MBL, indicating that dMM increased MBL binding by increasing high-mannose carbohydrates on the virus. In contrast, endoglycosidase F1 did not decrease the MBL interaction with NA-treated virus, suggesting that NA exposed novel MBL binding sites. Treatment with dMM increased the immunocapture of HIV by monoclonal antibodies 2F5 and 2G12, indicating that altering the glycosylation of viral glycoproteins increases the accessibility or reactivity of some epitopes. This study shows that specific alterations of the N-linked carbohydrates on HIV gp120/gp41 can enhance MBL-mediated neutralization of virus by strengthening the interaction of HIV-1 with MBL.
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PMID:Glycosylation inhibitors and neuraminidase enhance human immunodeficiency virus type 1 binding and neutralization by mannose-binding lectin. 1256 May 67

The AIDS or HIV associated dementia is a cognitive-motor disease, characterized by a strong deficit of several cognitive processes such as attention, memory, sensory perception, motor control among others. The HIV associated dementia affects 30% of adult to 50% of infant HIV positive subjects. Since neurons are not infected by HIV, its principal target in the brain is microglia. The pathophysiology of this syndrome, therefore, remains to be disclosed. Several hypothesis have been proposed, one of them suggests that opportunistic infections can affect the brain. Another hypothesis suggests that microglia secretes toxic products as a result of HIV infection and those are the ones causing the damage and finally, the hypothesis, suggesting that the brain is damaged as a result of the insult caused by HIV-derived proteins. In vitro studies suggest that the HIVgp120, a viral surface protein, is highly neurotoxic. For example HIVgp120 increases cytoplasmic Ca+2 by two ways: facilitating glutamate neurotransmission increasing Ca+2 conductance, and activating the IP3 pathway, facilitating Ca+2 release from the smooth endoplasmic reticulum. This Ca+2 in turn, activates several internal signaling pathways such as the MAPK pathway. We use an animal model to test the HIVgp120 effect on neurophysiological signals and behavior as well as several pharmacological approaches to prevent the HIVgp120 neurotoxic effects. This review updates with the most recent literature discussing the potential mechanisms implicated in the pathophysiology of the AIDS dementia complex. We, in addition, hope the reader will be able to correlate the clinical symptoms observed in the HIV infected subjects and the HIVgp120-induced behavioral changes observed in animal models. Likewise, we discuss the new drugs we are testing, in order to offer a new pharmacological treatment to the patient.
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PMID:[HIV glycoprotein 120: possible etiological agent of AIDS-associated dementia]. 1258 19

Human immunodeficiency virus type 1 (HIV-1) Vpu protein promotes both extracellular release of viral particles and degradation of CD4 in the endoplasmic reticulum. The correlation of anti-Vpu antibody (Ab) reactivity to Vpu and AIDS disease progression was studied in 162 HIV-1/AIDS patients after they had received highly active antiretroviral therapy (HAART) for 1 year. Anti-Vpu Ab reactivity was analyzed by Western blot using a recombinant Vpu protein. Results showed that at baseline (prior to initiation of HAART), 31.5% of patients (51/162) had anti-Vpu Ab. The proportion of anti-Vpu Ab in patients with CD4 counts > or =500, 200-500 and <200/mm(3) were 40.6, 34.7 and 14.3%, respectively (chi(2) test, p < 0.05). In addition, decreasing levels of anti-Vpu Ab reactivity were significantly correlated with increasing levels of HIV-1 viral load. After receiving HAART for 1 year, 7 of 111 anti-Vpu Ab-negative patients (6.3%) seroconverted (- --> + group) and 8 of 51 anti-Vpu Ab-positive (15.7%) patients became negative (+ --> - group). Among 104 anti-Vpu Ab-negative patients, 40 were selected for analysis of the VPU gene. All of them had an intact VPU gene. Patients were further divided into four groups according to their anti-Vpu Ab serostatus and anti-HIV-1 Ab was measured. The results showed that only the anti-Vpu Ab seroconverted group (- --> +) had increased serum levels of anti-HIV-1 Abs after 1 year of HAART, while the other three groups (+ --> +, - --> - and + --> -) had decreased serum levels of anti-HIV-1 Abs after 1 year of HAART (p < 0.05). In conclusion, the presence of anti-Vpu Ab is associated with improved prognosis following HIV-1 infection, and seroconversion of anti-Vpu Ab in patients on HAART indicates significant recovery of immunity.
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PMID:Antibody reactivity to HIV-1 Vpu in HIV-1/AIDS patients on highly active antiretroviral therapy. 1259 63

HIV-1 Nef protein down-regulates several important immunoreceptors through interactions with components of the intracellular sorting machinery. Nef expression is also known to induce modifications of the endocytic pathway. Here, we analyzed the effects of Nef on retrograde transport, from the plasma membrane to the endoplasmic reticulum using Shiga toxin B-subunit (STxB). Nef expression inhibited access of STxB to the endoplasmic reticulum, but did not modify the surface expression level of STxB receptor, Gb3, nor its internalization rate as measured with a newly developed assay. Mutation of the myristoylation site or of a di-leucine motif of Nef involved in the interaction with the clathrin adaptor complexes AP1 and AP2 abolished the inhibition of retrograde transport. In contrast, mutations of Nef motifs known to interact with PACS-1, beta COP or a subunit of the v-ATPase did not modify the inhibitory activity of Nef on retrograde transport. Ultrastructural analysis revealed that Nef was present in clusters located on endosomal or Golgi membranes together with internalized STxB. Furthermore, in strongly Nef-expressing cells, STxB accumulated in endosomal structures that labeled with AP1. Our observations show that Nef perturbs retrograde transport between the early endosome and the endoplasmic reticulum. The potential transport steps targeted by Nef are discussed.
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PMID:Effects of HIV-1 Nef on retrograde transport from the plasma membrane to the endoplasmic reticulum. 1271 60

Human immunodeficiency virus binds and enters cells via the Envelope glycoprotein gp160 at its surface. In infected cells, gp160 is found not only on the plasma membrane but also in the endoplasmic reticulum (ER). Our aim was to establish rate-determining steps in the maturation process of gp160, using a radioactive pulse-chase approach. We found that gp160 has an intricate folding process: disulfide bonds start to form during synthesis but undergo extensive isomerization until the correct native conformation is reached. Removal of the leader peptide critically depends on formation of at least some disulfide bonds in subunit gp120 during folding. Envelope folds extremely slowly and therefore resides in the ER longer than other proteins, but the yield of properly folded molecules is high and degradation is undetectable. The large quantity of gp160 in the ER hence is a result of its slow transit through this compartment. We show here that newly synthesized HIV-1 Envelope glycoprotein apparently follows a slow but high-yield folding path in which co- and post-translational formation of disulfide bonds in gp120, disulfide isomerization and conformation dependent removal of the leader sequence are determining and intertwined events.
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PMID:Folding of HIV-1 envelope glycoprotein involves extensive isomerization of disulfide bonds and conformation-dependent leader peptide cleavage. 1277 88

Hepatitis C virus (HCV) glycoproteins E1 and E2 are believed to be retained in the endoplasmic reticulum (ER) or cis-Golgi compartment via retention signals located in their transmembrane domains. Here we describe the detection of E1 and E2 at the surface of transiently transfected HEK 293T and Huh7 cells. Surface-localized E1E2 heterodimers presented exclusively as non-covalently associated complexes. Surface-expressed E2 contained trans-Golgi modified complex/hybrid type carbohydrate and migrated diffusely between 70 and 90 kDa while intracellular E1 and E2 existed as high mannose 35 kDa and 70 kDa precursors, respectively. In addition, surface-localized E1E2 heterodimers were incorporated into E1E2-pseudotyped HIV-1 particles that were competent for entry into Huh7 cells. These studies suggest that functional HCV glycoproteins are not retained exclusively in the ER and transit through the secretory pathway.
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PMID:Cell surface expression of functional hepatitis C virus E1 and E2 glycoproteins. 1283 74


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