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)

Since 1998, many cases of antiretroviral therapy-related paronychia of the toes or fingers and ingrown toenails have been reported. Most of them were related to indinavir. Other indinavir-induced mucocutaneous disorders resembling the adverse effects of systemic retinoid therapy have also been reported. Although there is some uncertainty in the literature regarding a cause-effect relationship, results of several epidemiological and in vitro studies, together with cumulated clinical experience leave no doubt that indinavir causes a retinoid-like effect and nail alterations. Indeed, indinavir is the only antiretroviral drug that produces these disorders, although ritonavir may enhance indinavir-induced retinoid-like effects through pharmacokinetic interactions leading to increased plasma indinavir concentrations. Approximately 30% of patients receiving indinavir show two or more retinoid-like manifestations and 4-9% develop paronychia. These adverse effects are not related to other epidemiological variables such as the patient's sex, age or other risk factors or immune status. They seem to be exposure dependent and, therefore, largely dose-dependent. Chronic paronychia is considered generally to be caused by contact irritants and candidal infection. Nevertheless, indinavir is currently the most frequent cause of chronic or recurrent paronychia in HIV-infected patients. In addition, retinoid-like manifestations such as cutaneous xerosis and cheilitis are frequent mucocutaneous adverse effects related to indinavir. The exact mechanism of indinavir-induced retinoid-like effects is unclear. Hypotheses for pathogenesis include interference with retinoid metabolism by enhancing the retinoic acid signalling pathway, or by increasing retinoic acid synthesis, or by reducing cytochrome p450-mediated retinoic acid oxidative metabolism. Replacement of therapy by an antiretroviral regimen not containing indinavir, while retaining other protease inhibitors and lamivudine, resolves retinoid-like manifestations without recurrences.
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PMID:Indinavir-induced retinoid-like effects: incidence, clinical features and management. 1240 31

The synthesis of retinoid vitamin A-vitamin B(6) conjugate analogues from a vitamin B(6) coenzyme analogue and putative HIV-1 trans-activating transcriptional regulatory protein Tat antagonist (Z)-5(')-O-phosphono-pyridoxylidenerhodanine (B6PR) monosodium salt hemiheptadecahydrate [(Z)-B6PRNa8.5H(2)O] is discussed here. All-trans-retinoic acid (ATRA) is coupled to B6PR by a modified Stork enamine acylation. It results in a product library of more than eight compounds, each with at least one intact all-trans or 13-cis vitamin A double bond system. This yellow oily concentrate mixture was subjected to matrix-assisted laser desorption/ionization-time-of-flight (MALDI-ToF) mass spectrometry (MS), UV/VIS-spectrophotometry, and proton nuclear magnetic resonance spectroscopy (1H-NMR). The chemical structures of six components of the concentrate mixture could be established by combination of these analytical methods. The two main components are 65% 2(')C,3O-(all-trans-retinylidyne)B6PT (B6RA) and 25% 2(')C-(all-trans-retinoyl)B6PT, chemically derived from (5RS)-5-(5(')-O-phosphono-pyridoxyl)-2,4-thiazolidinedione (B6PT). This new retinoid selection could be of further interest in antiviral applications, especially treating conditions caused by RNA viruses like HIV.
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PMID:Synthesis of retinoid vitamin A-vitamin B6 conjugate analogues for antiviral chemotherapy. 1250 21

Human immunodeficiency virus type 1 (HIV-1)-associated central nervous system disorders, including encephalopathy, often occur in the late stage of HIV-1 infection. Some inflammatory cytokines and HIV-1 antigens released from infected microglia or brain macrophages are considered to play an important role in neuropathogenesis. In this study, an in vitro assay system has been established for the evaluation of neural cell death, which would be predictive of the pathogenesis of neural cell death in vivo. The human neuroblastoma cell line SK-N-SH was differentiated to a neural phenotype with retinoic acid, while the promyelocytic cell line HL-60 and its HIV-1-infected clone OM-10.1 were differentiated to macrophages with phorbol myristate acetate. When neural (differentiated SK-N-SH) cells were cocultured with either uninfected or HIV-1-infected macrophages (differentiated HL-60 or OM-10.1 cells, respectively) for 3-5 days, significant neural cell death was observed in the cells cocultured with infected macrophages. Direct contact with macrophages was not necessary for the induction of neural cell death, since indirect coculture or coculture supernatants could also induce neural cell death. Large amounts of cytokines and chemokines were released in the coculture supernatants. The CXCR4 antagonist AMD3100 and the HIV-1 transcription inhibitor K-37 partially inhibited neural cell death. These results indicate that this system seems to be a useful tool for the evaluation of compounds against HIV-1-induced neural cell death.
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PMID:Establishment of an in vitro assay system mimicking human immunodeficiency virus type 1-induced neural cell death and evaluation of inhibitors thereof. 1260 87

Gene therapy to treat primary and secondary CNS diseases, including neuro-AIDS, has not yet been effective. New approaches to delivering therapeutic genes to the central nervous system are therefore required. Recombinant SV40 vectors (rSV40) transduce both dividing and quiescent cells efficiently, and so we tested them for their ability to deliver anti-HIV-1 transgenes to terminally differentiated human NT2-derived neurons (NT2-N). These vectors transduced >95% of immature as well as mature human neurons efficiently, without detectable toxicity and without requiring selection. rSV40 gene delivery was stable to retinoic acid-induced neuronal differentiation. The rSV40 vectors used in these studies, SV(RevM10) and SV(AT), respectively carried the cDNAs for RevM10, a trans-dominant mutant of HIV-1 Rev, and human alpha1-antitrypsin. As measured by HIV-1 p24 antigen assays and by immunostaining for gp120, NT2-N treated with these vectors strongly resisted challenge with different strains of HIV-1. Protection from HIV replication and HIV-induced cytotoxicity was conferred by SV(AT) and SV(RevM10) and remained constant throughout retinoic acid-induced neuronal differentiation and for the duration of these studies (> or =11 weeks). rSV40 transduction of human neurons might therefore be a practicable approach to gene delivery for the treatment of CNS diseases, including neuro-AIDS.
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PMID:Inhibiting AIDS in the central nervous system: gene delivery to protect neurons from HIV. 1278 54

Familial partial lipodystrophy (FPL) and lipodystrophy observed in HIV-1 infected patients receiving highly active antiretroviral therapy (HAART) share multiple clinical and metabolic features. Recently, missense mutations of LMNA encoding lamin A/C have been described in FPL providing evidence for a pivotal role of lamin A/C in the regulation of adipocytes. Moreover, the cellular retinoic acid binding protein (CRABP) has been suggested to be involved in HAART associated lipodystrophy. In this study, we excluded mutations within the complete coding region and the promoter of LMNA and the CRABP II gene in HIV-1 infected patients with lipodystrophy and also any correlation of the nucleotide polymorphism at codon 566 in exon 10 of LMNA with metabolic abnormalities. Protease inhibitors including indinavir have been shown to reduce adipocyte cell differentiation and increase apoptosis of adipocytes in vitro. Indinavir leads to altered retinoic acid signaling most likely by an activation of the RAR/RXR heterodimer, perhaps by displacing all-trans-retinoic acid from CRABP. Since LMNA is regulated by a retinoic acid responsive element (L-RARE) in the promoter region, we propose that indinavir impairs retinoic acid homeostasis and/or interact via the L-RARE within the LMNA promoter. This results in altered LMNA expression and subsequent impaired adipocyte differentiation, lipodystrophic body habitus, and metabolic disturbances in HIV infected patients receiving HAART.
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PMID:Lack of mutations in LMNA, its promoter region, and the cellular retinoic acid binding protein II (CRABP II) in HIV associated lipodystrophy. 1284 77

In human immunodeficiency virus type 1 (HIV-1)-infected individuals, virus-induced production of interferon alpha (IFN-alpha) is impaired. In order to obtain regulated expression of IFN-alpha that responds to HIV-1 infection, a recombinant SV40 vector was designed that carries the human IFN-alpha2 cDNA under the control of the HIV-1 long terminal repeat (LTR) (SV[HIVLTR]IFN). Thus, the IFN-alpha2 gene would be trans-activated on infection with HIV-1. This vector was tested to determine if central nervous system (CNS) cell types that may be potential HIV-1 targets could be transduced and protected from HIV. SV[HIVLTR]IFN transduced NT2 cells, a human neuronal precursor cell line, mature neurons derived from NT2 precursor cells, and human primary monocyte-derived macrophages. IFN-alpha2 expression was retained in mature neurons after SV[HIVLTR]IFN-transduced NT2 precursor cells were induced to differentiate using retinoic acid. IFN-alpha expression was detected only after exposing transduced cells to HIV. Furthermore, SV[HIVLTR]IFN-delivered IFN-alpha2 expression significantly inhibited replication of multiple strains of HIV in both NT2 and NT2-derived mature neurons. SV[HIVLTR]IFN transduction also inhibited HIV-1(BaL) replication in human primary monocyte-derived macrophages. Therefore, we have demonstrated the effectiveness of IFN-alpha2, delivered by an SV40 vector driven by HIV-1 LTR as a promoter, to protect several CNS-based, potentially HIV-susceptible cell types. These findings may have implications for therapy of HIV-1 infection in the CNS.
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PMID:Inhibition of HIV-1 in the central nervous system by IFN-alpha2 delivered by an SV40 vector. 1456 57

Deficiency in vitamin A has been associated with adverse clinical outcomes in drug users with HIV-1 infection. Retinoids have been demonstrated to suppress proinflammatory cytokine production by immune cells in vitro. These effects are induced by ligand-mediated activation of the retinoid receptors--retinoic acid receptor (RAR) and retinoid X receptor (RXR). In these studies, the effects of all-trans-retinoid acid (ATRA, a RAR agonist), 9-cis-retinoic acid (9cis RA; RAR and RXR agonist), LG101305 (RXR agonist), LG100815 (RAR antagonist) and LG101208 (RXR antagonist) on TNF-alpha production by phytohemagglutanin-activated U937 cells and the modulation of these effects by morphine were examined. TNF-alpha production was suppressed in all cultures exposed to retinoid agonist and antagonist agents. For cells exposed to RXR agonists or RAR antagonist, incubation with morphine resulted in the reversal of TNF-alpha suppression and this effect was inhibited by naloxone. These data suggest that interactions between RXR and morphine are involved in the immune effects of retinoids on TNF-alpha production by activated U937 cells. Such information may be important for understanding interactions between drugs of abuse and immune function in individuals with chronic proinflammatory states such as HIV-1 infection.
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PMID:RXR-induced TNF-alpha suppression is reversed by morphine in activated U937 cells. 1474 37

Vitamin A deficiency has been correlated with increased severity of human immunodeficiency virus type 1 (HIV-1)-associated disease. Moreover, vitamin A supplementation can reduce AIDS-associated morbidity and mortality. Our group and others have shown that retinoids, the bioactive metabolites of vitamin A, repress HIV-1 replication in monocytic cell lines and primary macrophages by blocking long-terminal-repeat (LTR)-directed transcription. Based on these studies, we hypothesize that retinoids are natural repressors of HIV-1 in vivo. We show here that all-trans-retinoic acid (RA)-mediated repression of HIV-1 activation requires pretreatment for at least 12 h and is blocked by the protein synthesis inhibitors cycloheximide and puromycin. Studies of the kinetics of RA-mediated repression in U1 cells and primary monocyte-derived macrophages (MDMs) reveal that the repressive effects of RA on HIV-1 expression are long-lasting but reversible. We demonstrate that HIV-1 expression is activated when U1 cells or MDMs are cultured in retinoid-free synthetic medium and show that physiological concentrations of RA repress this activation. In addition, the synthetic pan-retinoic acid receptor antagonist BMS-204 493 activates HIV-1 replication in U1 cells in a dose-dependent manner, suggesting that RA-induced transactivation of cellular gene expression is required for HIV-1 repression. Together, these data support the hypothesis that retinoids present in tissue culture media in vitro and serum in vivo maintain HIV-1 in a transcriptionally repressed state in monocytes/macrophages.
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PMID:Retinoid-dependent restriction of human immunodeficiency virus type 1 replication in monocytes/macrophages. 1499 Jul 1

All-trans retinoic acid (RA) represses HIV-1 transcription and replication in cultured monocytic cells and in primary monocyte-derived macrophages. Here we examine the role of histone acetylation and chromatin remodeling in RA-mediated repression. RA pretreatment of latently infected U1 promonocytes inhibits HIV-1 expression in response to the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA). TSA is thought to activate HIV-1 transcription by inducing histone hyperacetylation within a regulatory nucleosome, nuc-1, positioned immediately downstream from the transcription start site. Acetylation of nuc-1 is thought to be a critical step in activation that precedes nuc-1 remodeling and, subsequently, transcriptional initiation. Here we demonstrate that TSA treatment induces H3 and H4 hyperacetylation and nuc-1 remodeling. Although RA pretreatment inhibits nuc-1 remodeling and HIV-1 transcription, it has no effect on histone acetylation. This suggests that acetylation and remodeling are not obligatorily coupled. We also show that growth of U1 cells in retinoid-deficient medium induces nuc-1 remodeling and HIV-1 expression but does not induce histone hyperacetylation. These findings suggest that remodeling, not histone hyperacetylation, is the limiting step in transcriptional activation in these cells. Together, these data suggest that RA signaling maintains the chromatin structure of the HIV-1 promoter in a transcriptionally non-permissive state that may contribute to the establishment of latency in monocyte/macrophages.
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PMID:Retinoic acid inhibition of chromatin remodeling at the human immunodeficiency virus type 1 promoter. Uncoupling of histone acetylation and chromatin remodeling. 1529 18

We report a 27-year-old man with HIV-1 infection who developed acute promyelocytic leukemia (APL) with a novel complex three-way chromosomal translocation t(15;16;17). Induction of remission and consolidation with all-trans-retinoic acid (ATRA)- and anthracycline-based chemotherapy was followed by maintenance therapy consisting of ATRA, 6-mercaptopurine (6-MP), and methotrexate (MTX). Highly active antiretroviral therapy (HAART) was continued with brief interruptions. He remains in complete remission 40 months after diagnosis.
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PMID:Acute promyelocytic leukemia and HIV-1 infection: case report and review of the literature. 1549 46


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