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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In recent years, lipodystrophy and its related complications have become one of the major problems confronting HIV-infected patients on antiretroviral therapy. More than ten years after having been described for the first time, comprehensive knowledge of its underlying molecular basis, the natural history of body fat changes and metabolic abnormalities, and even a working definition of lipodystrophy are all still lacking. No standardized objective assessment of body fat has been incorporated into clinical practice for patient monitoring. Although a huge amount of data has been generated, no clinically proven treatment for any feature of lipodystrophy is currently available. The only intervention that has been shown to reverse lipoatrophy had been the discontinuation of thymidine analogues, although even then the results obtained are at most partial or modest. Recently published studies using uridine (NucleomaxX) and pravastatin resulted in a significant increase of subcutaneous fat. The potential for reversing lipodystrophy once it has developed is limited, but promising results in preventing it are obtained with thymidine analogue-sparing initial antiretroviral regimens. These results raise the question of whether we may be facing a definitive solution to the lipodystrophy syndrome.
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PMID:HIV-associated lipodystrophy syndrome. 1750 76

Persistent immune activation is a hallmark of chronic viremic HIV-1 infection. Activation of cells of the innate immune system, such as NK cells, occurs rapidly upon infection, and is sustained throughout the course of the disease. However, the precise underlying mechanism accounting for the persistent HIV-1-induced activation of NK cells is poorly understood. In this study, we assessed the role of uridine-rich ssRNA derived from the HIV-1 long terminal repeat (ssRNA40) on activation of NK cells via TLR7/8. Although dramatic activation of NK cells was observed following stimulation of PBMC with ssRNA40, negligible activation was observed following stimulation of purified NK cells despite their expression of TLR8 mRNA and protein. The functional activation of NK cells by this HIV-1-encoded TLR7/8 ligand could not be reconstituted with exogenous IL-12, IFN-alpha, or TNF-alpha, but was critically dependent on the direct contact of NK cells with plasmacytoid dendritic cells or CD14(+) monocytes, indicating an important level of NK cell cross-talk and regulation by accessory cells during TLR-mediated activation. Coincubation of monocyte/plasmacytoid dendritic cells, NK cells, and ssRNA40 potentiated NK cell IFN-gamma secretion in response to MHC-devoid target cells. Studies using NK cells derived from individuals with chronic HIV-1 infection demonstrated a reduction of NK cell responsiveness following stimulation with TLR ligands in viremic HIV-1 infection. These data demonstrate that HIV-1-derived TLR ligands can contribute to the immune activation of NK cells and may play an important role in HIV-1-associated immunopathogenesis and NK cell dysfunction observed during acute and chronic viremic HIV-1 infection.
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PMID:Single-stranded RNA derived from HIV-1 serves as a potent activator of NK cells. 1754 2

Halogenation of bases is a widespread method used for solving crystal structures of nucleic acids. However, this modification may have important consequences on RNA folding and thus on the success of crystallization. We have used a combination of UV thermal melting, steady-state fluorescence, X-ray crystallography, and gel electrophoresis techniques to study the influence of uridine halogenation (bromination or iodination) on the RNA folding. The HIV-1 Dimerization Initiation Site is an RNA hairpin that can adopt an alternative duplex conformation and was used as a model. We have shown that, unexpectedly, the RNA hairpin/duplex ratio is strongly dependent not only on the presence but also on the position of halogenation.
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PMID:Influence of C-5 halogenation of uridines on hairpin versus duplex RNA folding. 1763 Mar 26

HIV-1/highly active antiretroviral therapy-associated lipodystrophy syndrome (HALS) is presently the most common long-term adverse effect limiting the doubtless efficacy of antiretroviral therapy. It has a great impact on the quality of life of patients, it is stigmatising and its psychologically devastating consequences may ultimately impact on the adherence to treatment of patients, eventually leading to treatment failure. Despite considerable advances in recent times, the pathogenesis of HALS remains elusive. Factors involved belong to three categories: those intrinsic to the host, some of them modifiable and some not, those associated with antiretroviral therapy, that are sometimes modifiable as well, and finally those related to HIV-1 infection and its consequences, most often not modifiable. The most commonly used strategies for HALS reversion have included host-dependent factors such as lifestyle and dietary modifications and antiretroviral-dependent factors such as switching or avoiding the use of drugs more prone to promote HALS. Lifestyle modifications and switching thymidine analogues have been associated with moderate success. Pharmacological interventions have included the use of insulin-sensitising agents and hormone therapy with disappointing results, whereas treatment with pravastatin or pioglitazone, and uridine supplementation seem to be associated with fat gain in preliminary studies. The only interventions with almost immediate results that may render a patient's appearance similar to his past one have included filling techniques for facial lipoatrophy and ultrasound-assisted liposuction for cervical fat pad hypertrophy. Among the filling options, semipermanent reabsorbable materials and autologous fat transfer have been associated with acceptable outcomes. As of now, the best hope should rely on the use of drugs friendly for fat, on defining the appropriate timing for starting antiretroviral and on continuing the research effort to understand the basic mechanisms underlying HALS pathogenesis. Only through this effort can the best chances for preventing or reverting established HALS be recognised.
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PMID:Strategies in the treatment of HIV-1-associated adipose redistribution syndromes. 1769 90

Emissive nucleoside analogues that are sensitive to their microenvironment can serve as probes for exploring RNA folding and recognition. We have previously described the synthesis of an environmentally sensitive furan-containing uridine and its triphosphate, and have demonstrated that T7 RNA polymerase recognizes this modified ribonucleoside triphosphate as a substrate in in vitro transcription reactions. Here we report the enzymatic preparation of fluorescently tagged HIV-1 TAR constructs and study their interactions with a Tat peptide. Two extreme labeling protocols are examined, where either all native uridine residues are replaced with the corresponding modified fluorescent analogue, or only key residues are site-specifically modified. For the HIV-1 Tat-TAR system, labeling all native uridine residues resulted in relatively small changes in emission upon increasing concentrations of the Tat peptide. In contrast, when the two bulge U residues were site-specifically labeled, a reasonable fluorescence response was observed upon Tat titration. The scope and limitations of such fluorescently tagged RNA systems are discussed.
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PMID:Using an emissive uridine analogue for assembling fluorescent HIV-1 TAR constructs. 1843 40

Despite impressive decreases in mortality and morbidity, significant adverse events have surfaced as a result of combination antiretroviral therapy (ART). They include lipoatrophy, or subcutaneous fat wasting of the face, arms, buttocks, or legs, which can be associated with central fat accumulation. Although the underlying mechanism of ART-related body fat abnormalities has not been definitively established, mitochondrial toxicity is increasingly implicated in the lipoatrophy component of these fat abnormalities. Several studies evaluating switches off of nucleoside analogues have showed modest but statistically significant increases in limb fat. Because ART switches result in slow and small improvements and are not an option in many patients, other therapeutic interventions are needed. Although peroxisome proliferator-activated receptor chi agonist thiazolidinediones would be expected to have positive effects on lipoatrophy, initial clinical studies are conflicting. Other interventions of uridine, pravastatin, and facial fillers have been evaluated in small studies.
Curr HIV/AIDS Rep 2008 May
PMID:Pathogenesis and management of lipoatrophy. 1851 Aug 90

Raltegravir is an HIV integrase inhibitor that is metabolized through glucuronidation by uridine diphosphate glucuronosyltransferase 1A1, and its use is anticipated in combination with atazanavir (a uridine diphosphate glucuronosyltransferase 1A1 inhibitor). Two pharmacokinetic studies of healthy subjects assessed the effect of multiple-dose atazanavir or ritonavir-boosted atazanavir on raltegravir levels in plasma. Atazanavir and atazanavir plus ritonavir modestly increase plasma levels of raltegravir.
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PMID:Atazanavir modestly increases plasma levels of raltegravir in healthy subjects. 1851 46

Lipodystrophy (LD) is a common adverse effect of HIV treatment with highly active antiretroviral therapy, which comprises morphological and metabolic changes. The underlying mechanisms for LD are thought to be due to mitochondrial toxicity and insulin resistance, which results from derangements in levels of adipose tissue-derived proteins (adipocytokines) that are actively involved in energy homeostasis. Several management strategies for combating this syndrome are available, but they all have limitations. They include: switching from thymidine analogues to tenofovir or abacavir in lipoatrophy, or switching from protease inhibitors associated with hyperlipidaemia to a protease-sparing option; injection into the face with either biodegradable fillers such as poly-L-lactic acid and hyaluronic acid (a temporary measure requiring re-treatment) or permanent fillers such as bio-alcamid (with the risk of foreign body reaction or granuloma formation); and structured treatment interruption with the risk of loss of virological control and disease progression. There is therefore a need to explore alternative therapeutic options. Some new approaches including adipocytokines, uridine supplementation, glitazones, growth hormone (or growth hormone-releasing hormone analogues), metformin and statins (used alone or in combination) merit further investigation.
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PMID:HIV-associated lipodystrophy: a review of underlying mechanisms and therapeutic options. 1856 73

Members of the APOBEC family of cellular cytidine deaminases represent a recently identified group of proteins that provide immunity to infection by retroviruses and protect the cell from endogenous mobile retroelements. Yet, HIV-1 is largely immune to the intrinsic antiviral effects of APOBEC proteins because it encodes Vif (viral infectivity factor), an accessory protein that is critical for in vivo replication of HIV-1. In the absence of Vif, APOBEC proteins are encapsidated by budding virus particles and either cause extensive cytidine to uridine editing of negative sense single-stranded DNA during reverse transcription or restrict virus replication through deaminase-independent mechanisms. Thus, the primary function of Vif is to prevent encapsidation of APOBEC proteins into viral particles. This is in part accomplished by the ability of Vif to induce the ubiquitin-dependent degradation of some of the APOBEC proteins. However, Vif is also able to prevent encapsidation of APOBEC3G and APOBEC3F through degradation-independent mechanism(s). The goal of this review is to recapitulate current knowledge of the functional interaction of HIV-1 and its Vif protein with the APOBEC3 subfamily of proteins and to summarize our present understanding of the mechanism of APOBEC3-dependent retrovirus restriction.
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PMID:HIV-1 Vif, APOBEC, and intrinsic immunity. 1859 77

AIDS restriction genes have been defined in which allelic variations have been shown to influence infection or disease progression. Members of the APOBEC family of cellular polynucleotide cytidine deaminases (e.g., APOBEC3G) have been identified as a host factor that inhibits HIV-1 replication. It deaminates cytidine to uridine in nascent minus-strand viral DNA, inducing G-to-A hypermutation in the plus-strand viral DNA. The impact of codon-changing variant APOBEC3G H186R polymorphism on HIV-1 susceptibility and progression is not clear. We conducted genetic risk association study in HIV-1-exposed seronegative (HES; n = 50) individuals, HIV-1 seronegative (HSN; n = 320) healthy control, and HIV-1 seropositive patients (HSP; n = 190). The APOBEC3G H186R genotypes were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in DNA extracted from peripheral blood and confirmed by direct sequencing the randomly selected 58 samples. Frequency of rare homozygous RR (mutant type) and HR (heterozygous mutant) genotype was 0% while HH (wild type) was 100% among North Indians. In conclusion, we demonstrated that no genetic H186R polymorphism in exon 4 of APOBEC3G gene is found and therefore neither associated with differential susceptibility to HIV-1 infection/progression among North Indians.
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PMID:Absence of H186R polymorphism in exon 4 of the APOBEC3G gene among North Indian individuals. 1865 34


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