Background: Human immunodeficiency virus type 1 (HIV-1) infection and Acquired immunodeficiency syndrome are mayor global public health issues. HIV-1 infection is now manageable as a chronic disease thanks to the development of antiretroviral therapy; however, the existence of HIV drug resistance and collateral effects have increased the search for therapeutic alternatives. Compounds of marine resources have been studied for their antiviral potential. Objectives: To evaluate the antiviral activity of isolated bromotyrosine-derivative compounds from the Colombian marine sponges, Verongula rigida and Aiolochoria crassa against HIV-1 infection in vitro. Methods: Cytotoxicity of 11 bromotyrosine-derivative compounds was determined by the MTT assay. Inhibition of HIV-1 replication was performed using the U373-MAGI cell line, which was infected with recombinant green fluorescent protein (GFP)-expressing viruses pseudotyped, in the presence or absence of the compounds. The percentage of infected cells was evaluated by flow cytometry. In addition, the inhibition of reverse transcription and nuclear import was determined by quantification of early and late reverse transcription products and 2-LTR circles, respectively, using quantitative PCR. Results: Aeroplysinin-1, purealidin B and 3-bromo-5-hydroxy-Omethyltyrosine inhibited the HIV-1 replication in a dose-dependent manner, with a median maximum percentage of inhibition of 74% (20 μM), 57% (80 μM) and 47% (80 μM), respectively. Importantly, none of these concentrations were cytotoxic. Aeroplysinin-1, 19-deoxyfistularin 3, purealidin B, fistularin 3 and 3-bromo-5-hydroxy-O-methyltyrosine inhibited the nuclear import efficiently; while 3,5-dibromo-N,N,N,O-tetramethyltyraminium, aeroplysinin-1, purealidin B, fistularin 3 and 3-bromo-5-hydroxy-Omethyltyrosine inhibited X4 HIV-1 cell entry with a median maximum percentage of inhibition ranging between 2 to 30%. Conclusions: Aeroplysinin-1, 19-deoxyfistularin 3, purealidin B, fistularin 3 and 3-bromo-5-hydroxy-O-methyltyrosine inhibited HIV replication at different steps. This study opens the possibility of chemically synthesizing these compounds and evaluating them as alternative therapies against HIV-1.
Human peripheral blood mononuclear cells (PBMCs) are part of the innate and adaptive immune system, and form a critical interface between both systems. Studying the metabolic profile of PBMC could provide valuable information about the response to pathogens, toxins or cancer, the detection of drug toxicity, in drug discovery and cell replacement therapy. The primary purpose of this study was to develop an improved processing method for PBMCs metabolomic profiling with nuclear magnetic resonance (NMR) spectroscopy. To this end, an experimental design was applied to develop an alternative method to process PBMCs at low concentrations. The design included the isolation of PBMCs from the whole blood of four different volunteers, of whom 27 cell samples were processed by two different techniques for quenching and extraction of metabolites: a traditional one using organic solvents and an alternative one employing a high-intensity ultrasound probe, the latter with a variation that includes the use of deproteinizing filters. Finally, all the samples were characterized by 1H-NMR and the metabolomic profiles were compared by the method. As a result, two new methods for PBMCs processing, called Ultrasound Method (UM) and Ultrasound and Ultrafiltration Method (UUM), are described and compared to the Folch Method (FM), which is the standard protocol for extracting metabolites from cell samples. We found that UM and UUM were superior to FM in terms of sensitivity, processing time, spectrum quality, amount of identifiable, quantifiable metabolites and reproducibility.
Abstract.-Marine sponges have been used for the isolation and purification of compounds with therapeutic properties for human use. These compounds are used mainly against viruses because these microorganisms mutate and create resistance easily to available treatments. In the last 60 years, marine sponges have been the subject of scient ific research, which have addressed the discovery of compounds with activity against Herpes Simplex Virus (HSV) such as Ara-A; the avarol used against Human Immunodeficiency Virus Type 1 (HIV-1) and calyceramides against Influenza Virus. This article present a review of the chemistry and mechanism of action of the compounds isolated from marine sponges that have shown antiviral activity, to encourage the search for new molecules or their modification in order to obtain several sources of drug production and antiviral treatments. This review found that in vitro cell models have been the most used techniques and the HSV and HIV-1 are the main microorganisms studied for the determination of the antiviral activity; finally, it was found that the biological activities are directly related to the structure of the compounds, especially when they are analogs of amino acids or nucleotides. Resumen.-Las esponjas marinas se han utilizado para el aislamiento y purificación de compuestos con propiedades terapéuticas para uso en humanos, los cuales se usan principalmente contra virus, debido a que estos microorganismos mutan y crean fácilmente resistencia a los tratamientos disponibles. En los últimos 60 años las esponjas marinas han sido objeto de investigaciones científicas, las cuales han permitido el descubrimiento de compuestos como el Ara-A, avarol y las caliceramidas con actividad contra el Virus Herpes Simple (VHS), el Virus de la Inmunodeficiencia Humana tipo 1(VIH-1) y el Virus de Influenza, respectivamente. Este trabajo presenta una revisión de la química y el mecanismo de acción de los compuestos aislados de esponjas marinas que han mostrado actividad antiviral, de modo que se incentive la búsqueda de nuevas moléculas o su modificación con el fin de conseguir fuentes de producción de medicamentos y tratamientos antivirales. La revisión plantea que los modelos celulares in vitro han sido las técnicas más utilizadas y que el VHS y el VIH-1 son los microorganismos más estudiados para la determinación de la actividad antiviral; finalmente, se sugiere que las actividades biológicas en general están directamente relacionadas con la estructura de los compuesto s, en especial cuando son análogos de aminoácidos o nucleótidos.Palabras clave: Esponjas marinas, actividad antiviral, Virus Herpes Simple (VHS), Virus de la Inmunodeficiencia Humana tipo 1 (VIH-1)
How the human body reacts to the exposure of HIV-1 is an important research goal. Frequently, HIV exposure leads to infection, but some individuals show natural resistance to this infection; they are known as HIV-1-exposed but seronegative (HESN). Others, although infected but without antiretroviral therapy, control HIV-1 replication and progression to AIDS; they are named controllers, maintaining low viral levels and an adequate count of CD4+ T lymphocytes. Biological mechanisms explaining these phenomena are not precise. In this context, metabolomics emerges as a method to find metabolites in response to pathophysiological stimuli, which can help to establish mechanisms of natural resistance to HIV-1 infection and its progression. We conducted a cross-sectional study including 30 HESN, 14 HIV-1 progressors, 14 controllers and 30 healthy controls. Plasma samples (directly and deproteinized) were analyzed through Nuclear Magnetic Resonance (NMR) metabolomics to find biomarkers and altered metabolic pathways. The metabolic profile analysis of progressors, controllers and HESN demonstrated significant differences with healthy controls when a discriminant analysis (PLS-DA) was applied. In the discriminant models, 13 metabolites associated with HESN, 14 with progressors and 12 with controllers were identified, which presented statistically significant mean differences with healthy controls. In progressors, the metabolites were related to high energy expenditure (creatinine), mood disorders (tyrosine) and immune activation (lipoproteins), phenomena typical of the natural course of the infection. In controllers, they were related to an inflammation-modulating profile (glutamate and pyruvate) and a better adaptive immune system response (acetate) associated with resistance to progression. In the HESN group, with anti-inflammatory (lactate and phosphocholine) and virucidal (lactate) effects which constitute a protective profile in the sexual transmission of HIV. Concerning the significant metabolites of each group, we identified 24 genes involved in HIV-1 replication or virus proteins that were all altered in progressors but only partially in controllers and HESN. In summary, our results indicate that exposure to HIV-1 in HESN, as well as infection in progressors and controllers, affects the metabolism of individuals and that this affectation can be determined using NMR metabolomics.
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