Antiretroviral Therapy for HIV-2 Infection in Non-Endemic Regions.

Human immunodeficiency virus type 2 (HIV-2) was isolated in AIDS patients in 1986. Around 1-2 million people are infected worldwide. The virus is less transmissible than HIV-1, being sexual contacts the most frequent route of acquisition. In the absence of antiretroviral therapy, most HIV-2 carriers will develop AIDS; however, it takes longer than in HIV-1 infection. There is no global pandemic caused by HIV-2, as the virus is largely confined to West Africa. Due to historical ties, HIV-2 is also prevalent in Portugal and its former colonies in Brazil, India, Mozambique, and Angola. Other European countries with hundreds to thousands of HIV-2 infections are France, Belgium, and Spain. A few hundred have been reported in North America, mostly in West African foreigners. Globally, HIV-2 infections are steadily declining. Although CD4 declines occur more slowly in HIV-2 than in HIV-1 patients, the CD4 recovery with antiretroviral treatment is smaller in the former. HIV-2 is naturally resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and some protease inhibitors. In contrast, HIV-2 is susceptible to all NRTIs and integrase inhibitors. Drug resistance in HIV-2 may develop earlier than in HIV-1 and select for mutations at distinct sites. Misdiagnosis of HIV-2 in patients wrongly considered as HIV-1 positive or in those dually infected may result in treatment failures with undetectable HIV-1RNA. Given the relatively large number of West Africans migrated to the European Union and North America, HIV-2 infection either alone or as coinfection with HIV-1 should be excluded at least once in all HIV-seroreactive persons. This should be stressed in the face of atypical HIV serological profiles, immunovirological disconnect (CD4 cell count loss despite undetectable HIV-1 viremia), and/or high epidemiological risks (birth in or sex partners from HIV-2 endemic regions). Superinfection with any HIV variant may occur in persons infected with the other, since there is no cross-protection. Thus, earlier antiretroviral therapy is warranted for either HIV-1 or HIV-2, given that it would protect from each other superinfection in persons at risk.

HIV type 2 epidemic in Spain: challenges and missing opportunities.

: HIV type 2 (HIV-2) is a neglected virus despite estimates of 1-2 million people infected worldwide. HIV-2 is less efficiently transmitted than HIV-1 by sex and from mother to child. Although AIDS may develop in HIV-2 carriers, it takes longer than in HIV-1-infected patients. In contrast with HIV-1 infection, there is no global pandemic caused by HIV-2, as the virus is largely confined to West Africa. In a less extent and due to socioeconomic ties and wars, HIV-2 is prevalent in Portugal and its former colonies in Brazil, India, Mozambique and Angola. Globally, HIV-2 infections are steadily declining over time. A total of 338 cases of HIV-2 infection had been reported at the Spanish HIV-2 registry until December 2016, of whom 63% were men. Overall 72% were sub-Saharan Africans, whereas 16% were native Spaniards. Dual HIV-1 and HIV-2 coinfection was found in 9% of patients. Heterosexual contact was the most likely route of HIV-2 acquisition in more than 90% of cases. Roughly one-third presented with CD4 cell counts less than 200 cells/µl and/or AIDS clinical events. Plasma HIV-2 RNA was undetectable at baseline in 40% of patients. To date, one-third of HIV-2 carriers have received antiretroviral therapy, using integrase inhibitors 32 individuals. New diagnoses of HIV-2 in Spain have remained stable since 2010 with an average of 15 cases yearly. Illegal immigration from Northwestern African borders accounts for over 75% of new HIV-2 diagnoses. Given the relatively large community of West Africans already living in Spain and the continuous flux of immigration from endemic regions, HIV-2 infection either alone or as coinfection with HIV-1 should be excluded once in all HIV-seroreactive persons, especially when showing atypical HIV serological profiles, immunovirological disconnect (CD4 cell count loss despite undetectable HIV-1 viremia) and/or high epidemiological risks (birth in or sex partners from endemic regions).

Phylodynamic and Phylogeographic Profiles of Subtype B HIV-1 Epidemics in South Spain.

BACKGROUND: Since 1982, HIV-1 epidemics have evolved to different scenarios in terms of transmission routes, subtype distribution and characteristics of transmission clusters. We investigated the evolutionary history of HIV-1 subtype B in south Spain. PATIENTS & METHODS: We studied all newly diagnosed HIV-1 subtype B patients in East Andalusia during the 2005-2012 period. For the analysis, we used the reverse transcriptase and protease sequences from baseline resistance, and the Trugene® HIV Genotyping kit (Siemens, Barcelona, Spain). Subtyping was done with REGA v3.0. The maximum likelihood trees constructed with RAxML were used to study HIV-1 clustering. Phylogeographic and phylodynamic profiles were studied by Bayesian inference methods with BEAST v1.7.5 and SPREAD v1.0.6. RESULTS: Of the 493 patients infected with HIV-1 subtype B, 234 grouped into 55 clusters, most of which were small (44 clusters ≤ 5 patients, 31 with 2 patients, 13 with 3). The rest (133/234) were grouped into 11 clusters with ≥ 5 patients, and most (82%, 109/133) were men who have sex with men (MSM) grouped into 8 clusters. The association with clusters was more frequent in Spanish (p = 0.02) men (p< 0.001), MSM (p<0.001) younger than 35 years (p = 0.001) and with a CD4+ T-cell count above 350 cells/ul (p<0.001). We estimated the date of HIV-1 subtype B regional epidemic diversification around 1970 (95% CI: 1965-1987), with an evolutionary rate of 2.4 (95%CI: 1.7-3.1) x 10-3 substitutions/site/year. Most clusters originated in the 1990s in MSMs. We observed exponential subtype B HIV-1 growth in 1980-1990 and 2005-2008. The most significant migration routes for subtype B went from inland cities to seaside locations. CONCLUSIONS: We provide the first data on the phylodynamic and phylogeographic profiles of HIV-1 subtype B in south Spain. Our findings of transmission clustering among MSMs should alert healthcare managers to enhance preventive measures in this risk group in order to prevent future outbreaks.

Metabolomic responses in caged clams, Ruditapes decussatus, exposed to agricultural and urban inputs in a Mediterranean coastal lagoon (Mar Menor, SE Spain).

The Mar Menor is a coastal lagoon affected by the growth of intensive agriculture and urban development in the surrounding area. Large amounts of chemical pollutants from these areas are discharged into El Albujón, a permanent water-course flowing into the lagoon. Biomarkers such as the activity of acetylcholinesterase or antioxidant enzymes have been previously tested in this lagoon demonstrating the presence of neurotoxicity and oxidative stress in clams transplanted in sites affected by the dispersion of the effluent from El Albujón. To complete this traditional toxicology work, a metabolomic profiling of these transplanted organisms has been carried out for the detection of metabolic biomarkers induced by agricultural/urban pollutants. More than 70 metabolites have been quantified using a targeting metabolomics platform based on HPLC-MS. The intracellular metabolic pattern was analyzed by PCA from the digestive gland of clams after 7 and 22 days of transplantation. Results showed a different profile of metabolite between organisms collected from control and exposed sites. At the shorter exposure time, there was an increase in several metabolites in the latter when compared with those from control sites, whereas metabolic profiling at 22 days showed that those metabolites were drastically diminished, with even lower levels than at control sites. These metabolites included: (i) 12 amino acids from the 21 proteogenic and HomoSer, (ii) osmotic protectants such as γ-butyrobetaine and taurine and (iii) nucleotides such as ITP. Regarding sulfur-containing molecules, taurine could be highlighted as a potential biomarker since its concentration was reduced by more than 30 times after 22 days of exposure, whereas the antioxidant glutathione remained constant in the organisms from both control and exposed sites. Although targeted metabolomics has been shown as an early technique of pollutant effect detection, the two-phase pattern could highlight a more complicated metabolite response to pollutants than classical biomarkers.

Metabolic profiling of insect cell lines: Unveiling cell line determinants behind system's productivity.

Baculovirus infection boosts the host biosynthetic activity towards the production of viral components and the recombinant protein of interest, hyper-productive phenotypes being the result of a successful adaptation of the cellular network to that scenario. Spodoptera frugiperda derived Sf9 and Trichoplusia ni derived High Five cell lines have a major track record for the production of recombinant proteins, with High Five cells presenting higher productivities. A metabolic profiling of the two insect cell lines was pursued to underpin specific cellular traits behind productive phenotypes. Multivariate analysis identified cell-line dependent metabolic signatures linked to productivity. Pathway analysis highlighted cellular pathways of paramount importance in supporting infection and protein production. Moreover, better producer phenotypes proved to be correlated with the capacity of cells to shift their metabolism in favor of energy-generating pathways to fuel biosynthesis, a scenario observed in the High Five cell line. Metabolomic profiling allowed us to identify metabolic pathways involved in infection and recombinant protein production, which can be selected as targets for further improvement of the system.

Lipid biomarkers and metabolic effects of lycopene from tomato juice on liver of rats with induced hepatic steatosis.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver disorders, covering steatosis to nonalcoholic steatohepatitis (NASH). Dietary factors may modulate its evolution, and antioxidants have been proposed as therapeutic agents. Among them, lycopene has been demonstrated to prevent the development of steatohepatitis and even to inhibit NASH-promoted early hepatocarcinogenesis induced by a high-fat diet in rats. These conclusions have been related to its antioxidant activity; however, NAFLD is more complex than a simple redox imbalance state since it disturbs several metabolic systems in the liver. In consequence, there is a lack of information related to the action of lycopene beyond antioxidant biomarkers. In this work, NAFLD was induced in rats using a hypercholesterolemic and high-fat diet to evaluate the effect of lycopene consumption from tomato juice on liver metabolism. Several classical antioxidant biomarkers related to NAFLD were measured to check the state of this disease after 7 weeks of the controlled diet. Moreover, a metabolomics platform was applied to measure more than 70 metabolites. Results showed clear differences in the classical antioxidant biomarkers as well as in the metabolic pattern, attending not only to the diet but also to the intake of lycopene from tomato juice. Interestingly, tomato juice administration partially reverted the metabolic pattern from a high-fat diet to a normal diet even in metabolites not related to the redox state, which could lead to new targets for therapeutic agents against NAFLD and to achieving a better understanding of the role of lycopene in liver metabolism.

Steady-state acid-base response at exercise levels close to maximum lactate steady state.

OBJECTIVE: To study acid-base status during a constant-load treadmill test at exercise levels close to the maximum lactate steady-state. DESIGN: Two tests were performed: one maximal and one steady-state at a load corresponding to the mean of the two ventilatory thresholds observed in the first test. SETTING: University Sports Science Laboratory. PARTICIPANTS: Twenty-three male Sports Science students, aged 26.7 (+/- 4.9 SD) years, 176.1 (+/- 6.3) cm in height, and weighing 72.8 (+/- 6.7) kg. MAIN OUTCOME MEASURES: Capillary blood gases, metabolites, electrolytes. RESULTS: Acid-base status variables declined significantly during the maximal test. Lactate concentrations were above the values observed at onset of blood lactate accumulation. All the blood variables did not vary significantly at the various experimental times, except pH values and PCO2 values. Bicarbonate concentration remained constant. Plasma potassium, chlorine and sodium concentration did not increase. CONCLUSION: During a steady-state test at a load corresponding to approximately 80% of VO2max, the acid-base status in capillary blood remained constant even though the lactate concentration was over 4 mmol/L. However, despite the maintenance of a constant acid-base status, other physiological variables did not behave in the same fashion.

Análisis físico-químico del estado ácido-base durante el ejercicio / Physicochemical analysis of acid-base balance during exercise

De forma tradicional, se explica el estado ácido-base en términos cuantitativos de la variable dependiente pH y dos variables elementales independientes, lactato y bicarbonato, en relación a la intensidad del ejercicio. Cuando la intensidad del ejercicio alcanza un valor determinado, el incremento de la concentración de ácido láctico en plasma determina un aumento de la concentración de protones ([H+]), con un descenso de la concentración de bicarbonato ([HC03-]). Sin embargo, la explicación dada al estado ácido-básico durante el ejercicio, aunque sencilla y de fácil compresión, tiene considerables limitaciones, que han hecho necesario dar una visión físico-química. Esta nueva concepción indica que los factores que afectan a la [H +) se pueden agrupar en una expresión polinómica de cuarto grado: A[H+)4 + B[H+P + C[H+]2 + D[H+) + E = O Los coeficientes de esta expresión dependen principalmente de la diferencia de iones fuertes (DIF), la presión parcial de dióxido de carbono (PpC02) y de la concentración de aniones totales (AT-). Por tanto, para conocer el estado ácido-básico en ejercicio de intensidad progresiva en términos físico-químicos es necesario conocer la concentración de las tres variables inde pendientes (DIF, PpC02 y AT -). Partiendo de la situación de reposo, el organismo "reordena" las variables independientes al objeto de mantener estable la concentración de protones. Es objetivo de esta revisión analizar, desde el punto de vista físico químico la regulación del estado ácido-base en esfuerzos de resistencia

Tradicionally, the state is explained acid-bases on quantitative terms of the dependent variable pH and two independent elementary variables, lactate and bicarbonate, in relation to the intensity of the exercise. When the intensity of the exercise reaches a determined value, the increase of lactic acid concentration in plasma determines an increase of the proton concentration ([H+]), with a reduction of the bicarbonate concentration ([HC03-]). However, the explanation given to the acid-basic state during the exercise, although simple and of easy compression, has considerable limitations, which have done necessary to give to a physicalchemistry point of view. This new conception indicates, that the factors that affect to [ H + ) can group in a polinómic expression of fourth degree: A[H+)4 + B[H+P + C[H+]2 + D[H+) + E = O The coefficients of this expression depend mainly on the strong ion difference (DIF), the partial dioxide pressure of carbon (PpCO) and the total anion concentration (AT -). Therefore, to know the acid-basic state in incremental exercise in terms physical-chemistries it is necessary to know the concentration the three independent variables (DIF, PpC02 and AT -). Starting off of the rest situation, the organism "rearranges" the independent variables to maintain the proton concentration stable. He is objective of this revision to analyze, from the physical-chemestry point of view, the regulation of the state acid-bases on endurance exercise