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Identification of a highly conserved valine-glycine-phenylalanine amino acid triplet required for HIV-1 Nef function
No full textBACKGROUND: The Nef protein of HIV facilitates virus replication and disease progression in infected patients. This role as pathogenesis factor depends on several genetically separable Nef functions that are mediated by interactions of highly conserved protein-protein interaction motifs with different host cell proteins. By studying the functionality of a series of nef alleles from clinical isolates, we identified a dysfunctional HIV group O Nef in which a highly conserved valine-glycine-phenylalanine (VGF) region, which links a preceding acidic cluster with the following proline-rich motif into an amphipathic surface was deleted. In this study, we aimed to study the functional importance of this VGF region. RESULTS: The dysfunctional HIV group O8 nef allele was restored to consensus sequence, and mutants of canonical (NL4.3, NA-7, SF2) and non-canonical (B2 and C1422) HIV-1 group M nef alleles were generated in which the amino acids of the VGF region were changed into alanines (VGF->AAA) and tested for their capacity to interfere with surface receptor trafficking, signal transduction and enhancement of viral replication and infectivity. We found the VGF motif, and each individual amino acid of this motif, to be critical for downregulation of MHC-I and CXCR4. Moreover, Nef's association with the cellular p21-activated kinase 2 (PAK2), the resulting deregulation of cofilin and inhibition of host cell actin remodeling, and targeting of Lck kinase to the trans-golgi-network (TGN) were affected as well. Of particular interest, VGF integrity was essential for Nef-mediated enhancement of HIV virion infectivity and HIV replication in peripheral blood lymphocytes. For targeting of Lck kinase to the TGN and viral infectivity, especially the phenylalanine of the triplet was essential. At the molecular level, the VGF motif was required for the physical interaction of the adjacent proline-rich motif with Hck. CONCLUSION: Based on these findings, we propose that this highly conserved three amino acid VGF motif together with the acidic cluster and the proline-rich motif form a previously unrecognized amphipathic surface on Nef. This surface appears to be essential for the majority of Nef functions and thus represents a prime target for the pharmacological inhibition of Nef
Associations between atopic markers in asthma and intestinal helminth infections in Cuban schoolchildren
No full textTotal serum IgE (tIgE), allergen-specific IgE (sIgE), and skin prick test (SPT) are commonly used markers for atopy and atopic disease. The association between these measures and their relationship to clinical symptoms differs in affluent and non-affluent countries. We investigated the role of intestinal helminth infections in observed variations in atopic markers and asthma, and possible diagnostic and epidemiological consequences. A cross-sectional study was conducted in Cuban schoolchildren (n = 1285; 4-14 yrs). Atopy was determined by SPT, sIgE, and tIgE; asthma by International Study of Asthma and Allergies in Childhood questionnaire; and intestinal helminth infections by stool examination. Percentages of tIgE, sIgE, and SPT positives were 88.9%, 25.5%, and 16.5%, respectively. Asthma was found in 20.8%, and helminth infections in 20.9% of the children. All three atopic markers were significantly associated with each other and with asthma. Median tIgE levels were higher in helminth-infected than in uninfected children, irrespective of their status of atopy/asthma. Discordant results between SPT and sIgE were observed in 22.6% of the children. Among SPT positives, 41% were sIgE negative. The proportion of SPT negatives among sIgE positives was 74% in helminth-infected and 58.4% in uninfected children (p < 0.05). Helminth infections affected tIgE levels, reconfirming the limited value of tIgE for diagnosis of atopy and asthma in tropical areas. Higher frequencies of sIgE than positive SPTs were observed, especially in helminth-infected children. This corresponds with current hypothesis on the role of helminths in atopy. However, the observed proportion of sIgE negatives among children with positive SPT suggests that other mechanisms may also be involved
Addressing access barriers to health services: an analytical framework for selecting appropriate interventions in low-income Asian countries
No full textWhile World Health Organization member countries embraced the concept of universal coverage as early as 2005, few low-income countries have yet achieved the objective. This is mainly due to numerous barriers that hamper access to needed health services. In this paper we provide an overview of the various dimensions of barriers to access to health care in low-income countries (geographical access, availability, affordability and acceptability) and outline existing interventions designed to overcome these barriers. These barriers and consequent interventions are arranged in an analytical framework, which is then applied to two case studies from Cambodia. The aim is to illustrate the use of the framework in identifying the dimensions of access barriers that have been tackled by the interventions. The findings suggest that a combination of interventions is required to tackle specific access barriers but that their effectiveness can be influenced by contextual factors. It is also necessary to address demand-side and supply-side barriers concurrently. The framework can be used both to identify interventions that effectively address particular access barriers and to analyse why certain interventions fail to tackle specific barriers
Therapy of uncomplicated falciparum malaria in Europe: MALT
No full textBACKGROUND: Malaria continues to be amongst the most frequent infectious diseases imported to Europe. Whilst European treatment guidelines are based on data from studies carried out in endemic areas, there is a paucity of original prospective treatment data. The objective was to summarize data on treatments to harmonize and optimize treatment for uncomplicated malaria in Europe. METHODS: A prospective observational multicentre study was conducted, assessing tolerance and efficacy of treatment regimens for imported uncomplicated falciparum malaria in adults amongst European centres of tropical and travel medicine. RESULTS: Between December 2003 and 2009, 504 patients were included in 16 centres from five European countries. Eighteen treatment regimens were reported,, the top three being atovaquone-proguanil, mefloquine, and artemether-lumefantrine. Treatments significantly differed with respect to the occurrence of treatment changes (p=0.005) and adverse events (p=0.001), parasite and fever clearance times (p<0.001), and hospitalization rates (p=0.0066) and durations (p=0.001). Four recrudescences and two progressions to severe disease were observed. Compared to other regimens, quinine alone was associated with more frequent switches to second line treatment, more adverse events and longer inpatient stays. Parasite and fever clearance times were shortest with artemether-mefloquine combination treatment. Vomiting was the most frequent cause of treatment change, occurring in 5.5% of all patients but 9% of the atovaquone-proguanil group. CONCLUSIONS: This study highlights the heterogeneity of standards of care within Europe. A consensus discussion at European level is desirable to foster a standardized management of imported falciparum malaria
