The nef gene product of human immunodeficiency virus type 1 (HIV-1) is important for the induction of AIDS, and key to its function is its ability to manipulate T-cell function by targeting cellular signal transduction proteins. We reported that Nef coprecipitates a multiprotein complex from cells which contains tumor suppressor protein p53. We now show that Nef interacts directly with p53. Binding assays showed that an N-terminal, 57-residue fragment of Nef (Nef 1-57) contains the p53-binding domain. Nef also interacted with p53 during HIV-1 infection in vitro. As p53 plays a critical role in the regulation of apoptosis, we hypothesized that Nef may alter this process. Nef inhibited UV light-induced, p53-dependent apoptosis in MOLT-4 cells, with Nef 1-57 being as effective as its full-length counterpart. The inhibition by Nef of p53 apoptotic function is most likely due its observed ability to decrease p53 protein half-life and, consequently, p53 DNA binding activity and transcriptional activation. These data show that HIV-1 Nef may augment HIV replication by prolonging the viability of infected cells by blocking p53-mediated apoptosis.

BackgroundThis paper reports the process of establishing a transparent, accountable, evidence-based program for introduction of new technologies and clinical practices (TCPs) in a large Australian healthcare network. Many countries have robust evidence-based processes for assessment of new TCPs at national level. However many decisions are made by local health services where the resources and expertise to undertake health technology assessment (HTA) are limited and a lack of structure, process and transparency has been reported.MethodsAn evidence-based model for process change was used to establish the program. Evidence from research and local data, experience of health service staff and consumer perspectives were incorporated at each of four steps: identifying the need for change, developing a proposal, implementation and evaluation. Checklists assessing characteristics of success, factors for sustainability and barriers and enablers were applied and implementation strategies were based on these findings. Quantitative and qualitative methods were used for process and outcome evaluation. An action research approach underpinned ongoing refinement to systems, processes and resources.ResultsA Best Practice Guide developed from the literature and stakeholder consultation identified seven program components: Governance, Decision-Making, Application Process, Monitoring and Reporting, Resources, Administration, and Evaluation and Quality Improvement. The aims of transparency and accountability were achieved. The processes are explicit, decisions published, outcomes recorded and activities reported. The aim of ascertaining rigorous evidence-based information for decision-making was not achieved in all cases. Applicants proposing new TCPs provided the evidence from research literature and local data however the information was often incorrect or inadequate, overestimating benefits and underestimating costs. Due to these limitations the initial application process was replaced by an Expression of Interest from applicants followed by a rigorous HTA by independent in-house experts.ConclusionThe program is generalisable to most health care organisations. With one exception, the components would be achievable with minimal additional resources; the lack of skills and resources required for HTA will limit effective application in many settings. A toolkit containing details of the processes and sample materials is provided to facilitate replication or local adaptation by those wishing to establish a similar program.Electronic supplementary materialThe online version of this article (doi:10.1186/s12913-015-1178-4) contains supplementary material, which is available to authorized users.

BackgroundThis is the third in a series of papers reporting a program of Sustainability in Health care by Allocating Resources Effectively (SHARE) in a local healthcare setting. Leaders in a large Australian health service planned to establish an organisation-wide, systematic, integrated, evidence-based approach to disinvestment. In order to introduce new systems and processes for disinvestment into existing decision-making infrastructure, we aimed to understand where, how and by whom resource allocation decisions were made, implemented and evaluated. We also sought the knowledge and experience of staff regarding previous disinvestment activities.MethodsStructured interviews, workshops and document analysis were used to collect information from multiple sources in an environmental scan of decision-making systems and processes. Findings were synthesised using a theoretical framework.ResultsSixty-eight respondents participated in interviews and workshops. Eight components in the process of resource allocation were identified: Governance, Administration, Stakeholder engagement, Resources, Decision-making, Implementation, Evaluation and, where appropriate, Reinvestment of savings. Elements of structure and practice for each component are described and a new framework was developed to capture the relationships between them. A range of decision-makers, decision-making settings, type and scope of decisions, criteria used, and strengths, weaknesses, barriers and enablers are outlined. The term ‘disinvestment’ was not used in health service decision-making. Previous projects that involved removal, reduction or restriction of current practices were driven by quality and safety issues, evidence-based practice or a need to find resource savings and not by initiatives where the primary aim was to disinvest. Measuring resource savings is difficult, in some situations impossible. Savings are often only theoretical as resources released may be utilised immediately by patients waiting for beds, clinic appointments or surgery. Decision-making systems and processes for resource allocation are more complex than assumed in previous studies.ConclusionThere is a wide range of decision-makers, settings, scope and type of decisions, and criteria used for allocating resources within a single institution. To our knowledge, this is the first paper to report this level of detail and to introduce eight components of the resource allocation process identified within a local health service.Electronic supplementary materialThe online version of this article (doi:10.1186/s12913-017-2207-2) contains supplementary material, which is available to authorized users.