Functionally Inert HIV-Specific Cytotoxic T Lymphocytes Do Not Play a Major Role in Chronically Infected Adults and Children

The highly sensitive quantitation of virus-specific CD8+ T cells using major histocompatibility complex–peptide tetramer assays has revealed higher levels of cytotoxic T lymphocytes (CTLs) in acute and chronic virus infections than were recognized previously. However, studies in lymphocytic choriomeningitis virus infection have shown that tetramer assays may include measurement of a substantial number of tetramer-binding cells that are functionally inert. Such phenotypically silent CTLs, which lack cytolytic function and do not produce interferon (IFN)-γ, have been hypothesized to explain the persistence of virus in the face of a quantitatively large immune response, particularly when CD4 help is impaired. In this study, we examined the role of functionally inert CTLs in chronic HIV infection. Subjects studied included children and adults (n = 42) whose viral loads ranged from <50 to >100,000 RNA copies/ml plasma. Tetramer assays were compared with three functional assays: enzyme-linked immunospot (Elispot), intracellular cytokine staining, and precursor frequency (limiting dilution assay [LDA]) cytotoxicity assays. Strong positive associations were observed between cell numbers derived by the Elispot and the tetramer assay (r = 0.90). An even stronger association between tetramer-derived numbers and intracellular cytokine staining for IFN-γ was present (r = 0.97). The majority (median 76%) of tetramer-binding cells were consistently detectable via intracellular IFN-γ cytokine staining. Furthermore, modifications to the LDA, using a low input cell number into each well, enabled LDAs to reach equivalence with the other methods of CTL enumeration. These data together show that functionally inert CTLs do not play a significant role in chronic pediatric or adult HIV infection

Influence of external contextual factors on the implementation of health and social care interventions into practice within or across countries : a protocol for a 'best fit' framework synthesis

Background: The widespread implementation of interventions is often hindered by a decline and variability in effectiveness across implementation sites. It is anticipated that variations in the characteristics of the external context in different sites, such as the political and funding environment, socio-cultural context, physical environment or population demographics can influence implementation outcome. However, there is only a limited understanding about which and how external contextual factors influence implementation. We aim to develop a comprehensive framework conceptualising the influence of external contextual factors on implementation, particularly when spreading health and social care interventions within or across countries. Methods: The review will use the ‘best fit’ framework synthesis approach. In the first stage of the review, we will examine existing frameworks, models, concepts and theories on external contextual factors and their influence on implementation from a variety of sectors and disciplines including health and social care, education, environmental studies and international development fields. The resulting a priori meta-framework will be tested and refined in the second review stage by analysing evidence from empirical studies focusing on the implementation of health and social care interventions within or across countries. Searches will be conducted in bibliographic databases such as MEDLINE, ERIC, HMIC and IBSS, grey literature sources and on relevant websites. We will also search reference lists, relevant journals, perform citation searches and ask experts in the field. There is no restriction to study type, setting, intervention type or implementation strategy to enable obtaining a broad and in-depth knowledge from various sources of evidence. Discussion: The review will lead to a comprehensive framework for understanding the influence of external contextual factors on implementation, particularly when spreading health and social care interventions within or across countries. The framework is anticipated to help identify factors explaining the decline and variability in effectiveness of interventions and assessing the prospects of implementation effectiveness, when spreading interventions. We do not intend to only develop another stand-alone implementation framework but one that can be used in conjunction with existing frameworks. The framework can be honed and validated in future empirical research. Systematic review registration: PROSPERO CRD4201808448

National health policy-makers’ views on the clarity and utility of Countdown to 2015 country profiles and reports: findings from two exploratory qualitative studies

Background: The use of sets of indicators to assess progress has become commonplace in the global health arena. Exploratory research has suggested that indicators used for global monitoring purposes can play a role in national policy-making, however, the mechanisms through which this occurs are poorly understood. This article reports findings from two qualitative studies that aimed to explore national policy-makers’ interpretation and use of indicators from country profiles and reports developed by Countdown to 2015. Methods: An initial study aimed at exploring comprehension of Countdown data was conducted at the 2010 joint Women Deliver/Countdown conference. A second study was conducted at the 64th World Health Assembly in 2011, specifically targeting national policy-makers. Semi-structured interviews were carried out with 29 and 22 participants, respectively, at each event. Participants were asked about their understanding of specific graphs and indicators used or proposed for use in Countdown country profiles, and their perception of how such data can inform national policy-making. Responses were categorised using a framework analysis. Results: Respondents in both studies acknowledged the importance of the profiles for tracking progress on key health indicators in and across countries, noting that they could be used to highlight changes in coverage, possible directions for future policy, for lobbying finance ministers to increase resources for health, and to stimulate competition between neighbouring or socioeconomically similar countries. However, some respondents raised questions about discrepancies between global estimates and data produced by national governments, and some struggled to understand the profile graphs shown in the absence of explanatory text. Some respondents reported that use of Countdown data in national policy-making was constrained by limited awareness of the initiative, insufficient detail in the country profiles to inform policy, and the absence of indicators felt to be more appropriate to their own country contexts. Conclusions: The two studies emphasise the need for country consultations to ensure that national policy-makers understand how to interpret and use tools like the Countdown profile for planning purposes. They make clear the value of qualitative research for refining tools used to promote accountability, and the need for country level Countdown-like processes