Mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease (PD) and, as such, LRRK2 is considered a promising therapeutic target for age-related neurodegeneration. Although the cellular functions of LRRK2 in health and disease are incompletely understood, robust evidence indicates that PD-associated mutations alter LRRK2 kinase and GTPase activities with consequent deregulation of the downstream signaling pathways. We have previously demonstrated that one LRRK2 binding partner is P21 (RAC1) Activated Kinase 6 (PAK6). Here, we interrogate the PAK6 interactome and find that PAK6 binds a subset of 14-3-3 proteins in a kinase dependent manner. Furthermore, PAK6 efficiently phosphorylates 14-3-3γ at Ser59 and this phosphorylation serves as a switch to dissociate the chaperone from client proteins including LRRK2, a well-established 14-3-3 binding partner. We found that 14-3-3γ phosphorylated by PAK6 is no longer competent to bind LRRK2 at phospho-Ser935, causing LRRK2 dephosphorylation. To address whether these interactions are relevant in a neuronal context, we demonstrate that a constitutively active form of PAK6 rescues the G2019S LRRK2-associated neurite shortening through phosphorylation of 14-3-3γ. Our results identify PAK6 as the kinase for 14-3-3γ and reveal a novel regulatory mechanism of 14-3-3/LRRK2 complex in the brain.

Background HIV drug resistance (HIVDR) continues to threaten the effectiveness of worldwide antiretroviral therapy (ART). Emergence and transmission of HIVDR are driven by several interconnected factors. Though much has been done to uncover factors influencing HIVDR, overall interconnectedness between these factors remains unclear and African policy makers encounter difficulties setting priorities combating HIVDR. By viewing HIVDR as a complex adaptive system, through the eyes of multi-disciplinary HIVDR experts, we aimed to make a first attempt to linking different influencing factors and gaining a deeper understanding of the complexity of the system. Methods We designed a detailed systems map of factors influencing HIVDR based on semi-structured interviews with 15 international HIVDR experts from or with experience in sub-Saharan Africa, from different disciplinary backgrounds and affiliated with different types of institutions. The resulting detailed system map was conceptualized into three main HIVDR feedback loops and further strengthened with literature evidence. Results Factors influencing HIVDR in sub-Saharan Africa and their interactions were sorted in five categories: biology, individual, social context, healthcare system and ‘overarching’. We identified three causal loops cross-cutting these layers, which relate to three interconnected subsystems of mechanisms influencing HIVDR. The ‘adherence motivation’ subsystem concerns the interplay of factors influencing people living with HIV to alternate between adherence and non-adherence. The ‘healthcare burden’ subsystem is a reinforcing loop leading to an increase in HIVDR at local population level. The ‘ART overreliance’ subsystem is a balancing feedback loop leading to complacency among program managers when there is overreliance on ART with a perceived low risk to drug resistance. The three subsystems are interconnected at different levels. Conclusions Interconnectedness of the three subsystems underlines the need to act on the entire system of factors surrounding HIVDR in sub-Saharan Africa in order to target interventions and to prevent unwanted effects on other parts of the system. The three theories that emerged while studying HIVDR as a complex adaptive system form a starting point for further qualitative and quantitative investigation.

HIV drug resistance (HIVDR) is a complex problem with multiple interconnected and context dependent causes. Although the factors influencing HIVDR are known and well-studied, HIVDR remains a threat to the effectiveness of antiretroviral therapy. To understand the complexity of HIVDR, a comprehensive, systems approach is needed. Therefore, a local systems map was developed integrating all reported factors influencing HIVDR in the Dar es Salaam Urban Cohort Study area in Tanzania. The map was designed based on semi-structured interviews and workshops with people living with HIV and local actors who encounter people living with HIV during their daily activities. We visualized the feedback loops driving HIVDR, compared the local map with a systems map for Sub-Saharan Africa, previously constructed from interviews with international HIVDR experts, and suggest potential interventions to prevent HIVDR. We found several interconnected balancing and reinforcing feedback loops related to poverty, stigmatization, status disclosure, self-esteem, knowledge about HIVDR and healthcare system workload, among others, and identified three potential leverage points. Insights from this local systems map were complementary to the insights from the Sub-Saharan systems map showing that both viewpoints are needed to fully understand the system. This study provides a strong baseline for quantitative modelling, and for the identification of context-dependent, complexity-informed leverage points.

Systems mapping methods are increasingly used to study complex public health issues. Visualizing the causal relationships within a complex adaptive system allows for more than developing a holistic and multi-perspective overview of the situation. It is also a way of understanding the emergent, self-organizing dynamics of a system and how they can be influenced. This article describes a concrete approach for developing and analysing a systems map of a complex public health issue drawing on well-accepted methods from the field of social science while incorporating the principles of systems thinking and transdisciplinarity. Using our case study on HIV drug resistance in sub-Saharan Africa as an example, this article provides a practical guideline on how to map a public health problem as a complex adaptive system in order to uncover the drivers, feedback-loops and other dynamics behind the problem. Qualitative systems mapping can help researchers and policy makers to gain deeper insights in the root causes of the problem and identify complexity-informed intervention points.

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HIV drug resistance (HIVDR) in Tanzania is a complex problem with many interconnected causes. Some important factors contributing to the selection of drug resistant viruses in people infected with HIV are stigma, poverty, poor health, illiteracy, and insufficient adherence to antiretroviral therapy. Several studies have suggested the implementation of peer support groups as a way to shift the workload associated with adherence support, antiretroviral therapy (ART) distribution, and HIV education away from the doctors to the people living with HIV (PLHIV) themselves. We conducted interviews with local PLHIV to investigate the desirability and feasibility of a peer support group in the Pasada and Kisarawe hospitals in Dar es Salaam, Tanzania. A standardized questionnaire was completed by 27 PLHIV in July and August 2017 at the time of a follow-up visit. In this cohort, major causes for missing a dose of ART are lack of support from family and friends and forgetfulness. Reasons for wanting to join <target target-type="page-num" id="p-2"/>a peer support group include psychological support, fighting stigma, and increasing education about their disease. Interestingly, several respondents linked HIV peer support to business support groups such as village community banks (VICOBA). These are informal microfinance groups meant to offer economic stability to individuals. As this link was made by PLHIV themselves, we suggest that it may be worthwhile to explore mixed financial and HIV peer support groups in which HIV education is provided for both HIV positive and negative members. Such groups may reduce the risk of infection and stigma and provide combined psychological, financial, and logistic support to PLHIV.

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IntroductionHIV drug resistance (HIVDR) continues to threaten the effectiveness of worldwide antiretroviral therapy (ART). Emergence and transmission of HIVDR is driven by several interconnected factors. Though much has been done to uncover factors influencing HIVDR, overall interconnectedness between these factors remain unclear and African policy makers encounter difficulties setting priorities combating HIVDR. By employing a systems approach, involving multi-disciplinary HIVDR experts, we aimed to gain a deeper understanding of key determinants and their interactions driving HIVDR. MethodsWe designed a detailed system map of factors influencing HIVDR based on semi-structured interviews with 15 international HIVDR experts from or with experience in Sub-Saharan Africa. from different disciplinary backgrounds and institutions. The resulting detailed system map was conceptualized into three main HIVDR feedback loops and further strengthened with literature evidence.ResultsFactors influencing HIVDR in SSA and their interactions were sorted in five categories: biology, individual, social context, healthcare system and ‘overarching’. We identified three causal loops cross-cutting these layers, which relate to three interconnected subsystems of mechanisms influencing HIVDR. The ‘adherence motivation’ subsystem consists of opposite forces that ultimately create a balancing loop leading to a different set-point of adherence per individual which may vary over time. The ‘healthcare burden’ subsystem consists of a reinforcing loop leading to an increased HIVDR at local population level. The ‘ART overreliance’ subsystem is a balancing feedback loop leading to complacency among program managers when there is overreliance on ART with a perceived low risk to drug resistance. The three subsystems are interconnected at different levels. ConclusionsInterconnectedness of the three subsystems underlines the need to act on the entire system of factors surrounding HIVDR in Sub-Saharan Africa in order to target interventions and to prevent unwanted effects on other parts of the system.