Exploring equity in global health collaborations: a qualitative study of donor and recipient power dynamics in Liberia.

IntroductionGlobal health collaborations between individuals from high-resource and low-resource settings are complex and often built on hierarchical structures and power differentials that are difficult to change. There have been many calls and frameworks developed to facilitate more equity within these collaborations, yet little is known about the lived experiences of global health donors and recipients working within such collaborations and how those experiences can facilitate more equitable collaboration. Liberia, a postconflict, post-Ebola country, provides an ideal setting to study lived experiences of global health collaborations.MethodsOur qualitative analysis used key informant interviews representing the perspectives of those working on behalf of the Liberian government, Liberian academics, foreign donors and non-governmental organisations and implementing partners. Thematic analysis guided this analysis to explore topics such as financial control, accountability and decision making.ResultsThe first phase of the analysis mapped the existing patterns of priority setting. Priority-setting power was most strongly held by those with financial control (donors), and implementation plans tended to be built on metrics that aim to meet donor expectations. The second phase of the analysis explored the interplay between underlying factors that we identified in our data associated with driving collaborative inequity: history of prior of engagement, level of transparency and patterns of accountability.ConclusionsOur findings highlight that global health collaborations in Liberia are structured to hinder equitable partnerships. The power structure tied to financial ownership offers little space for recipients to have an equitable role in collaborations, which maintains dependence on external aid and ensures that weak systems remain weak. While our study is limited to Liberia, we anticipate that these dynamics are common elsewhere and reinforce the importance of intentional efforts to ensure equitable decision making and power structures in similar settings worldwide.

Transforming medical education in Liberia through an international community of inquiry.

A critical component of building capacity in Liberia's physician workforce involves strengthening the country's only medical school, A.M. Dogliotti School of Medicine. Beginning in 2015, senior health sector stakeholders in Liberia invited faculty and staff from U.S. academic institutions and non-governmental organizations to partner with them on improving undergraduate medical education in Liberia. Over the subsequent six years, the members of this partnership came together through an iterative, mutual-learning process and created what William Torbert et al describe as a "community of inquiry," in which practitioners and researchers pair action and inquiry toward evidence-informed practice and organizational transformation. Incorporating faculty, practitioners, and students from Liberia and the U.S., the community of inquiry consistently focused on following the vision, goals, and priorities of leadership in Liberia, irrespective of funding source or institutional affiliation. The work of the community of inquiry has incorporated multiple mixed methods assessments, stakeholder discussions, strategic planning, and collaborative self-reflection, resulting in transformation of medical education in Liberia. We suggest that the community of inquiry approach reported here can serve as a model for others seeking to form sustainable global health partnerships focused on organizational transformation.

Development of a community-based COVID-19 intervention in rural Ghana: a document analysis.

BACKGROUND: The COVID-19 pandemic has caused the loss of millions of lives and economic breakdowns in many countries across the globe. Despite the limited availability of vaccines and the challenges of poor health infrastructure, few interventions have been developed and implemented for those who live in rural areas, particularly in sub-Saharan Africa. In response, Cocoa360, a global health nonprofit in rural Ghana designed an intervention called Cocoa360's COVID-19 Preparedness and Outbreak Prevention Plan (CoCoPOPP). This paper aimed to examine the extent to which CoCoPOPP's design aligned with the Promoting Action on Research Implementation in Health Services (PARIHS) framework. METHODS: We reviewed documents influencing CoCoPOPP's design between March and June 2021. A total of 11 documents were identified for analysis. Using the Promoting Action on Research Implementation in Health Services (PARIHS) framework as a guide, thematic analysis was done to analyze the extracted data. RESULTS: Overall, CoCoPOPP's design aligned with the evidence, context, and facilitation domains of the PARIHS framework. It positioned CoCoPOPP as an intervention that considered the unique context of a rural Ghanaian setting. It was guided by robust and high-quality published and non-published evidence and engaged external and internal stakeholders during its implementation. CoCoPOPP's context-dependent nature positions it for potential replication in sub-Saharan Africa's rural communities with similar farming contexts. Specific areas that were less well and/or not addressed were the unintended negative consequences of community engagement, the absence of primary data in the guiding evidence, and the lack of a facilitation continuum coupled with the role of power during the facilitation process. CONCLUSION: CoCoPOPP, Cocoa360's response to the COVID-19 pandemic in rural Ghana, is an evidence-driven, context-dependent public health intervention that has been designed to reduce COVID-19 infections and prevent potential deaths. This study underscores the importance of considering the unique community and cultural contexts, employing evidence, and engaging local and external actors as facilitators when designing interventions to respond to global health pandemics.

Gaps and Opportunities in HIV Service Delivery in High Volume HIV Care Centers in Liberia: Lessons From the Field.

Background: Human Immunodeficiency Virus (HIV) infection continues to have a profound humanitarian and public health impact in western and central Africa, a region that risks being left behind in the global response to ending the AIDS epidemic. In Liberia, where the health system is being rebuilt following protracted civil wars and an Ebola virus disease outbreak, the Resilient and Responsive Health System (RRHS) is assisting with quality HIV services delivery through support from PEPFAR and HRSA but gaps remain across the cascade of care from diagnosis to viral load suppression. Objective: To highlight gaps in HIV service delivery in Liberia, identify opportunities and offer recommendations for improving the quality of service delivery. Methods: A narrative review of relevant literature was conducted following a search of all local and online databases known to the authors. Findings: Antiretroviral therapy (ART) has transformed the HIV response in Liberia by averting deaths, improving quality of life, and preventing new HIV infections but critical gaps remain. These include weak HIV prevention and testing strategies; suboptimal ART initiation and retention in care; low viral load testing volumes, commodity supply chain disruptions and a HIV workforce built on non-physician healthcare workers. In the context of the prevailing socioeconomic, heath system and programmatic challenges, these will impact achievement of the UNAIDS targets of 95-95-95 by 2030 and ending the epidemic. Conclusion: Combination prevention approaches are necessary to reach the most at risk populations, while a robust health workforce operating through facilities and communities will be needed to reach people with undiagnosed HIV earlier to provide efficient and effective services to ensure that people know their HIV status, receive and sustain ART to achieve viral suppression to maintain a long and healthy life within the framework of overall health system strengthening, achieving universal health coverage and the sustainable development goal.

Health Management Workforce Capacity-Building in Liberia, Post-Ebola.

Following the Ebola crisis in Liberia in 2014-15, the Liberian Ministry of Health developed a strategy to build a fit-for-purpose health workforce, focusing on both health care providers and health managers. To help fulfill national capacity-building goals for health management, a team of faculty, staff, and practitioners from the Yale School of Medicine, the University of Liberia, the National Public Health Institute of Liberia, and the Ministry of Health collaboratively developed and launched the health management program in Liberia in July 2017. The team worked to build specific management and leadership competencies for healthcare workers serving in management and leadership roles in Liberia's health sector using two concurrent strategies-1) implementation of a hospital-based partnership-mentorship model in the two largest hospitals in the capital city of Monrovia, and 2) establishment of an executive education-style advanced Certificate in Health Systems Leadership and Management at the University of Liberia. Here we describe the health management program in Liberia, its focus, and its evolution from program launch in 2017 to the present, as well as ongoing efforts to transition program activities to local partner ownership by the end of 2021.

Facing COVID-19 in Liberia: Adaptations of the Resilient and Responsive Health Systems Initiative.

The 5-year Resilient and Responsive Health Systems (RRHS)-Liberia Initiative, funded by PEPFAR via HRSA, launched in 2017 and was designed to support the implementation of Liberia's National Health Workforce Program as a means to improving HIV-related health outcomes. The COVID-19 pandemic, arrived in Liberia just five years after Ebola and during RRHS-Liberia's fourth year, impacted educational programs and threatened the project's continued work. This paper presents the challenges that the COVID-19 pandemic posed to the RRHS partners, as well as adaptations they made to maintain progress towards project goals: 1) contributing to Liberia's 95-95-95 HIV targets via direct service delivery, and 2) building a resilient and responsive health workforce in Liberia via instruction and training. Direct health service impacts included decreased patient volumes and understaffing; adaptations included development of and trainings on safety protocols, provision of telehealth services, and community health worker involvement. Instruction and training impacts included suspension of in-person teaching and learning; adaptations included utilization of multiple online learning and virtual conferencing tools, and increasing clinical didactics in lieu of bedside mentorship. The RRHS team recommends that these adaptations be continued with significant investment in technology, IT support, and training, as well as close coordination among partner institutions. Ultimately, the RRHS Liberia consortium and its partners made significant strides in response to ensuring ongoing education during the pandemic, an experience that will inform continued service delivery, teaching, and learning in Liberia.

Training the next generation of Africa's doctors: why medical schools should embrace the team-based learning pedagogy.

BACKGROUND: As far back as 1995, the Cape Town Declaration on training Africa's future doctor recognized the need for medical schools to adopt active-learning strategies in order to nurture holistic development of the doctor. However, medical education in Africa remains largely stuck with traditional pedagogies that emphasize the 'hard skills' such as knowledge and clinical acumen while doing little to develop 'soft skills' such as effective communication, teamwork, critical thinking or life-long learning skills. By reviewing literature on Africa's epidemiologic and demographic transitions, we establish the need for increasing the output of well-trained doctors in order to match the continent's complex current and future healthcare needs. Challenges that bedevil African medical education such as outdated curricula, limited educational infrastructure and chronic resource constraints are presented and discussed. Furthermore, increased student enrollments, a trend observed at many schools, coupled with chronic faculty shortages have inadvertently presented specific barriers against the success of small-group active-learning strategies such as Problem-Based and Case-Based Learning. We argue that Team-Based Learning (TBL) offers a robust alternative for delivering holistic medical education in the current setting. TBL is instructor-driven and embodies key attributes that foster development of both 'hard' and 'soft' skills. We elaborate on advantages that TBL is likely to bring to the African medical education landscape, including increased learner enthusiasm and creativity, accountability, peer mentorship, deep learning and better knowledge retention. As with all new pedagogical methods, challenges anticipated during initial implementation of TBL are discussed followed by the limited pilot experiences with TBL in Africa. CONCLUSION: For its ability to enable a student-centered, active learning experience delivered at minimum cost, we encourage individual instructors and African medical schools at large, to adopt TBL as a complementary strategy towards realizing the goal of training Africa's fit-for-purpose doctor.

Process evaluation of knowledge transfer across industries: Leveraging Coca-Cola's supply chain expertise for medicine availability in Tanzania.

Persistent gaps in the availability of essential medicines have slowed the achievement of global health targets. Despite the supply chain knowledge and expertise that ministries of health might glean from other industries, limited empirical research has examined the process of knowledge transfer from other industries into global public health. We examined a partnership designed to improve the availability of medical supplies in Tanzania by transferring knowledge from The Coca-Cola system to Tanzania's Medical Stores Department (MSD). We conducted a process evaluation including in-depth interviews with 70 participants between July 2011 and May 2014, corresponding to each phase of the partnership, with focus on challenges and strategies to address them, as well as benefits perceived by partners. Partners faced challenges in (1) identifying relevant knowledge to transfer, (2) translating operational solutions from Coca-Cola to MSD, and (3) maintaining momentum between project phases. Strategies to respond to these challenges emerged through real-time problem solving and included (1) leveraging the receptivity of MSD leadership, (2) engaging a boundary spanner to identify knowledge to transfer, (3) promoting local recognition of commonalities across industries, (4) engaging external technical experts to manage translation activities, (5) developing tools with visible benefits for MSD, (6) investing in local relationships, and (7) providing time and space for the partnership model to evolve. Benefits of the partnership perceived by MSD staff included enhanced collaboration and communication, more proactive orientations in managing operations, and greater attention to performance management. Benefits perceived by Coca-Cola staff included strengthened knowledge transfer capability and enhanced job satisfaction. Linking theoretical constructs with practical experiences from the field, we highlight the challenges, emergent strategies, and perceived benefits of a partnership across industry boundaries that may be useful to others seeking to promote the transfer of knowledge to improve global health.

Spending on social and public health services and its association with homicide in the USA: an ecological study.

OBJECTIVE: To examine whether state-level spending on social and public health services is associated with lower rates of homicide in the USA. DESIGN: Ecological study. SETTING: USA. PARTICIPANTS: All states in the USA and the District of Columbia for which data were available (n=42). PRIMARY OUTCOME MEASURE: Homicide rates for each state were abstracted from the US Department of Justice Federal Bureau of Investigation's Uniform Crime Reporting. RESULTS: After adjusting for potential confounding variables, we found that every $10 000 increase in spending per person living in poverty was associated with 0.87 fewer homicides per 100 000 population or approximately a 16% decrease in the average homicide rate (estimate=-0.87, SE=0.15, p<0.001). Furthermore, there was no significant effect in the quartile of states with the highest percentages of individuals living in poverty but significant effects in the quartiles of states with lower percentages of individuals living in poverty. CONCLUSIONS: Based on our findings, spending on social and public health services is associated with significantly lower homicide rates at the state level. Although we cannot infer causality from this research, such spending may provide promising avenues for homicide reduction in the USA, particularly among states with lower levels of poverty.

Community factors related to healthy eating & active living in counties with lower than expected adult obesity rates.

BACKGROUND: Adult obesity rates in the United States have reached epidemic proportions, yet vary considerably across states and counties. We sought to explore community-level factors that may be associated with reduced adult obesity rates at the county level. METHODS: We identified six U.S. counties that were positive deviants for adult obesity and conducted semi-structured interviews with community leaders and government officials involved in efforts to promote healthier lifestyles. Using site visits and in-depth qualitative interviews, we identified several recurrent themes and strategies. RESULTS: Participants: 1) developed a nuanced understanding of their communities; 2) recognized the complex nature of obesity, and 3) implemented a county-wide strategic approach for promoting healthy living. This county-wide approachwas used to a) break down silos and build partnerships, b) access community resources and connections, and c) transfer ownership to community members. CONCLUSIONS: We found that county leaders focused on establishing a county-wide structure to connect and support community-led initiatives to promote healthy living, reduce obesity, and foster sustainability. Findings from this study can help inform county-level efforts to improve healthy living and combat the multi-faceted challenges of adult obesity across the U.S.

Variation In Health Outcomes: The Role Of Spending On Social Services, Public Health, And Health Care, 2000-09.

Although spending rates on health care and social services vary substantially across the states, little is known about the possible association between variation in state-level health outcomes and the allocation of state spending between health care and social services. To estimate that association, we used state-level repeated measures multivariable modeling for the period 2000-09, with region and time fixed effects adjusted for total spending and state demographic and economic characteristics and with one- and two-year lags. We found that states with a higher ratio of social to health spending (calculated as the sum of social service spending and public health spending divided by the sum of Medicare spending and Medicaid spending) had significantly better subsequent health outcomes for the following seven measures: adult obesity; asthma; mentally unhealthy days; days with activity limitations; and mortality rates for lung cancer, acute myocardial infarction, and type 2 diabetes. Our study suggests that broadening the debate beyond what should be spent on health care to include what should be invested in health-not only in health care but also in social services and public health-is warranted.

State variation in HIV/AIDS health outcomes: the effect of spending on social services and public health.

OBJECTIVE: Despite considerable advances in the prevention and treatment of HIV/AIDS, the burden of new infections of HIV and AIDS varies substantially across the country. Previous studies have demonstrated associations between increased healthcare spending and better HIV/AIDS outcomes; however, less is known about the association between spending on social services and public health spending and HIV/AIDS outcomes. We sought to examine the association between state-level spending on social services and public health and HIV/AIDS case rates and AIDS deaths across the United States. DESIGN: We conducted a retrospective, longitudinal study of the 50 U.S. states over 2000-2009 using a dataset of HIV/AIDS case rates and AIDS deaths per 100 000 people matched with a unique dataset of state-level spending on social services and public health per person in poverty. METHODS: We estimated multivariable regression models for each HIV/AIDS outcome as a function of the social service and public health spending 1 and 5 years earlier in the state, adjusted for the log of state GDP per capita, regional and time fixed effects, Medicaid spending as % of GDP, and socio-demographic, economic, and health resource factors. RESULTS: States with higher spending on social services and public health per person in poverty had significantly lower HIV and AIDS case rates and fewer AIDS deaths, both 1 and 5 years post expenditure (P ≤ 0.05). CONCLUSION: Our findings suggest that spending on social services and public health may provide a leverage point for state policymakers to reduce HIV/AIDS case rates and AIDS deaths in their state.

Integrating new practices: a qualitative study of how hospital innovations become routine.

BACKGROUND: Hospital quality improvement efforts absorb substantial time and resources, but many innovations fail to integrate into organizational routines, undermining the potential to sustain the new practices. Despite a well-developed literature on the initial implementation of new practices, we have limited knowledge about the mechanisms by which integration occurs. METHODS: We conducted a qualitative study using a purposive sample of hospitals that participated in the State Action on Avoidable Rehospitalizations (STAAR) initiative, a collaborative to reduce hospital readmissions that encouraged members to adopt new practices. We selected hospitals where risk-standardized readmission rates (RSRR) had improved (n = 7) or deteriorated (n = 3) over the course of the first 2 years of the STAAR initiative (2010-2011 to 2011-2012) and interviewed a range of staff at each site (90 total). We recruited hospitals until reaching theoretical saturation. The constant comparative method was used to conduct coding and identification of key themes. RESULTS: When innovations were successfully integrated, participants consistently reported that a small number of key staff held the innovation in place for as long as a year while more permanent integrating mechanisms began to work. Depending on characteristics of the innovation, one of three categories of integrating mechanisms eventually took over the role of holding new practices in place. Innovations that proved intrinsically rewarding to the staff, by making their jobs easier or more gratifying, became integrated through shifts in attitudes and norms over time. Innovations for which the staff did not perceive benefits to themselves were integrated through revised performance standards if the innovation involved complex tasks and through automation if the innovation involved simple tasks. CONCLUSIONS: Hospitals have an opportunity to promote the integration of new practices by planning for the extended effort required to hold a new practice in place while integration mechanisms take hold. By understanding how integrating mechanisms correspond to innovation characteristics, hospitals may be able to foster integrating mechanisms most likely to work for particular innovations.

State-level spending on health care and social services for people living with HIV/AIDS in the USA: a systematic review.

Every year for the past decade, approximately 50,000 people have been diagnosed with HIV or AIDS in the USA, and the incidence of HIV/AIDS varies considerably from state to state. Studies have shown that health care services, most notably treatment with combination antiretroviral therapy, can help people living with HIV/AIDS (PLWHA) live healthier, longer lives, and prevent the spread of HIV from person to person. In addition, social services, such as housing support and provision of meals, have also shown to be important for helping PLWHA adhere to antiretroviral treatment and maintain contact with health care providers for improved health outcomes. Although spending on health care and social services for PLWHA varies across the USA, the relationship between state-level spending on these services and HIV/AIDS-related outcomes is not clear. We therefore conducted a systematic review of peer-reviewed literature to identify studies that explore state-level spending on health care services and/or social services for PLWHA and HIV/AIDS-related health outcomes in the USA.

A single amino acid substitution converts a transmembrane protein activator of the platelet-derived growth factor ß receptor into an inhibitor.

Receptors for PDGF play an important role in cell proliferation and migration and have been implicated in certain cancers. The 44-amino acid E5 protein of bovine papillomavirus binds to and activates the PDGFß receptor (PDGFßR), resulting in oncogenic transformation of cultured fibroblasts. Previously, we isolated an artificial 36-amino acid transmembrane protein, pTM36-4, which transforms cells because of its ability to activate the PDGFßR despite limited sequence similarity to E5. Here, we demonstrated complex formation between the PDGFßR and three pTM36-4 mutants: T21E, T21Q, and T21N. T21Q retained wild type transforming activity and activated the PDGFßR in a ligand-independent manner as a consequence of binding to the transmembrane domain of the PDGFßR, but T21E and T21N were severely defective. In fact, T21N substantially inhibited E5-induced PDGFßR activation and transformation in both mouse and human fibroblasts. T21N did not prevent E5 from binding to the receptor, and genetic evidence suggested that T21N and E5 bind to nonidentical sites in the transmembrane domain of the receptor. T21N also inhibited transformation and PDGFßR activation induced by v-Sis, a viral homologue of PDGF-BB, as well as PDGF-induced mitogenesis and signaling by preventing phosphorylation of the PDGFßR at particular tyrosine residues. These results demonstrated that T21N acts as a novel inhibitor of the PDGFßR and validated a new strategy for designing highly specific short transmembrane protein inhibitors of growth factor receptors and possibly other transmembrane proteins.

Innovation spread: lessons from HIV.

Efficient spreading of evidence-based innovations among complex health systems remains an elusive goal despite extensive study in the social sciences. Biology provides a model of successful spread in viruses, which have evolved to spread with maximum efficiency using minimal resources. Here we explore the molecular mechanisms of human immunodeficiency virus (HIV) spread and identify five steps that are also common to a recent example of spread in complex health systems: reduction in door-to-balloon times for patients with ST-segment elevation myocardial infarction (STEMI). We then describe a new model we have developed, called AIDED, which is based on mixed-methods research but informed by the conceptual framework of HIV spread among cells. The AIDED model contains five components: Assess, Innovate, Develop, Engage and Devolve, and can describe any one of the following: the spread of HIV among cells, the spread of practices to reduce door-to-balloon time for patients with STEMI and the spread of certain family health innovations in low- and middle-income countries. We suggest that by looking to the biological sciences for a model of spread that has been honed by evolution, we may have identified fundamental steps that are necessary and sufficient for efficient, low-cost spread of health innovations among complex health systems.

A model for scale up of family health innovations in low-income and middle-income settings: a mixed methods study.

BACKGROUND: Many family health innovations that have been shown to be both efficacious and cost-effective fail to scale up for widespread use particularly in low-income and middle-income countries (LMIC). Although individual cases of successful scale-up, in which widespread take up occurs, have been described, we lack an integrated and practical model of scale-up that may be applicable to a wide range of public health innovations in LMIC. OBJECTIVE: To develop an integrated and practical model of scale-up that synthesises experiences of family health programmes in LMICs. DATA SOURCES: We conducted a mixed methods study that included in-depth interviews with 33 key informants and a systematic review of peer-reviewed and grey literature from 11 electronic databases and 20 global health agency web sites. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: We included key informants and studies that reported on the scale up of several family health innovations including Depo-Provera as an example of a product innovation, exclusive breastfeeding as an example of a health behaviour innovation, community health workers (CHWs) as an example of an organisational innovation and social marketing as an example of a business model innovation. Key informants were drawn from non-governmental, government and international organisations using snowball sampling. An article was excluded if the article: did not meet the study's definition of the innovation; did not address dissemination, diffusion, scale up or sustainability of the innovation; did not address low-income or middle-income countries; was superficial in its discussion and/or did not provide empirical evidence about scale-up of the innovation; was not available online in full text; or was not available in English, French, Spanish or Portuguese, resulting in a final sample of 41 peer-reviewed articles and 30 grey literature sources. STUDY APPRAISAL AND SYNTHESIS METHODS: We used the constant comparative method of qualitative data analysis to extract recurrent themes from the interviews, and we integrated these themes with findings from the literature review to generate the proposed model of scale-up. For the systematic review, screening was conducted independently by two team members to ensure consistent application of the predetermined exclusion criteria. Data extraction from the final sample of peer-reviewed and grey literature was conducted independently by two team members using a pre-established data extraction form to list the enabling factors and barriers to dissemination, diffusion, scale up and sustainability. RESULTS: The resulting model-the AIDED model-includes five non-linear, interrelated components: (1) assess the landscape, (2) innovate to fit user receptivity, (3) develop support, (4) engage user groups and (5) devolve efforts for spreading innovation. Our findings suggest that successful scale-up occurs within a complex adaptive system, characterised by interdependent parts, multiple feedback loops and several potential paths to achieve intended outcomes. Failure to scale up may be attributable to insufficient assessment of user groups in context, lack of fit of the innovation with user receptivity, inability to address resistance from stakeholders and inadequate engagement with user groups. LIMITATIONS: The inductive approach used to construct the AIDED model did not allow for simultaneous empirical testing of the model. Furthermore, the literature may have publication bias in which negative studies are under-represented, although we did find examples of unsuccessful scale-up. Last, the AIDED model did not address long-term, sustained use of innovations that are successfully scaled up, which would require longer-term follow-up than is common in the literature. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Flexible strategies of assessment, innovation, development, engagement and devolution are required to enable effective change in the use of family health innovations in LMIC.

Artificial transmembrane oncoproteins smaller than the bovine papillomavirus E5 protein redefine sequence requirements for activation of the platelet-derived growth factor beta receptor.

The bovine papillomavirus E5 protein (BPV E5) is a 44-amino-acid homodimeric transmembrane protein that binds directly to the transmembrane domain of the platelet-derived growth factor (PDGF) beta receptor and induces ligand-independent receptor activation. Three specific features of BPV E5 are considered important for its ability to activate the PDGF beta receptor and transform mouse fibroblasts: a pair of C-terminal cysteines, a transmembrane glutamine, and a juxtamembrane aspartic acid. By using a new genetic technique to screen libraries expressing artificial transmembrane proteins for activators of the PDGF beta receptor, we isolated much smaller proteins, from 32 to 36 residues, that lack all three of these features yet still dimerize noncovalently, specifically activate the PDGF beta receptor via its transmembrane domain, and transform cells efficiently. The primary amino acid sequence of BPV E5 is virtually unrecognizable in some of these proteins, which share as few as seven consecutive amino acids with the viral protein. Thus, small artificial proteins that bear little resemblance to a viral oncoprotein can nevertheless productively interact with the same cellular target. We speculate that similar cellular proteins may exist but have been overlooked due to their small size and hydrophobicity.

The bovine papillomavirus E5 protein and the PDGF beta receptor: it takes two to tango.

The extremely hydrophobic, 44-amino acid bovine papillomavirus (BPV) E5 protein is the smallest known oncoprotein, which orchestrates cell transformation by causing ligand-independent activation of a cellular receptor tyrosine kinase, the platelet-derived growth factor beta receptor (PDGFbetaR). The E5 protein forms a dimer in transformed cells and is essentially an isolated membrane-spanning segment that binds directly to the transmembrane domain of the PDGFbetaR, inducing receptor dimerization, autophosphorylation, and sustained mitogenic signaling. There are few sequence constraints for activity as long as the overall hydrophobicity of the E5 protein and its ability to dimerize are preserved. Nevertheless, the E5 protein is highly specific for the PDGFbetaR and does not activate other cellular proteins. Genetic screens of thousands of small, artificial hydrophobic proteins with randomized transmembrane domains inserted into an E5 scaffold identified proteins with diverse transmembrane sequences that activate the PDGFbetaR, including some activators as small as 32-amino acids. Analysis of these novel proteins has provided new insight into the requirements for PDGFbetaR activation and specific transmembrane recognition in general. These results suggest that small, transmembrane proteins can be constructed and selected that specifically bind to other cellular or viral transmembrane target proteins. By using this approach, we have isolated a 44-amino acid artificial transmembrane protein that appears to activate the human erythropoietin receptor. Studies of the tiny, hydrophobic BPV E5 protein have not only revealed a novel mechanism of viral oncogenesis, but have also suggested that it may be possible to develop artificial small proteins that specifically modulate much larger target proteins by acting within cellular or viral membranes.