Financing climate change adaptation

This paper examines the topic of financing adaptation in future climate change policies. A major question is whether adaptation in developing countries should be financed under the 1992 United Nations Framework Convention on Climate Change (UNFCCC), or whether funding should come from other sources. We present an overview of financial resources and propose the employment of a two-track approach: one track that attempts to secure climate change adaptation funding under the UNFCCC; and a second track that improves mainstreaming of climate risk management in development efforts. Developed countries would need to demonstrate much greater commitment to the funding of adaptation measures if the UNFCCC were to cover a substantial part of the costs. The mainstreaming of climate change adaptation could follow a risk management path, particularly in relation to disaster risk reduction. 'Climate-proofing' of development projects that currently do not consider climate and weather risks could improve their sustainability. © Overseas Development Institute, 2006

Do not forget families and households when addressing urban refugee education

There are currently more than 25.4 million refugees globally, representing the largest number of refugees in recorded history (UNHCR 2018). More than one in three refugees who fall under the auspices of United Nations Refugee Agency (UNHCR) protection are of school age (UNHCR 2019a). Dryden-Peterson (2015, 2016) points out that much of what is known about refugee education stems from research conducted in high-income countries of resettlement, ignoring the reality that the majority of refugees live in low- and middle-income countries (LMICs) neighboring their countries of origin. Additionally, 60% of refugees globally reside in cities (UNHCR 2019c), where UNHCR coordinates with host countries to integrate students with refugee backgrounds into the national education system (Dryden-Peterson 2016). We attempt to contribute to this literature while highlighting the importance of family and household factors in urban refugee education. ... This brief report draws on three authors’ (DN, JS, JT) continuing work with refugee populations in Kenya and, more specifically, upon two unique datasets. The first is data collected by two authors (JS, JAT) at different intervals in 2012 and 2014 as part of an urban refugee education assessment coordinated by a local non-governmental organization (NGO) and UNHCR Kenya to understand urban refugees’ barriers and facilitators to education in Nairobi. Data were collected with refugee learners attending primary and secondary schools, head teachers, school administrators and nongovernmental organization staff. The second dataset is from the third author’s (JAT) ethnographic research with urban-displaced refugee families and households in Nairobi from 2013–2014. This research sought to understand the lived experiences of urban refugees more generally. Education was not a central focus of this study; however, children’s access to education and experiences in school emerged as key areas of concern among refugee caregivers. As such, this work is used to provide additional context to household and family factors that affect the educational access and outcomes of urban-displaced refugees. Ethical approval was obtained from educational institutions (JAT) and the Kenyan National Commission for Science, Technology, and Innovation (NACOSTI). Kenya is an important case study for urban refugee education. The country remains a major refugee-hosting nation, with more than 473,000 refugees living in camps and cities (UNHCR 2019b). Although the Government of Kenya enforces encampment, 13% of the country’s refugee population reside in cities (mainly Nairobi) (UNHCR 2019b). This report focuses on Nairobi; however, we believe the presented research has broader application for policymakers, practitioners and researchers

Psychological Distress Prevalence and Associated Stressors and Supports Among Urban-Displaced Congolese Adults in Kenya

Background: There is limited understanding of the prevalence of psychological distress and associated stressors and supports among displaced adults in low- and middle-income first asylum countries. Method: This article reports the findings of a cross-sectional study. We recruited 245 Congolese adults (18–80 years) residing in Nairobi, Kenya using snowball sampling. Data were collected using an interviewer-administered questionnaire consisting of sociodemographic characteristics, the Self-Reporting Questionnaire (SRQ-20), and a locally developed stressors and supports survey. We used multivariable logistic regression to examine associations among sociodemographic, stressor, and support variables and the likelihood of experiencing psychological distress. Results: More than half of the participants (52.8%) reported symptoms indicative of psychological distress. Factors associated with increased psychological distress included perceiving to have a useful role in one’s family or community, AOR = 1.85; 95% CI [1.1.17, 3.11], p = .012, feeling confused or not knowing what to do, AOR = 2.13; 95% CI [1.20, 4.6], p = .014, and feeling afraid to leave home for medical/health care to help with an illness, AOR = 1.57; 95% CI [1.17, 2.15], p \u3c .01. Additionally, ethnic Banyamulenge Congolese adults without legal refugee status had an increased likelihood of experiencing psychological distress, AOR = .07; 95% CI [0, .74], p = .035. Conclusion: Future research is warranted to understand how to implement targeted mental health and psychosocial support (MHPSS) to improve urban-displaced adults’ sense of safety and belonging. Our findings suggest that legal refugee status is an important structural determinant of mental health, which should be considered in MHPSS practice and policy

Enfuvirtide Resistance Mutations: Impact on Human Immunodeficiency Virus Envelope Function, Entry Inhibitor Sensitivity, and Virus Neutralization

Enfuvirtide (ENF/T-20/Fuzeon), the first human immunodeficiency virus (HIV) entry inhibitor to be licensed, targets a structural intermediate of the entry process. ENF binds the HR1 domain in gp41 after Env has bound CD4, preventing conformational changes needed for membrane fusion. Mutations in HR1 that confer ENF resistance can arise following ENF therapy. ENF resistance mutations were introduced into an R5- and X4-tropic Env to examine their impact on fusion, infection, and sensitivity to different classes of entry inhibitors and neutralizing antibodies. HR1 mutations could reduce infection and fusion efficiency and also delay fusion kinetics, likely accounting for their negative impact on viral fitness. HR1 mutations had minimal effect on virus sensitivity to other classes of entry inhibitors, including those targeting CD4 binding (BMS-806 and a CD4-specific monoclonal antibody [MAb]), coreceptor binding (CXCR4 inhibitor AMD3100 and CCR5 inhibitor TAK-779), or fusion (T-1249), indicating that ENF-resistant viruses can remain sensitive to other entry inhibitors in vivo. Some HR1 mutations conferred increased sensitivity to a subset of neutralizing MAbs that likely target fusion intermediates or with epitopes preferentially exposed following receptor interactions (17b, 48D, 2F5, 4E10, and IgGb12), as well as sera from some HIV-positive individuals. Mechanistically, enhanced neutralization correlated with reduced fusion kinetics, indicating that, in addition to steric constraints, kinetics may also limit virus neutralization by some antibodies. Therefore, escape from ENF comes at a cost to viral fitness and may confer enhanced sensitivity to humoral immunity due to prolonged exposure of epitopes that are not readily accessible in the native Env trimer. Resistance to other entry inhibitors was not observed

Impact of Mutations in the Coreceptor Binding Site on Human Immunodeficiency Virus Type 1 Fusion, Infection, and Entry Inhibitor Sensitivity

An increasingly large number of antiviral agents that prevent entry of human immunodeficiency virus (HIV) into cells are in preclinical and clinical development. The envelope (Env) protein of HIV is the major viral determinant that affects sensitivity to these compounds. To understand how changes in Env can impact entry inhibitor sensitivity, we introduced six mutations into the conserved coreceptor binding site of the R5 HIV-1 strain YU-2 and measured the effect of these changes on CD4 and coreceptor binding, membrane fusion levels and rates, virus infection, and sensitivity to the fusion inhibitors enfuvirtide (T-20) and T-1249, the CCR5 inhibitor TAK-779, and an antibody to CD4. The mutations had little effect on CD4 binding but reduced CCR5 binding to various extents. In general, reductions in coreceptor binding efficiency resulted in slower fusion kinetics and increased sensitivity to TAK-779 and enfuvirtide. In addition, low CCR5 binding usually reduced overall fusion and infection levels. However, one mutation adjacent to the bridging sheet β21 strand, P438A, had little effect on fusion activity, fusion rate, infectivity, or sensitivity to enfuvirtide or T-1249 despite causing a marked reduction in CCR5 binding and a significant increase in TAK-779 sensitivity. Thus, our findings indicate that changes in the coreceptor binding site of Env can modulate its fusion activity, infectivity, and entry inhibitor sensitivity by multiple mechanisms and suggest that reductions in coreceptor binding do not always result in prolonged fusion kinetics and increased sensitivity to enfuvirtide

Conserved changes in envelope function during human immunodeficiency virus type 1 coreceptor switching

We studied the evolution of human immunodeficiency virus type 1 (HIV-1) envelope function during the process of coreceptor switching from CCR5 to CXCR4. Site-directed mutagenesis was used to introduce most of the possible intermediate mutations in the envelope for four distinct coreceptor switch mutants, each with a unique pattern of CCR5 and CXCR4 utilization that extended from highly efficient use of both coreceptors to sole use of CXCR4. Mutated envelopes with some preservation of entry function on either CCR5- or CXCR4-expressing target cells were further characterized for their sensitivity to CCR5 or CXCR4 inhibitors, soluble CD4, and the neutralizing antibodies b12-IgG and 4E10. A subset of mutated envelopes was also studied in direct CD4 or CCR5 binding assays and in envelope-mediated fusion reactions. Coreceptor switch intermediates displayed increased sensitivity to CCR5 inhibitors (except for a few envelopes with mutations in V2 or C2) that correlated with a loss in CCR5 binding. As use of CXCR4 improved, infection mediated by the mutated envelopes became more resistant to soluble CD4 inhibition and direct binding to CD4 increased. These changes were accompanied by increasing resistance to the CXCR4 inhibitor AMD3100. Sensitivity to neutralizing antibody was more variable, although infection of CXCR4-expressing targets was generally more sensitive to neutralization by both b12-IgG and 4E10 than infection of CCR5-expressing target cells. These changes in envelope function were uniform in all four series of envelope mutations and thus were independent of the final use of CCR5 and CXCR4. Decreased CCR5 and increased CD4 binding appear to be common features of coreceptor switch intermediates

HIV Type 1 from a Patient with Baseline Resistance to CCR5 Antagonists Uses Drug-Bound Receptor for Entry

CCR5 antagonists are a new class of antiretroviral drugs that block viral entry by disrupting interactions between the viral envelope (Env) glycoprotein and coreceptor. During the CCR100136 (EPIC) Phase IIb study of the CCR5 antagonist aplaviroc (APL) in treatment-naive individuals, a patient was identified who harbored virus strains that exhibited partial resistance to APL at the time of virologic failure. Retrospectively, it was found that APL resistance was present at baseline as well. To investigate the mechanism of APL resistance in this patient, we cloned HIV-1 env genes from plasma obtained at baseline and after virologic failure. Approximately 85% of cloned Envs were functional, and all exhibited partial resistance to APL. All Envs were R5-tropic, were partially resistant to other CCR5 antagonists including maraviroc on cells with high CCR5 expression, but remained sensitive to the fusion inhibitor enfuvirtide. Competition studies with natural CCR5 ligands revealed that the mechanism of drug resistance entailed the use of the drug-bound conformation of CCR5 by the Env proteins obtained from this individual. The degree of drug resistance varied between Env clones, and also varied depending on the cell line used or the donor from whom the primary T cells were obtained. Thus, both virus and host factors contribute to CCR5 antagonist resistance. This study shows that R5 HIV-1 strains resistant to CCR5 inhibitors can arise in patients, confirming a mechanism of resistance previously characterized in vitro. In addition, some patients can harbor CCR5 antagonist-resistant viruses prior to treatment, which may have implications for the clinical use of this new class of antiretrovirals

Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics

HIV entry inhibitors include coreceptor antagonists and the fusion inhibitor T-20. T-20 binds the first helical region (HR1) in the gp41 subunit of the viral envelope (Env) protein and prevents conformational changes required for membrane fusion. HR1 appears to become accessible to T-20 after Env binds CD4, whereas coreceptor binding is thought to induce the final conformational changes that lead to membrane fusion. Thus, T-20 binds to a structural intermediate of the fusion process. Primary viruses exhibit considerable variability in T-20 sensitivity, and determinants outside of HR1 can affect sensitivity by unknown mechanisms. We studied chimeric Env proteins containing different V3 loop sequences and found that gp120/coreceptor affinity correlated with T-20 and coreceptor antagonist sensitivity, with greater affinity resulting in increased resistance to both classes of entry inhibitors. Enhanced affinity resulted in more rapid fusion kinetics, reducing the time during which Env is sensitive to T-20. Reduced coreceptor expression levels also delayed fusion kinetics and enhanced virus sensitivity to T-20, whereas increased coreceptor levels had the opposite effect. A single amino acid change (K421D) in the bridging sheet region of the primary virus strain YU2 reduced affinity for CCR5 and increased T-20 sensitivity by about 30-fold. Thus, mutations in Env that affect receptor engagement and membrane fusion rates can alter entry inhibitor sensitivity. Because coreceptor expression levels are typically limiting in vivo, individuals who express lower coreceptor levels may respond more favorably to entry inhibitors such as T-20, whose effectiveness we show depends in part on fusion kinetics