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Results

Grant to Volunteering Matters 23 Mar 2015

The men go forth to Battle, the women wait and knit

Amount: £9,800
Funder: The National Lottery Heritage Fund
Recipient: Volunteering Matters
Region: North East
District: County Durham

Grant awarded to Community Service Volunteers (Training and Enterprise NE) (Tyne & Wear) 10 Mar 2009

To provide support and mentoring to people with mental health problems to help them volunteer in Newcastle.

Grant awarded to Community Service Volunteers (Training and Enterprise NE) (Tyne & Wear) 13 Jul 2004

To provide daycare services to older people living in high rise flats in Newcastle.

Positive Futures London 18 Nov 2015

This project, based on a established youth-led volunteering model is expanding as a result of self-referrals and is being delivered in Hackney, Haringey and Tower Hamlets. It will support young people aged 13 to 25 to deliver volunteering and social action projects which they have identified to be of benefit to the local community. The aim of project is that all of the young people who are participating in it will develop key skills and have positive experiences that will shape their personal development.

Amount: £387,576
Funder: The Big Lottery Fund
Recipient: Volunteering Matters
Region: London
District: Hackney London Boro

When is enough, enough? Physiological responses to fluid resuscitation in sub-Saharan African adults with sepsis 23 May 2018

How are cardiovascular responses to intravenous fluid determined by causative pathogen, duration of illness and pre-existing cardiac disease in patients with sepsis in Malawi? Over 30 million people develop sepsis every year. The first six hours of treatment is critical, as in severe cases mortality is 25-50%, predominantly due to early cardiovascular compromise. In low income countries, intravenous fluids are used as primary supportive treatment. However, the three existing African trials describe higher mortality in those receiving higher fluid volumes, without any pathophysiological explanation. I will identify important mediators of treatment success in Africa examining biologically plausible candidates: 1) pathogen-specific effects; 2) sub-acute physiological compensation from late presentation; 3) existing cardiovascular pathology (related to rheumatic heart disease, HIV and hypertension). I will investigate cardiovascular dynamics in Malawian adults during sepsis resuscitation and unpick the causes of aberrant physiology by careful aetiological description, detailed cardiac and pulmonary ultrasound monitoring, and measures of tissue perfusion. I will investigate novel and existing mathematical models as predictors of specific adverse outcomes (pulmonary oedema, kidney injury, circulatory collapse), providing a theoretical underpinning for personalised fluid management, and the capacity to hypothesis-test alternative strategies for future clinical trials.

Amount: £813,093
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Assessing the effects of piperonyl butoxide (PBO) exposure on malaria vector fitness 19 Jun 2017

Malaria occurrence has decreased remarkably across sub-Saharan Africa over the past 15 years. This is largely due to the mass distribution of LLINs. However, the main type of malaria vectors, including Anopheles gambiae and Anopheles funestus, have gained resistance to pyrethroids.This threatens the future effectiveness of LLINs, and alternative solutions and compounds are urgently needed. One solution is a long-lasting insecticidal treated net (LLIN) containing both a pyrethroid and a compound known as piperonyl butoxide (PBO). PBO is a synergist that inhibits a group of enzymes (P450s) inside the insect which metabolise pyrethroids causing resistance.P450 enzymes play a large role in other physiological processes in insects such as maintaining hormonal balance and synthesis of the external cuticle. By inhibiting P450s, exposure to PBO may negatively affect these processes causing further reductions in the Anopheles population. This project will look at the impact of exposing local vector populations in southern Malawi to PBO-LLINs and quantifying the impact of exposure on mosquito longevity and reproduction. Exposure to PBO-LLINs will also determine whether PBO modifies these mechanisms and make mosquitoes more susceptible to pyrethroids. This project will help inform policy makers of the effectiveness of PBO-LLINs as part of vector control strategies.

Amount: £129,219
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Assessing the entomological risk of emergence of massive Dengue, Zika and Chikungunya outbreaks and preparing to better control of Aedes vectors in Central Africa 22 Nov 2016

Aedes aegypti and Ae. albopictus are the main vectors of arboviruses’ diseases such as dengue, zika and chikungunya. Ae. aegypti is indigenous in Central Africa, whereas Ae. albopictus, originating from Asia, was first reported in the region (Cameroon) in the 2000s. Since then, this mosquito has colonized almost all countries of the region coinciding with the emergence of dengue, zika and chikungunya viruses in urban areas in some Central African countries. The control of such diseases is based on entomological surveillance and vector control. This requires extensive background information on the bio-ecology, vector competence and resistance status of the mosquito vectors involved. The current lack of such critical information prevents the design of adequate control measures making this region very vulnerable to likely arbovirus outbreaks. To fill these gaps, I plan in this project to: i) document the geographical distribution and infestation degree of Ae. aegypti and Ae. albopictus; ii) assess their vector competence toward dengue and Zika viruses; iii) characterize their resistance profiles and mechanisms against the main insecticides. This project will help to assess the epidemiological risk of emergence of massive arboviruses’ outbreaks in Central Africa and equip this region to prepare for it.

Amount: £280,602
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

An Analysis Of Networks And Education Resources Supporting Drug Resistant Infection Surveillance In Low And Middle Income Countries 30 Sep 2016

Supporting Surveillance Capacity for Antimicrobial Resistance: Regional Networks and Educational Resources The RFP contained three themes and this proposal is to address the terms of reference (ToR) for one of them, specifically ‘an analysis of networks and education resources supporting drug resistant infection surveillance in low and middle income countries (LMICs)’. The ToR presented two objectives (described in full in 2.1 and 2.2 below) which, in broad terms, require the identification and assessment of drug resistance surveillance ‘networks’ in LMICs and of available ‘educational resources’ designed to support effective implementation of such networks. We would define a drug resistance surveillance network as a group of institutions (nationally) or countries (regionally/globally) that gather, analyse, compile and share the results of any aspect of antimicrobial resistance (e.g. antimicrobial resistance, antimicrobial use and antimicrobial quality). The Capacity Research Unit (CRU), Liverpool School of Tropical Medicine (LSTM), has extensive experience assessing laboratory and research systems within LMICs and identifying site-­- and system-­- specific capacity strengthening pathways(1, 2). As such, we believe we are strongly positioned to meet the stated ToR objectives which we would achieve by drawing on our existing expertise and networks to complete the following five activities: 1) Identify drug resistance surveillance networks through a systematic review of the published and grey literature and through consultation with existing contacts in LMICs and relevant research and development organisations. 2) Assess the scope, strengths and weaknesses of each identified network against a study-­-specific evaluation matrix. The matrix will be informed by existing surveillance system benchmarks such as the WHOs Global Antimicrobial Resistance Surveillance System (GLASS) (3) and the OASIS tool for assessing epidemiological surveillance systems (4). The assessment of each surveillance network will be based on information obtained during the aforementioned review of published and grey literature and through key informant interviews with members from each network or individuals with working knowledge of a network. 3) Produce a report comparing and contrasting each network according to the evaluation matrix, identifying best performing networks regionally and detailing key recommendations for strengthening regional surveillance networks. 4) Identify existing educational resources to support strengthening of current drug resistant infection surveillance systems through a systematic review of the published and grey literature, through consultation with existing contacts in LMICS and relevant research and development organisations and during the aforementioned key informant interviews with network members. 5) Produce a report detailing the identified education resources, their respective scope (i.e. which component(s) of a surveillance system they are designed to support) and how to access them. The report will also detail current gaps in the available education resources, with respect to both scope and access. In completing the above, we envisage some cross over with another Fleming Fund RFP "An analysis of approaches to laboratory capacity strengthening for drug resistant infections in LMICs" for which CRU have also submitted a proposal.

Intermittent Preventive Treatment with DHA-piperaquine for malaria in pregnancy in areas with high sulphadoxine-pyrimethamine resistance in Africa 02 May 2016

Overall AIMTo provide the Malaria Policy Advisory Committee of the World Health Organisation (WHO) and National Malaria ControlProgrammes with the definitive evidence on the efficacy, safety, operational feasibility and cost-effectiveness of IntermittentPreventive Therapy in pregnancy (IPTp) with dihydroartemisinin-piperaquine (DP). This will enable WHO to determinewhether IPTp-DP is a viable alternative strategy to the current recommendation of IPTp with sulphadoxine-pyrimethamine(SP) in moderate to high transmission areas with high parasite resistance to SP.ObjectivesPrimary objectiveTo conduct a definitive trial to determine if Intermittent Preventive Therapy in pregnancy (IPTp) with dihydroartemisininpiperaquine(DP) is superior to the existing strategy of IPTp with sulphadoxine-pyrimethamine (SP) for controlling malariaand reducing adverse birth outcomes in areas with intense year-round malaria transmission and high SP resistance inwestern Kenya and southern Malawi.Secondary objectives1. To determine the safety of monthly IPTp-DP by conducting nested cardio monitoring studies to specifically look atwhether previously documented transient QTc prolongation associated with DP increases in magnitude with subsequentcourses.2. To conduct, on completion of the trial, a prospective meta-analysis combining the evidence from this and previous trialsto provide (with >=85% power) definitive evidence whether IPTp with DP is superior to the existing strategy of IPTp with SPfor controlling malaria and reducing adverse pregnancy outcomes in areas with intense year-round malaria transmissionand high SP resistance.3. To determine the cost-effectiveness of IPTp-DP compared to IPTp-SP.4. To determine the acceptability and feasibility of implementing IPTp-DP compared to IPTp-SP among pregnant womenand health providers.We will also take the opportunity to explore whether the resilient effect of SP on birthweight in areas with highly SPresistant P. falciparum parasites could reflect its broad antimicrobial activity and any associated effect on the gut ormaternal vaginal microbiota.

Amount: £539,692
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Assessing the impacts of insecticide resistance on vectorial competence of Anopheles gambiae from Uganda 22 Jun 2016

Malaria in Sub-Saharran Africa is caused by Plasmodium species, in particular P. falciparum, transmitted by the mosquito vector, Anopheles gambiae. Anti-vector strategies for controlling mosquito populations rely on the use of insecticides. Unfortunately, An. gambiae has developed intense insecticide resistance that not only prevents their killing but also may impact their physiology and susceptibility to infection with P. falciparum. Studies assessing infection in insecticide-resistant mosquitoes are needed urgently. The transmission of the human malaria parasite, P. falciparum by An. gambiae remains a crucial step yet weak point in the life cycle of the parasite. Certain factors can affect this process; For instance, mutations causing insecticide resistance may make mosquitoes more susceptible to human malaria parasites leading to increased transmission. This project aims to understand how insecticide resistance mutations in mosquitoes impact the transmission of malaria in a highly endemic region of Uganda by determining the prevalence and mean intensity of P. falciparum infection in insecticide-resistant and susceptible mosquitoes. These experiments will test the hypothesis that specific insecticide resistance mosquito genotypes affect parasite survival.

Amount: £104,663
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Malawi Liverpool Wellcome Trust Programme - Core Award 01 Jun 2017

We will achieve internationally excellent translational science to benefit human health with a focus on sub-Saharan Africa. MLW is built around excellent laboratories, strategically located in the largest hospital in Malawi, closely linked with the community and an integral part of the medical school. These relationships provide a valuable opportunity replicated in few centres in Africa to study major health issues spanning both community and hospital. We will manage two major Programmes: (1) Preventing death from severe infection, and (2) Transmission reduction in infectious diseases and continue to publish over 100 papers/year. Over the next 5 years, we will target clinical syndromes of sepsis, meningitis, diarrhoea and pneumonia with vaccine, behavioural and clinical management strategies. We will focus on transmission of HIV, TB and malaria with improved access to care, diagnosis and treatment. In addition, a Strategic Initiative will target selected high burden chronic diseases (lung impairment, stroke, blindness), particularly related to HIV. In partnership with the College of Medicine we will deliver Training that will attract, train and retain local and international senior scientists. Through our partnership with the Ministry of Health, our Policy Aims will ensure that our research is both relevant and applied to improve human health.

Amount: £25,084,066
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Fine-scale analysis of candidate genes associated with pyrethroid resistance in the malaria vector Anopheles funestus by target enrichment Next-Generation Sequencing 05 Apr 2012

Pyrethroid resistance in the malaria vector Anopheles funestus is disrupting malaria control in southern Africa and, unless barriers to reproduction occur, there are fears that this resistance front could spread very rapidly across the whole of Africa. As a contribution toward the improvement of our ability to control this vector, the aim of this proposal is to characterize the metabolic resistance to pyrethroid insecticides in field populations of An. funestus. Ultimately, the goal is to develo p a simple molecular assay that can be routinely employed for monitoring and evaluation in insecticide resistance management programs. The project encompasses three broad aims: Aim 1 is to identify the major pyrethroid resistance genes in field populations of An. funestus by using association and QTL mapping approaches. Aim 2 is to functionally characterize all candidate genes in QTL regions by quantitative PCR, in vitro expression and assessing candidate genes interaction with pyrethroids and finally by confirming their in vivo role by RNA interference experiment. Aim 3 is to design a diagnostic monitoring tool for insecticide resistance in field population of An. funestus. This project will be facilitated by the tools for this genetically intractable species which I generated during my postdoctoral research activities.

Amount: £88,000
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

An advanced cookstove intervention to prevent pneumonia in children under 5 years old in Malawi: a cluster randomised controlled trial. 06 Jun 2012

Trial type: Prevention. Design: Village-level cluster randomised controlled trial with two arms of equal size. Interventions: Experimental - The Philips fan-assisted stove with user training (replacing open fires). Control - Continuation of traditional cooking methods (open fire). Randomisation: By matched pairs of villages using computer-based system stratified by district to trial arms in a 1:1 ratio. Target population: Children up to 4.5 years old in Malawi allowing for a minimum of 6 months data collection before a child's 5th birthday. The trial will be broadly inclusive. HIV infection will not be an exclusion criterion. Duration of treatment period and follow-up: 24 months from randomisation. Primary outcome measure: Incidence of pneumonia in children under 5 years of age diagnosed by blinded physicians or medical officers using the WHO Integrated Management of Childhood Illness (IMCI) pneumonia assessment protocol. Economic, social, qualitative measures: Analyses will be carried out to explore factors that may be relevant for scale up of the intervention in the future. Sample size and potential power of the trial: Randomisation will be at the village level with an expected average number of children per village of 85 (77 after allowing for 10% loss to follow up). The between cluster CV has been set at the conservatively high level of 0.10. The latest data from Malawi suggest that around 9% of control group children will develop pneumonia severe enough to require treatment at a healthcare facility every year. We are using a highly conservative estimate of 5% (allowing for impact of pneumococcal vaccine). A sample of 59 villages per group will give 80% power to detect a 20% reduction in risk in the intervention group from 5% to 4% (a=0.05). Consumer involvement: Villagers, local stove producers and community leaders in Blantyre and Balaka districts have been involved with the development of this trial proposal through community engagement meetings.

Amount: £523,282
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Improving neonatal health in remote rural areas in China and Vietnam. 25 Mar 2014

Newborn (first 4 weeks of life) health remains a significant problem in China and Vietnam, especially in rural areas where they are 3 to 4 times more likely to die than in more developed areas. Most newborns can be treated with cost-effective interventions at facility and community levels, which do not require high-level training or costly equipment. Achieving high coverage of these interventions in the poorest areas could reduce neonatal deaths by at least 70%. While NH practice guidelines exist in China and Vietnam at national and local levels to guide on appropriate care and treatment, a major problem is ineffective implementation of the guidelines. This development study will assess the feasibility of using a participatory problem-solving intervention with local health managers to improve NH guideline implementation. If feasible, it will inform the design of a full-scale study to evaluate the effectiveness of the intervention. In the full-scale study, the research team would support local health managers through problem-solving and planning workshops, mentoring and capacity development to (1) assess the effectiveness of current guidelines; (2) identify barriers to improved implementation relating to service delivery (e.g. workforce issues, transport, equipment and supplies) and service demand (limited by remote access and traditional beliefs); (3) develop feasible strategies within current resource constraints e.g. re-organising services and the workforce, and using suitable community engagement models to stimulate demand for improved services; and 4) develop appropriate methods to monitor impact and unintended consequences. To assess the intervention's feasibility in remote, rural China and Vietnam the development study must address 4 questions: 1. What are the current health service management practices and the degree of freedom for decision-making at different systems levels for improving NH outcomes? 2. What are the opportunities for developing or strengthening community actions to support improved NH outcomes? 3. What is the potential for monitoring NH outcomes and measuring cost-effectiveness of interventions at different health systems levels? 4. What is the feasibility for local managers to use a participatory problem-solving intervention to implement existing practice guidelines for improving NH outcomes covering community, primary and referral levels and what would be the best vehicle for the intervention? We plan to conduct desk-based reviews of NH practice guidelines, challenges of monitoring NH impact in remote areas and NH intervention cost-effectiveness, before holding a 2-day workshop in Beijing to refine our field work plan and data collection tools and conduct 3 national key informant interviews (KIIs). We will then collect data in Guizhou, China using 4 methods: (i) KIIs: community level representatives, local health service managers, frontline health workers and provincial level policy makers and senior health officials; (ii) focus group discussions: recent mothers and community members; (iii) document review of community action agreements and provincial/national policies and plans; (iv) observation of health management information systems (HMIS) and accounting systems. A smaller research team will repeat this data collection protocol in Tay Nguyen, Vietnam, before analysing the two country datasets. This will inform the design the full-scale study and facilitate stakeholder engagement. We will produce 3 outputs on monitoring NH services in remote areas; practicalities of monitoring NH in remote China and Vietnam; and national policy space and local decision making freedom to improve NH services. Three levels of stakeholders will benefit: local (health service managers and staff), national (policy makers in China's MCH centres and Vietnam's NH technical working group) and international (e.g. Unicef, WHO, PMNCH and implementation science groups like WHO-led Implementation Research Platform).

Amount: £22,882
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Malawi-Liverpool-Wellcome Trust Clinical Research Programme. 17 Apr 2013

MLW is strategically placed to conduct high quality laboratory, clinical and epidemiological science relevant to health in sub-Saharan Africa. The programme is embedded within a rapidly growing medical school, co-located within the largest teaching hospital in Malawi with direct access to urban and rural populations. In the next 5 years, MLW research will increase fundamental understanding of disease mechanisms and burden, test novel interventions and ensure translation into health care. The cor e programme will ensure MLW delivers the following aims: (1) Pursuit of cutting-edge research focused on health problems with a high disease burden. Research management, mentorship, development of bioinformatics expertise, and clinical and diagnostic laboratory competencies, ensuring the highest quality. (2) Provision of a research training environment for clinicians, epidemiologists and laboratory scientists. Local research infrastructure, operational and financial systems, data manageme nt and research governance support. (3) Development of globally competitive research leaders. Moving towards local leadership, embedded within the University of Malawi College of Medicine, attracting further intermediate and senior Fellows, and encouraging re-entry of trained Malawian scientists. (4) Translation of scientific advances into human health improvements. Defining national and international research agendas through policy relevant evidence; policy committee membership; research synthesis workshops; and public engagement.

Amount: £13,200,000
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Supplementary funding 17 Apr 2013

MLW is strategically placed to conduct high quality laboratory, clinical and epidemiological science relevant to health in sub-Saharan Africa. The programme is embedded within a rapidly growing medical school, co-located within the largest teaching hospital in Malawi with direct access to urban and rural populations. In the next 5 years, MLW research will increase fundamental understanding of disease mechanisms and burden, test novel interventions and ensure translation into health care. The cor e programme will ensure MLW delivers the following aims: (1) Pursuit of cutting-edge research focused on health problems with a high disease burden. Research management, mentorship, development of bioinformatics expertise, and clinical and diagnostic laboratory competencies, ensuring the highest quality. (2) Provision of a research training environment for clinicians, epidemiologists and laboratory scientists. Local research infrastructure, operational and financial systems, data manageme nt and research governance support. (3) Development of globally competitive research leaders. Moving towards local leadership, embedded within the University of Malawi College of Medicine, attracting further intermediate and senior Fellows, and encouraging re-entry of trained Malawian scientists. (4) Translation of scientific advances into human health improvements. Defining national and international research agendas through policy relevant evidence; policy committee membership; research synthesis workshops; and public engagement.

Amount: £861,683
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

INTRAHOST DYNAMICS IN TREATED AND UNTREATED MALARIA PATIENTS. 26 Feb 2013

Plasmodium falciparum malaria infections in sub-Saharan Africa often consist of mixtures of different parasite genotypes. While current methods for genotyping infections can distinguish whether or not multiple parasite genotypes are present, they fail to resolve haplotypes present. This limits our ability to understand multiple-haplotype infections (MIs) which are thought to play key roles in disease severity, drug resistance evolution and malaria transmission. I aim to develop a Fluorescence Ac tivated Cell Sorting (FACS) method to examine the genetic composition of MIs from an area of intense malaria transmission in Malawi. I will isolate component clones of MIs using FACS or limiting dilution cloning and genotype these at 384 genome-wide polymorphic SNPs to determine the number and relatedness of parasite haplotypes within MIs. These data will be used to assess the relationship between within-host parasite genetic diversity and malaria severity, and to understand how malaria superinf ection is regulated in high transmission regions. I also propose to examine the impact of MIs on our ability to detect emerging drug-resistant malaria in the field, and to evaluate the suitability of an in vitro assay for measuring parasite susceptibility to artemisinin, a key antimalarial drug in sub-Saharan Africa.

Amount: £450,000
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Spatial and temporal distribution of the N1575Y allele and his impact on the malaria vector control activities. 26 Feb 2013

The primary goal of the proposed project is to understand the driving forces selecting for an emerging insecticide resistance mutation in the malaria mosquito, Anopheles gambiae. Pyrethroid resistance threatens to compromise the gains made in reducing malaria from large-scale distribution of long-lasting insecticide treated nets (LLINs) and indoor residual spraying (IRS) [8]. The pyrethroid resistance mutations, commonly referred to as knockdown resistance or kdr (L1014F/L1014S) are extending th eir range, and in the case of L1014F, approach fixation over much of West Africa. A secondary mutation, N1575Y, was recently detected at low but rising frequencies in Burkina Faso suggesting an ongoing selective sweep [5]. The resistant haplotype provided added benefit to mosquitoes exposed to pyrethroids/DDT (odds ratios = 1.93 2.60). The discovery of a new resistance mechanism while at a relatively low frequency is a unique opportunity to address some of the key questions in our understanding of resistance management strategies while providing important information for vector control operations within the local setting. The project will tackle these questions by estimating the selection of N1575Y over the past 20 years; investigating potential sources of selection pressures and exploring the fitness costs associated with kdr haplotypes.

Amount: £111,220
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Dissecting the role of insecticide resistance in the spread of vector-borne disease 08 Apr 2016

Insecticide resistance is the greatest challenge to vector-borne disease control. The vector population that persists following insecticide-based interventions will be adapted to mitigate the effects of insecticide. Mechanisms of insecticide resistance, which may include increased detoxification or target site insensitivity, will impact vector behaviour and physiology in ways that aren’t fully understood. Resistance mechanisms may lead to either increased or decreased capacity through changes in fitness, immunity and behaviour. Research into the full spectrum of pleiotropic effects is needed to inform the use of limited insecticide-based tools while ensuring transmission risk is minimised. This proposal aims to develop multiple strains of insecticide resistant Aedes aegypti which will differ in their dominant resistance mechanism. A multi-resistant strain from Recife will be differentially exposed to a combination of insecticides and synergists to select for one of three naturally occurring metabolic resistance mechanisms. A strain from Cayman with 80% knockdown resistant allele frequency will also be used. Transcriptional profiles will be evaluated during the course of insecticide selection and resistance reversal to determine changes in the expression of resistance, detoxification, immunity and development genes. The validated set of strains will enable experimental work on vectorial capacity of resistant mosquitoes for multiple vector-borne diseases.

Amount: £96,557
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Investigating the mechanisms for persistence of HIV in human alveolar macrophages. 24 Nov 2014

The host antiviral immune response is relatively effective at recognising and eliminating most HIV-infected cells. However, HIV manipulates resting memory CD4 T cells and persistently resides in them in a latent state, resulting in formation of viral reservoirs. These reservoirs are poorly recognised by antiviral cytotoxic cells and are less susceptible to the effects of the current antiretroviral therapy (ART), leading to incomplete clearance of the infection. In the lung, alveolar macrophages (AM) have a long life span, can harbour HIV and are relatively resistant to the cytopathic effects of HIV, making them an important potential viral reservoir. Recently, we have shown that HIV persists in AM in HIV-infected individuals on long term ART despite undetectable plasma viraemia. This fellowship proposes using bronchoalveolar lavage (BAL) and peripheral blood obtained from HIV-infected and uninfected Malawian adults to address the hypothesis that HIVs ability to hinder immune recognitio n and block the induction of apoptosis leads to its persistence in AM. Specifically, the following questions will be addressed a) How does HIV hinder immune recognition of HIV-infected AM by cytotoxic cells? b) How does HIV block progression to apoptosis in HIV-infected AM? c) Which viral proteins are responsible for modulation of macrophages?

Amount: £463,506
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine