EDCTP portfolio: Career Development Fellowships

Dr Andrew Ekii Obuku aims to identify the most potent phenotypes of CD8 T cells for controlling HIV-1 infection.

Early immune responses with virological control in HIV-1 infection

Natural immune responses are able to control viral replication from peak viraemia to viral set point in acute HIV-1 infection. However, these natural immune responses have not been fully characterised. Immune correlates of protection from HIV acquisition and progression to AIDS are not known, neither are the phenotypes of cells needed to be induced by HIV vaccines to confer protection.

The challenge

Defining the precise correlates of the cellular immune response to HIV-1 that are associated with control of HIV-1 replication in acute infection, has been the focus of intense study over the past two decades. The identification of such correlates has been pursued as part of a rational strategy to produce an HIV-1 vaccine capable of best mimicking the cellular immune response associated with control of HIV-1 viraemia. Once defined, such correlates will also help establish the necessary benchmarks for candidate vaccine down selection and efficacy testing.

In this study, Dr Obuku will attempt to delineate the different T cell phenotypes (including lymph node resident memory T cells) and their ability to inhibit viral replication. He will characterise the CD8 T cell phenotypes, before peak viraemia, at peak viraemia, at set point and post set point from blood and lymph nodes. He will also investigate the cell death pathways associated with the death of CD8 T cells from peak viraemia to set point. Moreover, he will compare the ability of the different CD8 T cell phenotypes to inhibit HIV-1 replication in a viral inhibition assay and identify the most potent phenotypes of CD8 T cells at controlling HIV-1 infection.

The project

The results of this study will contribute to the body of research that aims to determine how HIV vaccines can induce the immune system to confer protection.

Impact


test the safety and efficacy of this new formulation in young children

Bringing antiretroviral drugs to children

The CHAPAS trials have ensured that many more children with HIV have benefited
from life-saving antiretrovirals.

EDCTP portfolio: HIV & HIV-associated infections

The challenge

Natural immune responses are able to control viral replication from peak viraemia to viral set point in acute HIV-1 infection. However, these natural immune responses have not been fully characterised. Immune correlates of protection from HIV acquisition and progression to AIDS are not known, neither are the phenotypes of cells needed to be induced by HIV vaccines to confer protection.

Defining the precise correlates of the cellular immune response to HIV-1 that are associated with control of HIV-1 replication in acute infection, has been the focus of intense study over the past two decades. The identification of such correlates has been pursued as part of a rational strategy to produce an HIV-1 vaccine capable of best mimicking the cellular immune response associated with control of HIV-1 viraemia. Once defined, such correlates will also help establish the necessary benchmarks for candidate vaccine down selection and efficacy testing.

In this study, Dr Obuku will attempt to delineate the different T cell phenotypes (including lymph node resident memory T cells) and their ability to inhibit viral replication. He will characterise the CD8 T cell phenotypes, before peak viraemia, at peak viraemia, at set point and post set point from blood and lymph nodes. He will also investigate the cell death pathways associated with the death of CD8 T cells from peak viraemia to set point. Moreover, he will compare the ability of the different CD8 T cell phenotypes to inhibit HIV-1 replication in a viral inhibition assay and identify the most potent phenotypes of CD8 T cells at controlling HIV-1 infection.

The project

The later CHAPAS-3 trial compared the efficacy and safety of three fixed-dose combinations including two without stavudine (found to have some long-term side effects in adults, leading to a recommendation that its use be discontinued in children). The trial the first of its kind in Africa studied nearly 500 children at four sites in two African countries.

The results of this study will contribute to the body of research that aims to determine how HIV vaccines can induce the immune system to confer protection.

ratios forfixed-dose combinations and on appropriatedosage according to weight. 

The CHAPAS-3 trial confirmed the effectiveness of fixed-dose combinations, providing further impetus to the rollout of antiretrovirals to children. Its evidence on abacavir informed the WHO recommendation of abacavir-containing combinations for first-line therapy in children. Trial data have also been used to support applications for regulatory approval for new scored efavirenz tablets.

Impact

L’homme RF et al. Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets. AIDS. 2008;22(5):557–65.

Mulenga V et al. Abacavir, zidovudine, or stavudine as paediatric tablets for African HIVinfected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial. Lancet Infect Dis. 2016;16(2):169–79.

WHO. Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. 2010.

WHO. Consolidated guidelines on the use of antiretroviral drugs
for treating and preventing

HIV infection: Recommendations for a public health approach
(second edition). 2016

Projects: Children with HIV in Africa Pharmacokinetics and Adherence of Simple Antiretroviral Regimens (CHAPAS): CHAPAS-1 and -3

Project lead: Professor Chifumbe Chintu, University Teaching Hospital, Zambia (CHAPAS-1); Dr Veronica Mulenga, University Teaching Hospital, Zambia (CHAPAS-3)

Target population(s): Children with HIV

Sample size: 71 (CHAPAS-1); 480 (CHAPAS-3)

Countries involved: Ireland, the Netherlands, the UK, the USA, Zambia (CHAPAS-1); Uganda, Zambia (CHAPAS-3)

Project duration: 2005–2009 (CHAPAS-1); 2010 –2011 (CHAPAS-3)

EDCTP funding: €1.2M (CHAPAS-1); €4.6M (CHAPAS-3)

Total project funding: €1.2M (CHAPAS-1); €5.0M

About us

The European & Developing Countries Clinical Trials Partnership (EDCTP) is a public–public partnership between 14 European and 16 African countries, supported by the European Union. EDCTP’s vision is to reduce the individual, social and economic burden of poverty-related infectious diseases by affecting sub-Saharan Africa. EDCTP’s mission is to accelerate the development of new or improved medicinal products for the identification, treatment and prevention of infectious diseases, including emerging and re-emerging diseases, through pre- and postregistration clinical studies, with emphasis on phase II and III clinical trials. Our approach integrates conduct of research with development of African clinical research capacity and networking. The second EDCTP programme is implemented by the EDCTP Association supported under Horizon 2020, the European Union’s Framework Programme for Research and Innovation.

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