Publications

Funding for clinical research |drugs, vaccines, microbicides, diagnostics | HIV/AIDS, tuberculosis, malaria, other infectious diseases |sub-Saharan Africa

EDCTP portfolio: Career Development Fellowships

Dr Elouise Kroon studies innate immune response to TB infection and the exact cells involved in HIV-infected persons.

Resistance to Mycobacterum tuberculosis infection in HIV patients

Mycobacterium tuberculosis is a pathogen spread via the inhalation of airborne droplets containing the bacteria from an infected individual. However, some individuals, despite persistent and heavy exposure to M. tuberculosis do not become infected and are so-called resisters.

The existence of resistance to infection in tuberculosis (TB) pathogenesis is supported by multiple lines of evidence and is also observed in HIV-infected persons. HIV infection predisposes to TB. However, some HIV-infected persons do not become infected with M. tuberculosis and have no history of previous or current TB, despite low CD4 counts and living in environments with high TB incidence.

The contribution of the innate immune system and the exact cells involved in innate immune resistance to infection are not yet completely clear.

The challenge

Neutrophils are some of the first phagocytes recruited from the pulmonary vasculature to the pulmonary interstitium to control infection and are prominent candidates for possible involvement as primers for microbial clearance. Dr Kroon hypothesises that resistance of HIV-infected individuals to M. tuberculosis is due to neutrophils acting as effector cells. In that case, significant transcriptional differences and effector functions will exist in the neutrophil response between hosts who do not develop immune sensitisation to M. tuberculosis – as evidenced by IGRA/TST or innate resisters – and those who develop immune sensitisation, or infection susceptible (individuals).

For this study, Dr Kroon will use samples previously collected from a total of 60 HIV-infected persons screened and enrolled in the NIH-funded ResisTB study in Cape Town, South Africa. The samples are subdivided into 4 groups based on IGRA/TST results (positive/negative) and age category (18- 25 years, 35-60 years). Age is used as a surrogate for exposure intensity in an area of high M. tuberculosis transmission.

The objectives of the study are to compare neutrophil numbers, phenotype and activation markers between the specified study groups. Secondly, genomic total RNA will be extracted from the M. tuberculosis-infected and -uninfected neutrophils at different time points and characterised for the difference in transcriptional responses using RNA sequencing. Finally, differences in effector mechanisms of neutrophils, such as NETosis, will be investigated for the study groups using microscopy.

The project

By gaining a better understanding of the resister phenotype and the potential role of neutrophils in M. tuberculosis infection resistance, the study may reveal clinically important activities for prevention and treatment development.

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

Mycobacterium tuberculosis is a pathogen spread via the inhalation of airborne droplets containing the bacteria from an infected individual. However, some individuals, despite persistent and heavy exposure to M. tuberculosis do not become infected and are so-called resisters.

The existence of resistance to infection in tuberculosis (TB) pathogenesis is supported by multiple lines of evidence and is also observed in HIV-infected persons. HIV infection predisposes to TB. However, some HIV-infected persons do not become infected with M. tuberculosis and have no history of previous or current TB, despite low CD4 counts and living in environments with high TB incidence.

The contribution of the innate immune system and the exact cells involved in innate immune resistance to infection are not yet completely clear.

Neutrophils are some of the first phagocytes recruited from the pulmonary vasculature to the pulmonary interstitium to control infection and are prominent candidates for possible involvement as primers for microbial clearance. Dr Kroon hypothesises that resistance of HIV-infected individuals to M. tuberculosis is due to neutrophils acting as effector cells. In that case, significant transcriptional differences and effector functions will exist in the neutrophil response between hosts who do not develop immune sensitisation to M. tuberculosis – as evidenced by IGRA/TST or innate resisters – and those who develop immune sensitisation, or infection susceptible (individuals).

For this study, Dr Kroon will use samples previously collected from a total of 60 HIV-infected persons screened and enrolled in the NIH-funded ResisTB study in Cape Town, South Africa. The samples are subdivided into 4 groups based on IGRA/TST results (positive/negative) and age category (18- 25 years, 35-60 years). Age is used as a surrogate for exposure intensity in an area of high M. tuberculosis transmission.

The objectives of the study are to compare neutrophil numbers, phenotype and activation markers between the specified study groups. Secondly, genomic total RNA will be extracted from the M. tuberculosis-infected and -uninfected neutrophils at different time points and characterised for the difference in transcriptional responses using RNA sequencing. Finally, differences in effector mechanisms of neutrophils, such as NETosis, will be investigated for the study groups using microscopy.

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.

By gaining a better understanding of the resister phenotype and the potential role of neutrophils in M. tuberculosis infection resistance, the study may reveal clinically important activities for prevention and treatment development.

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