Microbial translocation in HIV-infected children in Uganda

HIV disease is common in Africa, and over 1000 children a day acquire HIV from their mothers. Although there are good drugs to treat HIV, some children still do not make substantial improvements, and it is not clear why. One reason might be because of some of the ways that HIV damages the body. One theory is that HIV damages the immune defences in the gut, which allows bacteria or bits of bacteria which normally live harmlessly in the gut to leak through the gut wall into the blood. This is called "microbial translocation". It is thought to interfere with the body's immune defence system; it can lead to poor response to anti-HIV medicines, and can cause early deaths and other complications such as heart disease. Although several studies have been undertaken in adults, very little is known about this process in children, whether HIV-infected or -uninfected. Trials are underway looking at ways to modify this process, but all are in adults; none are in children.

Scientists have used different laboratory tests to find signs of bacteria in the bloodstream. However, these tests are complicated and vulnerable to contamination. This means that some of the results found are equally likely to have come from the environment around the samples as the samples themselves. Little work has identified the specific bacteria that pass into the bloodstream. In poorer settings such as Uganda, many children suffer from undernutrition and are also exposed to more germs on a daily basis, e.g. through water and poor sanitation. It is unknown if or how these factors play a role in microbial translocation. As children have the potential to live for much longer on anti-HIV medicines, it is important to work out if microbial translocation may have a damaging effect on their health long term, as there may be potential for simple interventions to prevent this damage.

I propose to use a comprehensive range of tests to identify whether microbial translocation occurs in HIV-infected children and HIV-uninfected children in Uganda, and assess the role nutrition plays over time. The samples used are remnants that have been obtained as part of a clinical study looking at different anti-HIV drug regimens in Uganda. The carers of the children have already given permission for the stored blood samples to be used for tests relating to HIV, as would be done in this study. The tests involve isolating both bits of the bacteria and also their genetic material in the bloodstream and then identifying the specific types of bacteria that are present. I will also look at the body's immune defence response to these bits of the bugs and markers of gut damage in the bloodstream. I will investigate the impact of nutrition on whether or not bacterial particles do cross into the blood from the gut. I will establish whether anti-HIV treatment reduces or stops this happening completely, and explore whether there are other interventions (e.g. drugs) that could be used in the future to stop this happening and improve the outlook for HIV-infected children.

It is widely accepted that HIV damages intestinal mucosal immunity, allowing microbial translocation. This causes increased circulating levels of immunostimulatory bacterial products. This immunostimulation in the presence of HIV infection causes immune activation, which is associated with poor therapeutic response, increased all-cause mortality and non-AIDS related morbidity. Trials are underway aiming to modify microbial translocation to improve outcome; but all are in adults, none are in children.

A method used to support this hypothesis is identification of bacterial DNA in the bloodstream of HIV-infected people using broad-range molecular techniques, which are vulnerable to artefact. Little work has been done to identify bacterial species present, and minimal work has been done in HIV-infected children. What role microbial translocation plays in African settings is unclear, and the interactions of malnutrition, HIV and microbial translocation are yet to be elucidated.

I propose to use broad-range and specific molecular techniques to identify the presence of translocated microbial DNA in Ugandan HIV-infected children. I will compare results before and after commencing ART and with Ugandan HIV-uninfected controls, along with longitudinal data on clinical, virological and immunological outcome, nutritional status and intestinal damage. The children will be recruited from an ongoing clinical trial based in Uganda and Zambia which has completed recruitment. Carers have already given consent for stored samples to be used in studies investigating HIV pathogenesis.

This study should provide definitive answers about the presence and nature of circulating microbial products, and insights into their causes and potential control in HIV-infected children. There is potential for future development of therapeutic interventions aiming to modify microbial translocation in children and so improve outcome depending on the data generated by this project.

The primary beneficiaries of this research are people infected with HIV, children in particular. As life expectancy for children living with HIV continues to increase in both high- and low-middle income settings, the question of co-morbidity and early mortality on treatment as a consequence of late presentation will become increasingly important problems. If my project shows that microbial translocation and resultant immune dysfunction does have an impact on HIV pathogenesis and increased morbidity and mortality within this patient group, the results will also indicate the types of therapeutic interventions that would have potential to improve outcomes. As yet definitive evidence of the importance and mechanism of microbial translocation in children is lacking and this project aims to address the data deficit. There is potential for the data generated to contribute to future policy decisions about funding research projects investigating interventions. Interventional trials could be instigated and completed over the next 5-10 years.
Furthermore, the investigation of microbial translocation in children not infected with HIV in Kampala will provide novel data that could feed into nutritional, public health and sanitation research- in this case other academic fields will form part of the critical pathway that could lead to impact on policy in terms of resource allocation towards food, water and hygiene provision for people in Kampala and possibly beyond. Thus not only the HIV-infected population could benefit but potentially those uninfected as well.
In more general terms, I will be learning about cutting edge molecular techniques and bioinformatics: both fascinating, complex and expanding fields. Within UCL the Public Engagement department organizes and facilitates various events which would give me the opportunity to explain these techniques and their uses (in the context of this project and more broadly) to a wider audience, both UCL members, the general public, and school children. For example, UCL organizes "bite-sized lunchtime lectures" wherein during the course of my fellowship I would be able to explain my work to a wide-ranging audience, hopefully both illuminating this complex area and potentially inspiring future researchers.