The Causes and Consequences of Residual Immune Activation in HIV-infected Children on ART in Resource-Limited Settings
Lead Research Organisation:
University College London
Department Name: Institute of Child Health
Abstract
Most HIV research is done in rich countries, yet most HIV-infected children live in poor countries where other infections such as tuberculosis are common and many are malnourished. Children start HIV drugs later in poor countries due to issues around HIV diagnosis and treatment access. Therefore most of the evidence doctors have treating children with HIV comes from very different places to those where most infected children live.
These differences are particularly important because HIV is a virus which attacks the immune system that protects us from infections. HIV sends the immune system into overdrive - generalised uncontrolled activation - compared to the usual highly regulated way in which it responds to bugs. However, in poor countries, there are many bugs other than HIV that children are exposed to. Generalised undernutrition is also important because HIV damages the gut, allowing normally ?benign? bugs to pass into the bloodstream and over-stimulate the immune system.
Anti-HIV drugs suppress levels of HIV in the blood and so reduce activation - but they don t directly affect these other pathways. The first part of our project will work out the relative contribution of these other pathways to how children respond to anti-HIV drugs over the long-term. This will allow us to find other interventions which could improve outcomes on treatment, such as specific other drugs to attack important bugs or nutritional interventions.
Preliminary data from our team suggests that while activation reduces on HIV drugs, it remains higher than in uninfected children. The second part of our project will identify the causes for persistent activation on anti-HIV drugs, and will investigate its consequences, particularly interactions with loss of suppression of HIV in the blood. This is important because children will be on anti-HIV drugs for life and the success of enabling the immune system to develop normally in childhood will have a very important impact on how well the immune system will work when children become adults.
We plan to answer these questions using stored samples (and clinical data) already being collected from 1207 infected children starting anti-HIV drugs and being followed for 3-5 years in a MRC/DFID-funded trial in Uganda/Zimbabwe. This proposal builds on previous successful collaborations between UK and African scientists - with ongoing and extensive engagement with community representatives. All of the laboratory work would be done in Uganda/Zimbabwe, with supervision and mentoring from the UK.
These differences are particularly important because HIV is a virus which attacks the immune system that protects us from infections. HIV sends the immune system into overdrive - generalised uncontrolled activation - compared to the usual highly regulated way in which it responds to bugs. However, in poor countries, there are many bugs other than HIV that children are exposed to. Generalised undernutrition is also important because HIV damages the gut, allowing normally ?benign? bugs to pass into the bloodstream and over-stimulate the immune system.
Anti-HIV drugs suppress levels of HIV in the blood and so reduce activation - but they don t directly affect these other pathways. The first part of our project will work out the relative contribution of these other pathways to how children respond to anti-HIV drugs over the long-term. This will allow us to find other interventions which could improve outcomes on treatment, such as specific other drugs to attack important bugs or nutritional interventions.
Preliminary data from our team suggests that while activation reduces on HIV drugs, it remains higher than in uninfected children. The second part of our project will identify the causes for persistent activation on anti-HIV drugs, and will investigate its consequences, particularly interactions with loss of suppression of HIV in the blood. This is important because children will be on anti-HIV drugs for life and the success of enabling the immune system to develop normally in childhood will have a very important impact on how well the immune system will work when children become adults.
We plan to answer these questions using stored samples (and clinical data) already being collected from 1207 infected children starting anti-HIV drugs and being followed for 3-5 years in a MRC/DFID-funded trial in Uganda/Zimbabwe. This proposal builds on previous successful collaborations between UK and African scientists - with ongoing and extensive engagement with community representatives. All of the laboratory work would be done in Uganda/Zimbabwe, with supervision and mentoring from the UK.
Technical Summary
Over 80% of HIV-infected children on antiretroviral therapy (ART) now live in resource-limited settings, where co-infections, enteropathy, undernutrition and profound immunodeficiency are all common at ART initiation. These factors are likely to contribute to the high early mortality seen in ART programmes, and may impact long-term outcomes.
The generalised immune activation that characterises untreated HIV infection is strongly associated with disease progression. Viral suppression to undetectable levels with ART can reduce immune activation, but residual activation often persists despite ART. This proposal will test the hypothesis that high levels of co-infections, HIV-induced damage to the gut leading to microbial translocation, and malnutrition, drive persistent immune activation in HIV-infected children initiating ART in resource-limited settings, leading to suboptimal CD4 recovery and increased morbidity/mortality, despite ART. Given recent expansion of treatment programmes, it is now critical to better understand the pathogenesis of HIV in the context of ART, in order to optimise management by providing a rationale for prevention and treatment of co-infections, management of undernutrition and timing of ART initiation. This is particularly important for HIV-infected children, who will need to receive lifelong ART, and whose immune system in adulthood will depend critically on the treatment interventions undertaken in childhood. Further, ART programmes currently provide standardised first- and second- line therapy only (there is no third-line) so rational use of adjunctive therapies to maximise benefits of available treatment is essential for these children.
We will utilise stored samples (and clinical data) being collected from 1207 HIV-infected children starting ART in a MRC/DFID-funded trial (ARROW) in Uganda/Zimbabwe to address these hypotheses. First, we will investigate the predictive value of baseline markers of generalised immune activation on clinical and immunological outcome after ART initiation. Second, we will identify the causes of residual immune activation on ART, which is seen in one-third of children in this current study after 48 weeks of ART. We will focus on the potentially remediable areas of ongoing microbial translocation and/or the immune response to highly prevalent co-infections (CMV, EBV, TB). Third, we will investigate the virological and immunological consequences of residual immune activation in this cohort and clarify whether ongoing immune activation is a consequence or driver of HIV virological failure.
This proposal builds on previous successful collaborations between UK and African scientists - with ongoing and extensive engagement of community representatives. All of the laboratory work would be done in Uganda/Zimbabwe, with supervision and mentoring from the UK.
The generalised immune activation that characterises untreated HIV infection is strongly associated with disease progression. Viral suppression to undetectable levels with ART can reduce immune activation, but residual activation often persists despite ART. This proposal will test the hypothesis that high levels of co-infections, HIV-induced damage to the gut leading to microbial translocation, and malnutrition, drive persistent immune activation in HIV-infected children initiating ART in resource-limited settings, leading to suboptimal CD4 recovery and increased morbidity/mortality, despite ART. Given recent expansion of treatment programmes, it is now critical to better understand the pathogenesis of HIV in the context of ART, in order to optimise management by providing a rationale for prevention and treatment of co-infections, management of undernutrition and timing of ART initiation. This is particularly important for HIV-infected children, who will need to receive lifelong ART, and whose immune system in adulthood will depend critically on the treatment interventions undertaken in childhood. Further, ART programmes currently provide standardised first- and second- line therapy only (there is no third-line) so rational use of adjunctive therapies to maximise benefits of available treatment is essential for these children.
We will utilise stored samples (and clinical data) being collected from 1207 HIV-infected children starting ART in a MRC/DFID-funded trial (ARROW) in Uganda/Zimbabwe to address these hypotheses. First, we will investigate the predictive value of baseline markers of generalised immune activation on clinical and immunological outcome after ART initiation. Second, we will identify the causes of residual immune activation on ART, which is seen in one-third of children in this current study after 48 weeks of ART. We will focus on the potentially remediable areas of ongoing microbial translocation and/or the immune response to highly prevalent co-infections (CMV, EBV, TB). Third, we will investigate the virological and immunological consequences of residual immune activation in this cohort and clarify whether ongoing immune activation is a consequence or driver of HIV virological failure.
This proposal builds on previous successful collaborations between UK and African scientists - with ongoing and extensive engagement of community representatives. All of the laboratory work would be done in Uganda/Zimbabwe, with supervision and mentoring from the UK.
