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Screen, educate and treat: managing the challenge of TB
S1 HIV-1 infection of macrophages modulates host responses to Mycobacterium tuberculosis to contribute to immunopathogenesis and viral propagation
  1. G S Tomlinson1,
  2. P T G Elkington2,
  3. M Noursadeghi1
  1. 1University College London, London, UK
  2. 2Imperial College, London, UK

Abstract

Introduction and Objectives Human immunodeficiency virus (HIV)-1 infection increases the risk of active tuberculosis (TB) by 50-fold. The concurrent HIV and TB pandemics therefore represent a major threat to global health. We study the immunopathogenesis of co-infection with a focus on the role of macrophages. These are sentinel cells of the immune system that orchestrate innate and adaptive immune responses, and within the lung, in particular, can host both Mycobacterium tuberculosis (MTb) and productive HIV infection. We tested the hypothesis that HIV infection of macrophages modulates host responses to MTb, and contributes to the pathogenesis of co-infection.

Methods Innate immune responses to MTb were assessed in human macrophages with and without productive HIV-1 infection using genome-wide transcriptional profiling. Array data were validated by quantitative PCR of selected genes and Luminex analysis of cell culture supernatants. ELISA and ELIspot assays were used to assess the effects of co-infection on HIV replication and anti-mycobacterial T cell responses.

Results Major gene expression changes assessed by principle component analysis showed that HIV-infected macrophages exhibited attenuated primary transcriptional responses to MTb, but augmented responses at later time points. In keeping with this assessment, we found that MTb stimulation of macrophages induced early IL10 expression, which was attenuated in HIV co-infected cells, and associated with sustained increased expression of pro-inflammatory mediators at later time points. We confirmed the functional relationship between the IL10 response and consequent homeostatic control of inflammatory responses, by complementing deficient IL10 responses in HIV-infected cells to reverse the pro-inflammatory phenotype. We established that exaggerated inflammatory responses in HIV-infected cells were sustained at 72 h, and likely to affect both HIV replication and consequent anti-mycobacterial immune responses. We show that sustained inflammatory responses to MTb are associated with increased HIV replication and have the capacity to alter T cell responses by increasing Th17 polarisation.

Conclusion HIV-1 infection of macrophages attenuates IL10 responses to MTb, and leads to sustained pro-inflammatory responses that support viral propagation and immunopathogenesis of TB.

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