Immune Network Analysis Reveals Interleukin-17A Related Responses As Key Contributors to HIV-1 Associated Tuberculosis

Abstract

Background: Human immunodeficiency virus type 1 (HIV-1) mediated dysregulation of the immune response to TB and its effect on the response to antitubercular treatment (ATT) is incompletely understood. We performed in-depth analysis of the inflammatory profile of HIV-1-uninfected and co-infected TB patients undergoing ATT, with sub-analysis of the effect of antiretroviral therapy and HIV-1 viraemia in the latter group. Methods: A panel of 39 cytokines, acute phase proteins and soluble receptors were measured in plasma of a cohort of patients with pulmonary TB undergoing ATT in South Africa. We applied basic and advanced statistical analysis, including network and multivariate analysis, to investigate the dynamic inflammatory profile of TB patients during ATT. Findings: HIV-1 status markedly influenced the inflammatory profile regardless of ATT duration, with HIV-1 viral load driving differential inflammatory marker expression and correlation profiles observed in the HIV-1 co-infected group. Unexpectedly, IL-17A emerged as a key correlate of HIV-1 induced inflammation during HIV-TB co-infection. We validated these findings in a second cohort of hospitalized HIV-TB co-infected patients where the number of statistically significant correlations with this cytokine in network analysis predicted mortality. Interpretation: Our findings demonstrate the effect of HIV-1 co-infection on the complexity of plasma inflammatory profiles in TB patients. Through network analysis we identified IL-17A as an important node in HIV-TB co-infection, thus implicating this cytokine’s capacity to correlate with, and regulate, other inflammatory markers. Funding Statement: National Institutes of Health The Wellcome Trust UK Research and Innovation Cancer Research UK European and Developing Countries Clinical Trials Partnership South African Medical Research Council Declaration of Interest: The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ethical Approval Statement: The University of Cape Town (UCT) Faculty of Health Sciences Human Research Ethics Committee (HREC) approved the study (568/2012) and written informed consent was obtained from all study participants. The validation cohort involved hospitalized HIV-TB co-infected patients (UCT HREC 057/2013) who also provided written informed consent when possible. Hospitalized patients who were eligible for study participation but could not immediately provide informed consent due to decreased level of consciousness were enrolled and followed up daily until they regained the capacity to participate in the informed consent process. UCT HREC approved the per-protocol use of samples and information from those who died before providing informed consent, or who could not provide consent by the end of study follow-up. HIV-1 infected healthy controls with no evidence of active TB were also enrolled (UCT HREC 057/2013) and provided written informed consent.