PMID- 26986567 OWN - NLM STAT- MEDLINE DCOM- 20160826 LR - 20210109 IS - 1553-7374 (Electronic) IS - 1553-7366 (Print) IS - 1553-7366 (Linking) VI - 12 IP - 3 DP - 2016 Mar TI - In Vivo Molecular Dissection of the Effects of HIV-1 in Active Tuberculosis. PG - e1005469 LID - 10.1371/journal.ppat.1005469 [doi] LID - e1005469 AB - Increased risk of tuberculosis (TB) associated with HIV-1 infection is primarily attributed to deficient T helper (Th)1 immune responses, but most people with active TB have robust Th1 responses, indicating that these are not sufficient to protect against disease. Recent findings suggest that favourable outcomes following Mycobacterium tuberculosis infection arise from finely balanced inflammatory and regulatory pathways, achieving pathogen control without immunopathology. We hypothesised that HIV-1 and antiretroviral therapy (ART) exert widespread changes to cell mediated immunity, which may compromise the optimal host protective response to TB and provide novel insights into the correlates of immune protection and pathogenesis. We sought to define these effects in patients with active TB by transcriptional profiling of tuberculin skin tests (TST) to make comprehensive molecular level assessments of in vivo human immune responses at the site of a standardised mycobacterial challenge. We showed that the TST transcriptome accurately reflects the molecular pathology at the site of human pulmonary TB, and used this approach to investigate immune dysregulation in HIV-1/TB co-infected patients with distinct clinical phenotypes associated with TST reactivity or anergy and unmasking TB immune reconstitution inflammatory syndrome (IRIS) after initiation of ART. HIV-1 infected patients with positive TSTs exhibited preserved Th1 responses but deficient immunoregulatory IL10-inducible responses. Those with clinically negative TSTs revealed profound anergy of innate as well as adaptive immune responses, except for preservation of type 1 interferon activity, implicated in impaired anti-mycobacterial immunity. Patients with unmasking TB IRIS showed recovery of Th1 immunity to normal levels, but exaggerated Th2-associated responses specifically. These mechanisms of immune dysregulation were localised to the tissue microenvironment and not evident in peripheral blood. TST molecular profiling categorised different mechanisms of immunological dysfunction in HIV-1 infection beyond the effects on CD4 T cells, each associated with increased risk of TB disease and amenable to host-directed therapies. FAU - Bell, Lucy C K AU - Bell LC AD - Division of Infection and Immunity, University College London, London, United Kingdom. FAU - Pollara, Gabriele AU - Pollara G AD - Division of Infection and Immunity, University College London, London, United Kingdom. FAU - Pascoe, Mellissa AU - Pascoe M AD - Lung Infection and Immunity Unit, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa. FAU - Tomlinson, Gillian S AU - Tomlinson GS AD - Division of Infection and Immunity, University College London, London, United Kingdom. FAU - Lehloenya, Rannakoe J AU - Lehloenya RJ AD - Lung Infection and Immunity Unit, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa. FAU - Roe, Jennifer AU - Roe J AD - Division of Infection and Immunity, University College London, London, United Kingdom. FAU - Meldau, Richard AU - Meldau R AD - Lung Infection and Immunity Unit, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa. FAU - Miller, Robert F AU - Miller RF AD - Institute of Epidemiology and Healthcare, University College London, London, United Kingdom. FAU - Ramsay, Alan AU - Ramsay A AD - Cellular Pathology, University College Hospitals London, London, United Kingdom. FAU - Chain, Benjamin M AU - Chain BM AD - Division of Infection and Immunity, University College London, London, United Kingdom. FAU - Dheda, Keertan AU - Dheda K AD - Lung Infection and Immunity Unit, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa. FAU - Noursadeghi, Mahdad AU - Noursadeghi M AD - Division of Infection and Immunity, University College London, London, United Kingdom. LA - eng GR - WT_/Wellcome Trust/United Kingdom GR - MR/L001756/1/MRC_/Medical Research Council/United Kingdom GR - WT101766AIA/WT_/Wellcome Trust/United Kingdom GR - G0700569/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160317 PL - United States TA - PLoS Pathog JT - PLoS pathogens JID - 101238921 RN - 0 (IL10 protein, human) RN - 0 (Interferon Type I) RN - 130068-27-8 (Interleukin-10) SB - IM MH - Adult MH - Aged MH - CD4 Lymphocyte Count MH - CD4-Positive T-Lymphocytes/immunology MH - Computational Biology MH - Female MH - Gene Expression Profiling MH - HIV Infections/complications/*immunology/pathology MH - HIV Seropositivity MH - HIV-1/*immunology MH - Humans MH - Immune Reconstitution Inflammatory Syndrome/immunology MH - Interferon Type I/immunology MH - Interleukin-10/immunology MH - Male MH - Middle Aged MH - Mycobacterium tuberculosis/genetics/*immunology MH - Tuberculosis/complications/*immunology/pathology/virology MH - Tuberculosis, Pulmonary/complications/*immunology/pathology/virology MH - Young Adult PMC - PMC4795555 COIS- The authors have declared that no competing interests exist. EDAT- 2016/03/18 06:00 MHDA- 2016/08/27 06:00 PMCR- 2016/03/17 CRDT- 2016/03/18 06:00 PHST- 2015/10/12 00:00 [received] PHST- 2016/02/02 00:00 [accepted] PHST- 2016/03/18 06:00 [entrez] PHST- 2016/03/18 06:00 [pubmed] PHST- 2016/08/27 06:00 [medline] PHST- 2016/03/17 00:00 [pmc-release] AID - PPATHOGENS-D-15-02426 [pii] AID - 10.1371/journal.ppat.1005469 [doi] PST - epublish SO - PLoS Pathog. 2016 Mar 17;12(3):e1005469. doi: 10.1371/journal.ppat.1005469. eCollection 2016 Mar.