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Immunol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> In individuals living with HIV infection the development of tuberculosis (TB) is associated with rapid progression from asymptomatic TB infection to active TB disease. Sputum-based diagnostic tests for TB have low sensitivity in minimal and subclinical TB precluding early diagnosis. The immune response to novel <jats:italic>Mycobacterium tuberculosis in-vivo<\/jats:italic> expressed and latency associated antigens may help to measure the early stages of infection and disease progression and thereby improve early diagnosis of active TB disease.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Serial prospectively sampled cryopreserved lymphocytes from patients of the Swiss HIV Cohort Study developing TB disease (\u201ccases\u201d) and matched patients with no TB disease (\u201ccontrols\u201d) were stimulated with 10 novel <jats:italic>Mycobacterium tuberculosis<\/jats:italic> antigens. Cytokine concentrations were measured in cases and controls at four time points prior to diagnosis of TB: T1-T4 with T4 being the closest time point to diagnosis.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> 50 samples from nine cases and nine controls were included. Median CD4 cell count at T4 was 289\/ul for the TB-group and 456\/ul for the control group. Viral loads were suppressed in both groups. At T4 Rv2431c-induced and Rv3614\/15c-induced interferon gamma-induced protein (IP)-10 responses and Rv2031c-induced and Rv2346\/Rv2347c-induced tumor necrosis factor (TNF)-\u03b1 responses were significantly higher in cases compared to controls (<jats:italic>p<\/jats:italic> &amp;lt; 0.004). At T3 - being up to 2 years prior to TB diagnosis - Rv2031c-induced TNF-\u03b1 was significantly higher in cases compared to controls (<jats:italic>p<\/jats:italic> &amp;lt; 0.004). Area under the receiver operating characteristics (AUROC) curves resulted in an AUC &amp;gt; 0.92 for all four antigen-cytokine pairs.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> The <jats:italic>in vitro Mycobacterium tuberculosis<\/jats:italic>-specific immune response in HIV-infected individuals that progress toward developing TB disease is different from those in HIV-infected individuals that do not progress to developing TB. These differences precede the clinical diagnosis of active TB up to 2 years, paving the way for the development of immune based diagnostics to predict TB disease at an early stage.<\/jats:p>","DOI":"10.3389\/fimmu.2021.620622","type":"journal-article","created":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T04:42:05Z","timestamp":1615524125000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["HIV-Infected Patients Developing Tuberculosis Disease Show Early Changes in the Immune Response to Novel Mycobacterium tuberculosis Antigens"],"prefix":"10.3389","volume":"12","author":[{"given":"Noemi Rebecca","family":"Meier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Battegay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom H. 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