AUTHOR=Meier Noemi Rebecca , Battegay Manuel , Ottenhoff Tom H. M. , Furrer Hansjakob , Nemeth Johannes , Ritz Nicole 

TITLE=HIV-Infected Patients Developing Tuberculosis Disease Show Early Changes in the Immune Response to Novel Mycobacterium tuberculosis Antigens

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.620622

DOI=10.3389/fimmu.2021.620622

ISSN=1664-3224

ABSTRACT=<p><bold>Background:</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 <italic>Mycobacterium tuberculosis in-vivo</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.</p><p><bold>Methods:</bold> Serial prospectively sampled cryopreserved lymphocytes from patients of the Swiss HIV Cohort Study developing TB disease (“cases”) and matched patients with no TB disease (“controls”) were stimulated with 10 novel <italic>Mycobacterium tuberculosis</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.</p><p><bold>Results:</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)-α responses were significantly higher in cases compared to controls (<italic>p</italic> &lt; 0.004). At T3 - being up to 2 years prior to TB diagnosis - Rv2031c-induced TNF-α was significantly higher in cases compared to controls (<italic>p</italic> &lt; 0.004). Area under the receiver operating characteristics (AUROC) curves resulted in an AUC &gt; 0.92 for all four antigen-cytokine pairs.</p><p><bold>Conclusion:</bold> The <italic>in vitro Mycobacterium tuberculosis</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.</p>