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

Frontiers in Immunology, vol. 12, pp. 620622

Abstract

Background: 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 Mycobacterium tuberculosis in-vivo 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. Methods: 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 Mycobacterium tuberculosis 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. Results: 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 (p < 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 (p < 0.004). Area under the receiver operating characteristics (AUROC) curves resulted in an AUC > 0.92 for all four antigen-cytokine pairs. Conclusion: The in vitro Mycobacterium tuberculosis-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.

Authors 6

1. Noëmi Meier

   University of Basel · University Children’s Hospital Basel

   Affiliation as printed

   University of Basel Children's Hospital, Mycobacterial Research Laboratory, Basel, Switzerland

   University of Basel, Faculty of Medicine, Basel, Switzerland

2. Manuel Battegay

   University of Basel · University Hospital of Basel

   Affiliation as printed

   Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, University of Basel, Basel, Switzerland

   University of Basel, Faculty of Medicine, Basel, Switzerland

3. Tom H. M. Ottenhoff Aachen Department of Infectious Diseases

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center, Department of Infectious Diseases, Leiden, Netherlands

4. Hansjakob Furrer

   University of Bern · University Hospital of Bern

   Affiliation as printed

   Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland

5. Johannes Nemeth

   University of Zurich · University Hospital Zurich

   Affiliation as printed

   Division of Infectious Diseases, Zürich University Hospital, University of Zürich, Zurich, Switzerland

6. Nicole Ritz corresponding

   University of Basel · The University of Melbourne · Royal Children's Hospital · University Children’s Hospital Basel

   Affiliation as printed

   Royal Children's Hospital Melbourne, Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia

   University of Basel Children's Hospital, Mycobacterial Research Laboratory, Basel, Switzerland

   University of Basel Children's Hospital, Paediatric Infectious Diseases and Vaccinology Unit, Basel, Switzerland

   University of Basel, Faculty of Medicine, Basel, Switzerland