Complement pathway gene activation and rising circulating immune complexes characterize early disease in HIV-associated tuberculosis

Analysis of transcriptional differences between HIV infected persons with evidence of latent tuberculosis (TB) infection by Quantiferon Gold-in-tube, with and without evidence of subclinical TB disease on FDG-PET/CT scan. Tuberculosis is classically divided into two clinical states: latent infection and active disease. One-quarter of the global population is considered latently infected but diagnostic tests poorly predict the small proportion that will progress to disease. We recruited 35 asymptomatic, HIV-1 infected adults with latent TB by current diagnostic criteria, who underwent [18F]-fluoro-2-deoxy-D-glucose positron emission/computed tomography; ten had pulmonary abnormalities consistent with subclinical disease and were significantly more likely to progress. As positive control, we recruited 15 HIV-1 infected adults with symptomatic microbiologically confirmed active pulmonary TB, age, sex and CD4 matched to the 35 participants undergoing FDG-PET/CT. By whole-blood transcriptomic profiling we characterised 82-transcripts distinguishing those with subclinical pathology from those without. Transcripts representing the classical complement pathway were overabundant in both subclinical and active TB. We have demonstrated that latent TB is not a homogenous condition and defined a distinct high-risk subgroup with evidence of subclinical disease. These findings point the way to the future development of more predictive diagnostic tests. Total RNA extracted from whole blood of 35 HIV infected participants with evidence of latent TB (10 with subclinical pathology on PET/CT and 25 without) and 15 HIV infected participants with active TB