Abstract
BackgroundTuberculosis (TB) is the major cause of death in Human Immunodeficiency Virus (HIV)-infected individuals. However, diagnosis of TB in HIV remains challenging particularly when HIV infection is advanced. Several gene signatures and serum protein biomarkers have been identified that distinguish active TB from latent infection. Our study was designed to assess if gene expression signatures and cytokine levels would distinguish active TB in advanced HIV.MethodsWe conducted a case-control study of whole blood RNA-Seq and plasma cytokine/chemokine analysis in HIV-infected with CD4+ T cell count of ≤ 100 cells/μl, with and without active TB. Next, the overlap of the differentially expressed genes (DEG) with the published signatures was performed and then receiver operator characteristic (ROC) analysis was done on small gene discriminators to determine their performance in distinguishing TB in advanced HIV. ELISA was performed on plasma to evaluate cytokine and chemokine levels.ResultsHierarchical clustering of the transcriptional profiles showed that, in general, HIV-infected individuals with TB (TB-HIV) clustered separately from those without TB. IPA indicated that the TB-HIV signature was characterized by an increase in inflammatory signaling pathways. Analysis of overlaps between DEG in our data set with published TB signatures revealed that significant overlap was seen with one TB signature and one TB-IRIS signature. ROC analysis revealed that transcript levels of FcGR1A (AUC = 0.85) and BATF2 (AUC = 0.82), previously reported as consistent single gene classifiers of active TB irrespective of HIV status, performed successfully even in advanced HIV. Plasma protein levels of IFNγ, a stimulator of FcGR1A and BATF2, and CXCL10, also up-regulated by IFNγ, accurately classified active TB (AUC = 0.98 and 0.91, respectively) in advanced HIV. Neither of these genes nor proteins distinguished between TB and TB-IRIS.ConclusionsGene expression of FcGR1A and BATF2, and plasma protein levels of IFNγ and CXCL10 have the potential to independently detect TB in advanced HIV. However, since other lung diseases were not included in this study, these final candidates need to be validated as specific to TB in the advanced HIV population with TB.
Highlights
Tuberculosis (TB) is the major cause of death in Human Immunodeficiency Virus (HIV)-infected individuals
This study found that FcGR1A was the most reliable classifier of active TB and its expression was not confounded by HIV status or ethnic background
Participant demographics and baseline characteristics Sixteen HIV-infected participants with smear (+) or microbiologically confirmed TB (TB-HIV), 15 HIVinfected participants (HIV) that had no clinical symptoms of TB and 2 TB-HIV participants undergoing treatment with anti-retroviral therapy (ART) were studied
Summary
Tuberculosis (TB) is the major cause of death in Human Immunodeficiency Virus (HIV)-infected individuals. Diagnosis of TB in HIV remains challenging when HIV infection is advanced. Our study was designed to assess if gene expression signatures and cytokine levels would distinguish active TB in advanced HIV. The transition from latent TB infection (LTBI) to active disease in HIVinfected depends on host immunity and on the level of immunosuppression [4, 5]. In a high prevalence setting, 8.5% of asymptomatic, HIV-infected persons had positive sputum cultures for Mycobacterium tuberculosis (Mtb) [11]. Even when sputum culture is used to exclude active TB, asymptomatic cases may be misclassified in the immunosuppressed where disseminated disease may predominate [12]. New approaches to the diagnosis of TB in this group are imperative
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