Several immune-based assays have been suggested to differentiate latent from active tuberculosis (TB). However, their relative performance as well as their efficacy in HIV-infected persons, a highly at-risk population, remains unclear. In a study of 81 individuals, divided into four groups based on their HIV-1 status and TB disease activity, we compared the differentiation (CD27 and KLRG1), activation (HLA-DR), homing potential (CCR4, CCR6, CXCR3, and CD161) and functional profiles (IFNγ, IL-2, and TNFα) of Mycobacterium tuberculosis (Mtb)-specific CD4+ T cells using flow cytometry. Active TB disease induced major changes within the Mtb-responding CD4+ T cell population, promoting memory maturation, elevated activation and increased inflammatory potential when compared to individuals with latent TB infection. Moreover, the functional profile of Mtb-specific CD4+ T cells appeared to be inherently related to their degree of differentiation. While these specific cell features were all capable of discriminating latent from active TB, irrespective of HIV status, HLA-DR expression showed the best performance for TB diagnosis [area-under-the-curve (AUC) = 0.92, 95% CI: 0.82–1.01, specificity: 82%, sensitivity: 84% for HIV− and AUC = 0.99, 95% CI: 0.98–1.01, specificity: 94%, sensitivity: 93% for HIV+]. In conclusion, these data support the idea that analysis of T cell phenotype can be diagnostically useful in TB.

The diabetes mellitus burden is growing in countries where tuberculosis (TB) and HIV-1 remain major challenges, threatening TB control efforts. This study determined the association between TB and diabetes/impaired glucose regulation in the context of HIV-1.A cross-sectional study was conducted at a TB clinic in Cape Town (South Africa). Participants were screened for diabetes and impaired glucose regulation using fasting plasma glucose, oral glucose tolerance test and glycated haemoglobin (HbA1c).414 TB and 438 non-TB participants were enrolled. In multivariable analysis, diabetes was associated with TB (OR 2.4, 95% CI 1.3–4.3; p=0.005), with 14% population-attributable risk fraction; however, this association varied by diagnostic test (driven by HbA1c). The association remained significant in HIV-1-infected individuals (OR 2.4, 95% CI 1.1–5.2; p=0.030). A high prevalence of impaired glucose regulation (65.2% among TB cases) and a significant association with TB (OR 2.3, 95% CI 1.6–3.3; p<0.001) was also found.Diabetes and impaired glucose regulation prevalence was high and associated with TB, particularly in HIV-1-infected individuals, highlighting the importance of diabetes screening. The variation in findings by diagnostic test highlights the need for better glycaemia markers to inform screening in the context of TB and HIV-1.

A major challenge for the development of an effective vaccine against tuberculosis (TB) is that the attributes of protective CD4+ T cell responses are still elusive for human TB. Infection with human immunodeficiency virus-1 (HIV-1) is a major risk factor for tuberculosis (TB), and a better understanding of HIV-induced alterations of Mycobacterium tuberculosis (Mtb)-specific CD4+ T cells that leads to failed host resistance may provide insight into protective T cell immunity to TB. Eighty-six participants from a TB-endemic setting, either HIV-infected or -uninfected and with latent or active TB, were screened using Mtb-specific MHC class II tetramers. We examined the phenotype as well as function of ex vivo Mtb-specific tetramer+CD4+ T cells using flow cytometry. The numbers of Mtb-specific tetramer+CD4+ T cells were relatively well maintained in HIV-infected persons with active TB, despite severe immunodeficiency. However, while HIV-uninfected persons with latent TB infection exhibited ex vivo Mtb-specific CD4+ T cells predominantly of a CXCR3+CCR6+CCR4- (Th1*) phenotype; active TB or HIV infection was associated with a contraction of this subset. Nevertheless, in individuals with active TB and/or HIV infection, circulating ex vivo Mtb-specific CD4+ T cells did not display defects in exhaustion or polyfunctionality compared to healthy HIV-uninfected individuals with latent TB infection. Collectively, these data suggest that increased susceptibility to TB disease could be related to a loss of circulating Th1* CD4+ T cells rather than major changes in the number or function of circulating CD4+ T cells.