Abstract
Tuberculosis (TB) remains the most frequent cause of illness and death from an infectious agent, and its interaction with HIV has devastating effects. We determined plasma levels of dehydroepiandrosterone (DHEA), its circulating form DHEA-suphate (DHEA-s) and cortisol in different stages of M. tuberculosis infection, and explored their role on the Th1 and Treg populations during different scenarios of HIV-TB coinfection, including the immune reconstitution inflammatory syndrome (IRIS), a condition related to antiretroviral treatment. DHEA levels were diminished in HIV-TB and HIV-TB IRIS patients compared to healthy donors (HD), HIV+ individuals and HIV+ individuals with latent TB (HIV-LTB), whereas dehydroepiandrosterone sulfate (DHEA-s) levels were markedly diminished in HIV-TB IRIS individuals. HIV-TB and IRIS patients presented a cortisol/DHEA ratio significantly higher than HIV+, HIV-LTB and HD individuals. A positive correlation was observed between DHEA-s and CD4 count among HIV-TB individuals. Conversely, cortisol plasma level inversely correlated with CD4 count within HIV-TB individuals. M. tuberculosis-specific Th1 lymphocyte count was increased after culturing PBMC from HIV-TB individuals in presence of DHEA. We observed an inverse correlation between DHEA-s plasma level and Treg frequency in co-infected individuals, and CD4+FoxP3+ Treg frequency was increased in HIV-TB and IRIS patients compared to other groups. Strikingly, we observed a prominent CD4+CD25-FoxP3+ population across HIV-TB and HIV-TB IRIS patients, which frequency correlated with DHEA plasma level. Finally, DHEA treatment negatively regulated FoxP3 expression without altering Treg frequency in co-infected patients. These data suggest an enhancing role for DHEA in the immune response against M. tuberculosis during HIV-TB coinfection and IRIS.
Highlights
Tuberculosis continues to be the most successful pathogen around the world, and its interaction with HIV fuels both epidemics [1]
In order to determine an association of DHEA, dehydroepiandrosterone sulfate (DHEA-s) and cortisol levels with HIV-TB, immune reconstitution inflammatory syndrome (IRIS), HIV+ or HIV+ individuals with latent TB (HIV-LTB) conditions, we initially assessed adrenal hormone levels in plasma from patients and healthy donors (HD)
We observed a profound decrease in DHEA levels in TB patients, in parallel to an increase in cortisol [25], We observed that DHEA plasma levels were significantly diminished in HIV-TB and IRIS patients compared to HD, HIV-LTB and HIV+ individuals (p,0.05), whereas DHEA-s levels were markedly diminished in HIV-TB with IRIS individuals (p,0.01 compared to HD, Fig. 1A y 1B)
Summary
Tuberculosis continues to be the most successful pathogen around the world, and its interaction with HIV fuels both epidemics [1]. The great majority of TB cases result from reactivation of old lesions, likely due to the presence of predisposing factors such as malnutrition, steroid therapy or concomitant diseases, i.e., diabetes, leukaemia or HIV infection [3,4]. The introduction of the highly active antiretroviral therapy (HAART) to treat HIV infection resulted in the restoration of the immune system an improvement of immunity against HIV and other pathogens [5]. In some HIV-infected patients the restoration of pathogen-specific immune responses during the initial months of highly active antiretroviral treatment (HAART) could elicit immunopathological inflammatory responses, leading to the development of immune reconstitution inflammatory syndrome (IRIS). As occurs in most infectious diseases, clinical manifestations of TB and IRIS is the result of a complex series of interactions between pathogens and immune response [6]
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