Characterising the immunometabolic profile of HIV/TB co-infection

Abstract

The synergy between the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) during co-infection of a host is well established. While this synergy is driven by immunological deterioration, the metabolic mechanisms that contribute to the associated disease burden experienced during HIV/TB co-infection remain poorly understood. Although antiretroviral therapy (ART) suppresses viral replication, these therapeutics give rise to metabolic disruptions and adaptations beyond that induced by infection. In this study, the serum cytokine and metabolic profiles of 9 untreated HIV/TB co-infected, 12 HIV/TB co-infected on ART, and 22 HIVnegative TB-positive patients, as well as 29 healthy controls, were measured and compared. A cytometric bead array kit was used for multiplexed cytokine measurements, and an untargeted two-dimensional gas chromatography time-of-flight mass spectrometry approach was used for metabolomics analyses. There was no significant difference between the cytokine levels of the diseased groups when compared to each other or the controls, however, the co-infected individuals were characterised by increased interleukin (IL)-6, and interferon-gamma (IFN-γ) when compared to the controls. The concomitant increase of cytokines typically classified as T helper cell type (Th) 1 or Th2, and as pro-inflammatory or immunoregulatory, suggests a failure of immunoregulation, resulting in an increased disease burden. Metabolites indicative of cachexia, damage of the intestinal mucosa and dysbiosis of the microbiome characterised co-infected individuals from the TB-positive population, while co-infected individuals were distinguished from healthy controls by similar alterations with the addition of more extensive amino acid changes. Loss of gut integrity and subsequent microbial translocation results in increased inflammation and immune/cytokine activation, culminating in a reduced appetite and malabsorption, which support the profile of exacerbated wasting in HIV/TB co-infected individuals. Treating HIV in the co-infected group revealed that some altered metabolites returned to values comparable to those of the healthy or the TB-positive population. However, it is unclear whether this represents a return to a more healthy state, as other metabolic alterations were exacerbated upon treatment. These results suggest that HIV augments the HIV-Mtb synergy, at least in part, through its detrimental effects on gut health, which in turn, affects energy availability.