Mycobacterium tuberculosis infection associated immune perturbations correlate with antiretroviral immunity

Abstract

AbstractInfection withMycobacterium tuberculosis(MTB) remains one of the most important opportunistic infections in people with HIV-1 (PWH). While it is well accepted that active Tuberculosis (TB) leads to rapid progression of immunodeficiency in PWH, the interaction between MTB and HIV-1 during the asymptomatic phase of both infections remains poorly understood.Here, we show in a well-matched cohort of PWH with suppressed HIV-1 viral load that MTB infection is associated with a baseline transcriptional profile away from a Type 1 Interferon towards a proinflammatory cytokine response. The transcriptional changes are conserved during HIV-1 viremia and are inversely correlated with HIV-1 viral load, suggesting that MTB infection-associated perturbations of the innate immune system improve HIV-1 control. In line with these findings, the transcriptional profile of individuals with MTB infection overlaps with that of HIV-1 long term non-progressors. Conversely, during active TB, the transcriptional pattern is reversed, indicating loss of immune control and suggesting a shared immunological mechanism of control and progression for both HIV-1 and MTB infection.In conclusion, our data show that MTB infection is associated with a shift in the activation state of the immune system. This shift contributes to lower HIV-1 viral load in MTB/HIV-1 co- infection and is lost during disease progression.Significance statementMycobacterium tuberculosis (MTB) affects 23% of the human population, but little is known about its impact on human biology. MTB infection is associated with better HIV-1 control and fewer opportunistic infections, but with an increased risk of non-communicable diseases such as diabetes. To understand why this is the case, we studied individuals co-infected with HIV-1 and MTB infection and found that MTB infection affects the innate immune system, improving the control of HIV-1 replication. Animal and BCG vaccination studies also support the idea that MTB affects the innate immune system and provides immunity against other diseases. Overall, this study advances our understanding of how MTB infection can have unexpected effects on host responses and sheds light on its complex nature.Highlights–In people with HIV-1 (PWH), MTB infection is associated with a perturbation of the PBMC transcriptome independently of re-exposure to MTB specific antigen.–MTB infection is associated with a shift away from Type 1 Interferon towards a trained immunity type phenotype.–The perturbations associated with MTB infection correlate with improved retroviral control and are lost during progression to active tuberculosis.