Bird’s Eye View on Mycobacterium tuberculosis–HIV Coinfection: Understanding the Molecular Synergism, Challenges, and New Approaches to Therapeutics

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is the most common secondary infection in the Human Immunodeficiency Virus (HIV) infected population, accounting for more than one-fourth of deaths in people living with HIV (PLWH). Reciprocally, HIV infection increases the susceptibility to primary TB or reactivation of latent TB by several folds. The synergistic interactions between M.tb and HIV not only potentiate their deleterious impact but also complicate the clinical management of both the diseases. M.tb-HIV coinfected patients have a high risk of failure of accurate diagnosis, treatment inefficiency for both TB and HIV, concurrent nontuberculous mycobacterial infections, other comorbidities such as diabetes mellitus, severe cytotoxicity due to drug overburden, and immune reconstitution inflammatory syndrome (IRIS). The need of the hour is to understand M.tb-HIV coinfection biology and their collective impact on the host immunocompetence and to think of out-of-the-box treatment perspectives, including host-directed therapy under the rising view of homeostatic medicines. This review aims to highlight the molecular players, both from the pathogens and host, that facilitate the synergistic interactions and host-associated proteins/enzymes regulating immunometabolism, underlining potential targets for designing and screening chemical inhibitors to reduce the burden of both pathogens concomitantly during M.tb-HIV coinfection. To appreciate the necessity of revisiting therapeutic approaches and research priorities, we provide a glimpse of anti-TB and antiretroviral drug-drug interactions, project the gaps in our understanding of coinfection biology, and also enlist some key research initiatives that will help us deal with the synergistic epidemic of M.tb-HIV coinfection.