Tuberculosis (TB) remains the leading cause of death among people living with HIV. Although HIV-1 and Mycobacterium tuberculosis (Mtb) coinfection remains a major public health concern, this problem is not well characterized. Even patients on effective antiretroviral therapy (ART) face a four- to seven-fold higher risk of TB than those without HIV. A new study now reveals why: HIV deploys one of its own proteins to sabotage the immune system’s cellular cleanup crew.
In a paper titled “HIV-1 Tat Favors the Multiplication of Mycobacterium tuberculosis and Toxoplasma by Inhibiting Clathrin-Mediated Endocytosis and Autophagy,” researchers from the French National Centre for Scientific Research (CNRS) and collaborating universities show that the virus’s trans-activator of transcription, or Tat, protein hinders a key defense pathway inside macrophages. Their findings were published in PLOS Pathogens.
“Tuberculosis remains the leading cause of death among people living with HIV (PLWH). We thus identified a mechanism enabling HIV Tat to favor the multiplication of intracellular pathogens such as Mtb,” the authors wrote.
How Tat tips the balance
Tat, the team explained, continues to circulate in nanomolar concentrations in the blood and cerebrospinal fluid of HIV-positive individuals even when ART has driven viral RNA to undetectable levels. Once inside uninfected macrophages, Tat binds a phosphoinositide called PI(4,5)P2 and becomes palmitoylated, anchoring it to the plasma membrane.
This seemingly small interaction has dramatic consequences. By occupying PI(4,5)P2, Tat prevents the recruitment of AP-2, a key adaptor protein needed for clathrin-mediated endocytosis. Because this process supplies membranes required for autophagy, Tat effectively shuts down the machinery that would normally engulf and destroy intracellular pathogens.
In cultured human macrophages, exposure to physiological levels of Tat increased M. tuberculosis growth and similarly boosted the intracellular replication of Toxoplasma gondii, a parasite. Zebrafish larvae injected with Tat were also more susceptible to infection by Mycobacterium marinum, a close relative of the TB bacterium.
“Tat inhibits autophagy at an early stage,” the authors noted.
Therapeutic implications
The discovery helps explain a long-standing puzzle: why people with well-controlled HIV remain several times more vulnerable to TB than the general population. “ART is a combination of inhibitors that most often target HIV-1 enzymes, i.e., reverse transcriptase, integrase, and protease. However, the production of regulatory HIV-1 proteins such as Nef and Tat is largely unaffected by ART. These HIV regulatory proteins may contribute to the increased susceptibility to TB observed in PLWH under ART compared to HIV-uninfected individuals,” wrote the authors.
Because ART does not block Tat secretion, perhaps strategies to boost or mimic autophagy could complement current HIV treatment and reduce TB incidence.
By unmasking Tat’s stealthy sabotage of cellular defenses, this study not only deepens understanding of HIV-TB coinfection but also highlights a potential therapeutic avenue. Drugs that reactivate autophagy—or prevent Tat from interfering with the recruitment of AP-2—could provide a new weapon against the world’s deadliest infectious duo.
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