Human immunodeficiency virus (HIV) targets the immune system, and infection has debilitating effects on the whole body if left untreated. However, antiviral therapies now significantly extend lifespan and improve symptoms for people living with HIV by preventing the virus from replicating. Nevertheless, low levels of the virus can persist in the bloodstream and immune cells, often leading to chronic inflammation and comorbidities such as chronic kidney disease. Improved therapies could enhance quality of life and further extend the lifespan of people with HIV.
Thornton, Sommer, Sharma and colleagues investigated the role of Notch signalling in HIV-associated inflammation and its impact on HIV-driven kidney pathologies. Notch signalling plays an important role in cell fate decisions and is essential for early kidney development, but must be switched off at later stages. The authors focused on Notch3, which is usually expressed in vascular smooth muscle cells and is activated in some parts of the kidney upon injury. They used a transgenic mouse model of HIV-1, which lacks some of the genes required for viral replication and therefore mimics some aspects of the human disease that are observed following antiviral treatment. These mice exhibit regions of high Notch3 expression in their kidneys, which reflect NOTCH3 expression patterns found in biopsies from HIV patients with kidney disease.
Genetic knockout of Notch3 in this mouse model significantly improved survival and kidney function, as well as reduced HIV-associated effects on other tissues, such as skin lesions. Notch3 depletion also reduced immune cell infiltration in the kidney and decreased the expression of inflammatory genes that had been activated in the HIV model mice. Additionally, the authors used promoter reporter assays to demonstrate that Notch3 directly activates the HIV gene promoter to induce HIV gene expression in cultured kidney cells. Conversely, HIV infection also increases Notch3 expression, providing evidence of a positive feedback loop.
These results reveal a dual role for Notch3 in HIV progression by promoting inflammation as well as activating HIV gene expression. The promising effects of depleting Notch3 on disease progression suggest that it could be an attractive drug target. Inhibiting NOTCH3, in combination with antiviral therapies, could prevent chronic kidney disease and other inflammation-associated comorbidities in people living with HIV.
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