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Atazanavir Induced Senesence in Mice But Not Darunavir
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Clinical studies show that HIV-infected patients have on average a 10-year shorter life expectancy relative to those without infection (Lohse et al., 2007). That deficit shrinks to only 8-years with access to healthcare and timely initiation of ART (Marcus et al., 2016). Several factors in HIV patients might influence lifespan and susceptibility to chronic diseases. Low level viral replication, toxic side effects of ART medications and chronic immune activation have all been implicated as contributing factors (Pathai et al., 2014). The individual influence of ART on disease susceptibility has been difficult to parse out, given that these drugs are essential for HIV+ patients' long-term survival, and uninfected individuals have not taken ART drugs until the more recent introduction of pre-exposure prophylaxis.
Here, we show that the PI atazanavir, boosted with ritonavir (ATV/r), induces features of senescence which, surprisingly, are reversible upon removal of the drug.
When ATV/r was removed, mice regained physiological heart function, commensurate with a loss of senescence markers. Since these features are used to identify senescent cells in vivo, our results suggest that certain features of senescence may not be prognostic of cellular senescence as defined by irreversiblegrowth arrest. Biomedically
Antiretroviral protease inhibitors induce features of cellular senescence that are reversible upon drug removal
20 December 2022
Chisaka Kuehnemann1,2,3 | Jun-Wei B. Hughes1 | Pierre-Yves Desprez1,4 |
Simon Melov1 | Christopher D. Wiley1,3 | Judith Campisi1
Abstract
Antiretroviral drugs have dramatically improved the prognosis of HIV-infected patients, with strikingly reduced morbidity and mortality. However, long-term use can be associated with signs of premature aging. Highly active antiretroviral therapy generally comprises two nucleoside reverse transcriptase inhibitors (NRTIs), with one of three additional antiretroviral drug classes, including protease inhibitors (PIs).
One commonality between mitochondrial dysfunction (induced by NRTIs) and defects in lamin A (induced by PIs) is they can cause or accelerate cellular senescence, a state of essentially irreversible growth arrest, and the secretion of many bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP). We hypothesized that senescent cells increase following treatment with certain HIV therapies.
We compared the effects of two distinct HIV PIs: ritonavir-boosted atazanavir (ATV/r) and ritonavir-boosted darunavir (DRN/r), used in combination treatments for HIV infection.
Upon ATV/r, but not DRN/r, treatment, cells arrested growth, displayed multiple features of senescence, and expressed significantly upregulated levels of many SASP factors.
Furthermore, mice receiving sustained ATV/r treatment showed an increase in senescent cells and age-related decline in physiological function. However, removing treatment reversed the features of senescence observed in vivo and cell culture. Given how these features disappeared with drug removal, certain features of senescence may not be prognostic as defined by an irreversible growth arrest. Importantly, for patients that are treated or have been treated with ATV/r, our data suggest that switching to another PI that does not promote premature aging conditions (DRN/r) may improve the associated age-related complications.
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