Antiretroviral protease inhibitors induce features of cellular senescence that are reversible upon drug removal

Authors: KUEHNEMANN, CHISAKA - Buck Institute For Age Research; HUGHES, JUN-WEI - Buck Institute For Age Research; DESPREZ, PIERRE-YVES - California Pacific Medical Center; MELOV, SIMON - Buck Institute For Age Research; WILEY, CHRISTOPHER - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; CAMPISI, JUDITH - Buck Institute For Age Research

Submitted to: Aging Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/7/2022
Publication Date: 12/22/2022
Citation: Kuehnemann, C., Hughes, J.B., Desprez, P., Melov, S., Wiley, C., Campisi, J. 2022. Antiretroviral protease inhibitors induce features of cellular senescence that are reversible upon drug removal. Aging Cell. https://doi.org/10.1111/acel.13750.
DOI: https://doi.org/10.1111/acel.13750

Interpretive Summary: Approximately 1 million Americans are currently living with human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS). Due to the actions of antiretroviral drugs, HIV levels are now kept low and patents can go decades without developing AIDS. However, even in the absence of AIDS, HIV positive patients now appear in the clinic with conditions that collectively resemble premature aging. One driver of aging is cellular senescence, a stress or damage response in which cells undergo a permanent growth arrest coupled to the secretion of several factors that drive degenerative disease. Here we show that the antiretroviral drug atazanavir (ATV) induces senescence in cultured cells. Surprisingly, removal of the drug resulted in reversal of senescence in both cultured cells and in ATV-treated mice. Mice showed signs of premature aging in response to atazanavir treatment, which was similarly reversed when the drug was removed. These studies indicate that some aspects of both cellular senescence and aging may be reversible, and that diseases of aging driven by ATV may be reversed by performing intermittent treatment or switching to therapies that do not promote cellular senescence.

Technical 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 irreversible growth arrest, which includes the secretion of many bioactive molecules. We therefore hypothesized that senescence increased 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 the senescence-associated secretory phenotype (SASP) factors, known to promote inflammation. However, removing treatment reversed the senescent phenotypes. Despite initially expressing several markers of senescence, cells resumed proliferation and lost senescence markers. Further, mice receiving sustained ATV/r treatment showed increased senescence phenotypes and deficits in functional assays. However, upon ATV/r removal, aging features declined. Our findings suggest that for patients suffering from the toxic side effects of PI drugs like ATV/r, intermittent treatment regimens might be a novel strategy for reducing PI-induced premature aging phenotypes.