cells Review Antiretroviral Drugs Impact Autophagy with Toxic Outcomes Laura Cheney 1,*, John M. Barbaro 2 and Joan W. Berman 2,3 1 Division of Infectious Diseases, Department of Medicine, Montefiore Medical Center and Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA 2 Department of Pathology, Montefiore Medical Center and Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA; [email protected] (J.M.B.); [email protected] (J.W.B.) 3 Department of Microbiology and Immunology, Montefiore Medical Center and Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA * Correspondence: [email protected]; Tel.: +1-718-904-2587 Abstract: Antiretroviral drugs have dramatically improved the morbidity and mortality of peo- ple living with HIV (PLWH). While current antiretroviral therapy (ART) regimens are generally well-tolerated, risks for side effects and toxicity remain as PLWH must take life-long medications. Antiretroviral drugs impact autophagy, an intracellular proteolytic process that eliminates debris and foreign material, provides nutrients for metabolism, and performs quality control to maintain cell homeostasis. Toxicity and adverse events associated with antiretrovirals may be due, in part, to their impacts on autophagy. A more complete understanding of the effects on autophagy is essential for developing antiretroviral drugs with decreased off target effects, meaning those unrelated to viral suppression, to minimize toxicity for PLWH. This review summarizes the findings and highlights the gaps in our knowledge of the impacts of antiretroviral drugs on autophagy. Keywords: HIV; antiretroviral drugs; side effects; toxicity; autophagy; mitophagy; mitochondria; Citation: Cheney, L.; Barbaro, J.M.; ER stress Berman, J.W. Antiretroviral Drugs Impact Autophagy with Toxic Outcomes. Cells 2021, 10, 909. https://doi.org/10.3390/ 1. Introduction cells10040909 1.1. Antiretroviral Therapy Academic Editor: Christian Münz Almost 33 million people worldwide have died since the beginning of the human immunodeficiency virus (HIV) epidemic that began nearly 40 years ago, and approximately Received: 25 March 2021 38 million people worldwide are currently living with HIV [1]. It is one of the most Accepted: 14 April 2021 impactful epidemics in human history, with far reaching social, economic, and political Published: 15 April 2021 ramifications as well. Decades of research have led to the development of more than 30 different antiretrovi- Publisher’s Note: MDPI stays neutral ral drugs for treatment of HIV infection (Figure1). Currently, there are six major classes of with regard to jurisdictional claims in antiretrovirals, each targeting a different step in the virus life cycle (Figure2). Antiretroviral published maps and institutional affil- therapy (ART) has dramatically reduced mortality for people living with HIV (PLWH). iations. As a result of expanding access and changes in treatment guidelines, approximately 67% of PLWH worldwide are currently taking ART [1]. Additionally, at the end of 2020, over 900,000 people in 69 countries were receiving antiretroviral drugs to prevent HIV infection, called pre-exposure prophylaxis (PrEP) [2]. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Cells 2021, 10, 909. https://doi.org/10.3390/cells10040909 https://www.mdpi.com/journal/cells CellsCells2021 2021, ,10 10,, 909 x FOR PEER REVIEW 22 ofof 2020 Cells 2021, 10, x FOR PEER REVIEW 2 of 20 FigureFigure 1.1. Timeline of of antiretroviral antiretroviral drug drug development. development. Major Major mile milestonesstones are are encircled. encircled. Individual Individual drugs drugs are shown are shown with Figurethe year 1. Timelinethe United of Statesantiretroviral Food and drug Drug development. Administration Major gr mileantedstones approval are encircled. for use. Individual Individual drug drugs names are shown are colored with with the year the United States Food and Drug Administration granted approval for use. Individual drug names are thecoded year by the drug United class: States red = Food nucleoside and Drug reverse Administration transcriptase gr inhibitoranted approval (NRTI); orangefor use. = Individual protease Inhibitor drug names (PI); greenare colored = non- colored coded by drug class: red = nucleoside reverse transcriptase inhibitor (NRTI); orange = protease Inhibitor (PI); codednucleoside by drug reverse class: transcred = nucleosideriptase inhibitor reverse (NNRTI); transcriptase blue i=nhibitor fusion inhibitor;(NRTI); orange purple = protea= integrasese Inhibitor strand (PI); transfer green inhibitor = non- nucleosidegreen(ISTI); = brown non-nucleoside reverse = entry transc inhibitor. reverseriptase transcriptase inhibitor Islatravir (NNRTI);, in inhibitor pink, blueis (NNRTI); the = fusionfirst bluenucleoside inhibitor; = fusion purplereve inhibitor;rse =transcriptase inte purplegrase = strand integrase translocation transfer strand inhibitor inhibitor transfer (ISTI);inhibitor(NRTTI). brown (ISTI); Cobicistat, = brownentry in =inhibitor. gray, entry inhibitor.is anIslatravir analogue Islatravir,, in ofpink, ritonavir, in pink,is the is andfirst the the firstnucleoside first nucleoside antire revetroviral reverserse transcriptase booster transcriptase that translocationdoes translocation not have inhibitor inhibitorantiviral (NRTTI).(NRTTI).activity. RegisteredCobicistat, Cobicistat, inbrand in gray, gray, names, is is an analogue in black, areof of ritonavir, used for combinationand the first first pillsantire antiretroviral fortroviral space booster considerations. that that does does 1 tenofovir not not have have disoproxil antiviral antiviral activity.activity.fumarate; Registered 2PrEP = pre-exposurebrand names, prophylaxis; in black, are 3 used tenofovir for combination alafenamide; pills 4 FDA for spacespaceapproval considerations.considerations. pending for 1vaginal tenofovirtenofovir ring disoproxil disoproxil formula- fumarate;fumarate;tion; 5 currently 2PrEPPrEP =in = pre-exposure pre-exposurephase III trials; prophylaxis; 6approved 3 3in tenofovirtenofovir early 2021 alafenamide;alafenamide; as a long-acting4 4FDA FDA injectab approval approvalle, pending thepending firstfor of fo vaginalitsr vaginal kind. ring It ringis formulation;co-adminis- formula- 5 6 tion;5teredcurrently currently with ina long-acting phase in phase III trials; IIIformulation trials;6 approved approved of rilpivirine. in early in early 2021 2021 as a as long-acting a long-acting injectable, injectab thele, firstthe first of its of kind. its ki Itnd. is It co-administered is co-adminis- teredwith awith long-acting a long-acting formulation formulation of rilpivirine. of rilpivirine. Figure 2. The HIV life cycle and antiretroviral drug targets. (1) The HIV genome consists of two positive-sense single FigureFigurestrand 2.RNA The molecules, HIVHIV lifelife cycle cycle enclosed and and antiretroviral antireby a capsid.troviraldrug The drug capsid targets. targets. is ( 1surrounded) The(1) The HIV HIV genome by genomea lipid consists bilayer consists of envelope two of positive-sense two whichpositive-sense is studded single single strand with strandRNAthe viral molecules, RNA transmembrane molecules, enclosed enclosed byglycoprotein a capsid. by a capsid. The gp41, capsid Thewith iscapsid viral surrounded gp120 is surrounded po bysitioned a lipid by bilayeron a lipid top. envelopeGp120bilayer bindsenvelope which to the is which studded cluster is studded withof differentia- the with viral thetransmembranetion viral 4 (CD4) transmembrane receptor, glycoprotein inducing glycoprotein gp41, a conformational with gp41, viral with gp120 viral change positioned gp120 that po onensitionedables top. 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