Mitochondrial and Oxidative Impacts of Short and Long-term Administration of HAART on HIV Patients

Author(s): Joy E. Ikekpeazu, Oliver C. Orji, Ikenna K. Uchendu*, Lawrence U.S. Ezeanyika

Journal Name: Current Clinical Pharmacology
Continued as Current Reviews in Clinical and Experimental Pharmacology

Volume 15 , Issue 2 , 2020


Graphical Abstract:


Abstract:

Background: There may be a possible link between the use of HAART and oxidative stress-related mitochondrial dysfunction in HIV patients. We evaluated the mitochondrial and oxidative impacts of short and long-term administration of HAART on HIV patients attending the Enugu State University Teaching (ESUT) Hospital, Enugu, Nigeria following short and long-term therapy.

Methods: 96 patients categorized into four groups of 24 individuals were recruited for the study. Group 1 comprised of age-matched, apparently healthy, sero-negative individuals (the No HIV group); group 2 consisted of HIV sero-positive individuals who had not started any form of treatment (the Treatment naïve group). Individuals in group 3 were known HIV patients on HAART for less than one year (Short-term treatment group), while group 4 comprised of HIV patients on HAART for more than one year (Long-term treatment group). All patients were aged between 18 to 60 years and attended the HIV clinic at the time of the study. Determination of total antioxidant status (TAS in nmol/l), malondialdehyde (MDA in mmol/l), CD4+ count in cells/μl, and genomic studies were all done using standard operative procedures.

Results: We found that the long-term treatment group had significantly raised the levels of MDA, as well as significantly diminished TAS compared to the Short-term treatment and No HIV groups (P<0.05). In addition, there was significantly elevated variation in the copy number of mitochondrial genes (mtDNA: D-loop, ATPase 8, TRNALEU uur) in the long-term treatment group.

Conclusion: Long-term treatment with HAART increases oxidative stress and causes mitochondrial alterations in HIV patients.

Keywords: HIV/AIDS, HAART, mitochondrial dysfunction, oxidative stress, biochemical alterations, necrosis.

[1]
Maartens G, Celum C, Lewin SR. HIV infection: Epidemiology, pathogenesis, treatment, and prevention. Lancet 2014; 384(9939): 258-71.
[http://dx.doi.org/10.1016/S0140-6736(14)60164-1] [PMID: 24907868]
[2]
Klatt NR, Silvestri G. Perspective HIV CD4+ T cells and HIV: A paradoxical pas de Deux. Sci Transl Med 2012; 4(123)123ps4
[http://dx.doi.org/10.1126/scitranslmed.3003862] [PMID: 22378922]
[3]
Heil EL, Townsend ML, Shipp K, et al. Incidence of severe hepatotoxicity related to antiretroviral therapy in HIV /HCV co-infected patients In: Aids Res Treat-ment. 2010.
[4]
Fraser C, Lythgoe K, Leventhal GE, et al. Virulence and pathogenesis of HIV-1 infection: An evolutionary perspective. Science 2014; 343(6177)1243727
[http://dx.doi.org/10.1126/science.1243727] [PMID: 24653038]
[5]
Apostolova N, Blas-García A, Esplugues JV. Mitochondrial interference by anti-HIV drugs: Mechanisms beyond Pol-γ inhibition. Trends Pharmacol Sci 2011; 32(12): 715-25.
[http://dx.doi.org/10.1016/j.tips.2011.07.007] [PMID: 21899897]
[6]
Koczor CA, Lewis W. Nucleoside reverse transcriptase inhibitor toxicity and mitochondrial DNA. Expert Opin Drug Metab Toxicol 2010; 6(12): 1493-504.
[http://dx.doi.org/10.1517/17425255.2010.526602] [PMID: 20929279]
[7]
Malik AN, Czajka A. Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction? Mitochondrion 2013; 13(5): 481-92.
[http://dx.doi.org/10.1016/j.mito.2012.10.011] [PMID: 23085537]
[8]
Murphy MP. How mitochondria produce reactive oxygen species. Biochem J 2009; 417(1): 1-13.
[http://dx.doi.org/10.1042/BJ20081386] [PMID: 19061483]
[9]
Alfadda AA, Sallam RM. Reactive oxygen species in health and diseaseJ Biomed Bio-tech 2012.
[10]
Halliwell BH, Gutteridge JMC. Free radicals in biology and medicine. Oxford: Oxford University Press 2007; pp. 55-9.
[11]
Voss JG, Raju R, Logun C, et al. A focused microarray to study human mitochondrial and nuclear gene expression. Biol Res Nurs 2008; 9(4): 272-9.
[http://dx.doi.org/10.1177/1099800408315160] [PMID: 18398222]
[12]
Bai RK, Wong LJ. Simultaneous detection and quantification of mitochondrial DNA deletion(s), depletion, and over-replication in patients with mitochondrial disease. J Mol Diagn 2005; 7(5): 613-22.
[http://dx.doi.org/10.1016/S1525-1578(10)60595-8] [PMID: 16258160]
[13]
Ghatak S, Muthukumaran RB, Nachimuthu SK. A simple method of genomic DNA extraction from human samples for PCR-RFLP analysis. J Biomol Tech 2013; 24(4): 224-31.
[http://dx.doi.org/10.7171/jbt.13-2404-001] [PMID: 24294115]
[14]
Suresh DR, Annam V, Pratibha K, Prasad BV. Total antioxidant capacity--a novel early bio-chemical marker of oxidative stress in HIV infected individuals. J Biomed Sci 2009; 16: 61-4.
[http://dx.doi.org/10.1186/1423-0127-16-61] [PMID: 19583866]
[15]
Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 1978; 86(1): 271-8.
[http://dx.doi.org/10.1016/0003-2697(78)90342-1] [PMID: 655387]
[16]
Yar’zever IS, Abubakar U, Toriola AL, et al. Effects of 12 weeks cycle exercise programme on CD4 count and viral load in HIV sero-positive patients in Kano, Nigeria. J AIDS HIV Res 2013; 5(11): 415-21.
[17]
Deavall DG, Martin EA, Horner JM, Roberts R. Drug-induced oxidative stress and toxicity. J Toxicol 2012; 2012645460
[http://dx.doi.org/10.1155/2012/645460] [PMID: 22919381]
[18]
Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res 2010; 107(9): 1058-70.
[http://dx.doi.org/10.1161/CIRCRESAHA.110.223545] [PMID: 21030723]
[19]
Tanaka N, Goto Y, Akanuma J, et al. Mitochondrial DNA variants in a Japanese population of patients with Alzheimer’s disease. Mitochondrion 2010; 10(1): 32-7.
[http://dx.doi.org/10.1016/j.mito.2009.08.008] [PMID: 19703591]
[20]
Jitratkosol MH, Sattha B, Maan E, et al. Blood mitochondrial DNA mutations in HIV-infected women and their infants exposed to highly active antiretroviral therapy during pregnancy. AIDS 2012; 26: 1-9.
[http://dx.doi.org/10.1097/QAD.0b013e32835142eb]
[21]
Pinti M, Salomoni P, Cossarizza A. Anti-HIV drugs and the mitochondria. Biochim Biophys Acta 2006; 1757(5-6): 700-7.
[http://dx.doi.org/10.1016/j.bbabio.2006.05.001] [PMID: 16782042]
[22]
Aniagolu MO, Ezeanyika LUS, Parker J, et al. Changes in some antioxidants in HIV-positive patients on highly active antiretroviral therapy (case study of Nsukka, South East Nigeria). Asian Journal of Science and Technology 2015; 6(4): 1289-92.
[23]
Mgbekem MA, John ME, Umoh IB, et al. Plasma antioxidant micronutrients and oxidative stress in people living with HIV. Pak J Nutr 2011; 10(3): 214-9.
[http://dx.doi.org/10.3923/pjn.2011.214.219]
[24]
Akiibinu MO, Adeshiyan AA, Olalekan AO. Micronutrients and markers of oxidative stress in symptomatic HIV-positive/AIDS Nigerians: A call for adjuvant micronutrient therapy. IIOAB 2012; 3(2): 7-11.
[25]
Halliwell B, Whiteman M. Measuring reactive species and oxidative damage in vivo and in cell culture: How should you do it and what do the results mean? Br J Pharmacol 2004; 142(2): 231-55.
[http://dx.doi.org/10.1038/sj.bjp.0705776] [PMID: 15155533]
[26]
Lizette GV, Rosario GH, Jorge PÁ. Oxidative stress associated to disease progression and toxicity during antiretroviral therapy in human immunodeficiency virus infection. J Virol and Microbiol 2013; 80: 27-35.
[27]
Jiang B, Khandelwal AR, Rogers LK, et al. Antiretrovirals induce endothelial dysfunction via an oxidant-dependent pathway and promote neointimal hyperplasia. Toxicol Sci 2010; 117(2): 524-36.
[http://dx.doi.org/10.1093/toxsci/kfq213] [PMID: 20621964]
[28]
Kashou AH, Agarwal A. Oxidants and antioxidants in pathogenesis of HIV/AIDS. Open Reprod Sci J 2011; 3: 154-61.
[http://dx.doi.org/10.2174/1874255601103010154]
[29]
Deresz LF, Sprinz E, Kramer AS, et al. Regulation of oxidative stress in response to acute aerobic and resistance exercise in HIV-infected subjects: A case-control study. AIDS Care 2010; 22(11): 1410-7.
[http://dx.doi.org/10.1080/09540121003758549] [PMID: 20640951]
[30]
Wanchu A, Rana SV, Pallikkuth S, Sachdeva RK. Short communication: Oxidative stress in HIV-infected individuals: A cross-sectional study. AIDS Res Hum Retroviruses 2009; 25(12): 1307-11.
[http://dx.doi.org/10.1089/aid.2009.0062] [PMID: 20001519]
[31]
Wang X, Chai H, Yao Q, Chen C. Molecular mechanisms of HIV protease inhibitor-induced endothelial dysfunction. J Acquir Immune Defic Syndr 2007; 44(5): 493-9.
[http://dx.doi.org/10.1097/QAI.0b013e3180322542] [PMID: 17245228]
[32]
Drain PK, Kupka R, Mugusi F, Fawzi WW. Micronutrients in HIV-positive persons receiving highly active antiretroviral therapy. Am J Clin Nutr 2007; 85(2): 333-45.
[http://dx.doi.org/10.1093/ajcn/85.2.333] [PMID: 17284727]
[33]
Gil L, Tarinas A, Hernandez D, et al. Altered oxidative stress indexes related to disease progression marker in human immunodeficiency virus infected patients with antirretroviral therapy. Biomed Aging Pathol 2011; 1(1): 8-15.
[http://dx.doi.org/10.1016/j.biomag.2010.09.001]
[34]
Saikat S, Raja C. The role of antioxidants in human health educational society’s college of pharmacy, Kurnool, Andhra. Eur J Exp Biol 2011; 1(2): 53-61.
[35]
Teto G, Kanmogne DG, Torimiro J, et al. Very high lipid peroxidation indices in HAART-Naïve HIV-positive patients in Cameroon. Health Sci Dis 2011; 12(4): 1-4.
[36]
Abduljalil MM, Liman HM, Umar RA, et al. Effect of HIV and HAART on antioxidants markers in HIV positive patients in Sokoto State, Nigeria. Int J Sci Eng Res 2015; 6(2): 1069-74.
[37]
Asiimwe S. Nutri-medicinal plants used in the management of HIV/AIDS opportunistic infections in Western Uganda: Documentation, phytochemistry and bioactivity evaluation 2015.
[38]
Kovacic P, Somanathan R. Broad overview of oxidative stress and its complications in human health. Open J Prev Med 2013; 3(1): 32-41.
[http://dx.doi.org/10.4236/ojpm.2013.31005]
[39]
Sharma B. Oxidative stress in HIV patients receiving antiretroviral therapy. Curr HIV Res 2014; 12(1): 13-21.
[http://dx.doi.org/10.2174/1570162X12666140402100959] [PMID: 24694264]
[40]
McComsey GA, Walker UA. Role of mitochondria in HIV lipoatrophy: Insight into patho-genesis and potential therapies Mitochondrion 2005; 4(2,3): 111-8.
[41]
Alimonti JB, Ball TB, Fowke KR. Mechanisms of CD4+ T lymphocyte cell death in human immunodeficiency virus infection and AIDS. J Gen Virol 2003; 84(Pt 7): 1649-61.
[http://dx.doi.org/10.1099/vir.0.19110-0] [PMID: 12810858]
[42]
Soghoian DZ, Jessen H, Flanders M, et al. HIV-specific cytolytic CD4 T cell responses during acute HIV infection predict disease outcome. Sci Transl Med 2012; 4(123)123ra25
[http://dx.doi.org/10.1126/scitranslmed.3003165] [PMID: 22378925]
[43]
Herzenberg LA, De Rosa SC, Dubs JG, et al. Glutathione deficiency is associated with impaired survival in HIV disease. Proc Natl Acad Sci USA 1997; 94(5): 1967-72.
[http://dx.doi.org/10.1073/pnas.94.5.1967] [PMID: 9050888]


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Article Details

VOLUME: 15
ISSUE: 2
Year: 2020
Page: [110 - 124]
Pages: 15
DOI: 10.2174/1574884714666190905162237

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