J Pediatr Infect Dis 2021; 16(04): 148-153
DOI: 10.1055/s-0041-1722973
Original Article

Glutathione Deficiency in HIV-1-Infected Children with Short Stature

Ping Du
1   Department of Public Health Sciences, Penn State University College of Medicine, Pennsylvania, United States
,
Stephen M. Arpadi
2   Department of Pediatrics, Mailman School of Public Health, Columbia University, New York, United States
,
Joshua Muscat
1   Department of Public Health Sciences, Penn State University College of Medicine, Pennsylvania, United States
,
John P. Richie Jr.
1   Department of Public Health Sciences, Penn State University College of Medicine, Pennsylvania, United States
› Author Affiliations

Abstract

Objective This study was aimed to determine if glutathione (GSH) deficiency occurs in children with HIV infection and whether GSH deficiency is associated with HIV-related short stature.

Methods We conducted a cross-sectional study with two age-matched comparison groups in an inner city hospital-based pediatric AIDS/HIV outpatient clinic. Ten perinatally HIV-infected children aged 6 to 49 months with short stature (height–age percentile ≤5) were studied together with age-matched 10 HIV-infected children with normal height and 10 HIV-seronegative children with normal height. Total erythrocyte GSH (GSH and GSH disulfide) levels were determined by a modification of the 5,5′-dithiobis-2-nitrobenzoic acid glutathione disulfide reductase method. Other measures included complete blood counts, lymphocyte subset analysis, plasma albumin, cholesterol, vitamins A and E, and determination of HIV disease stage.

Discussion Erythrocyte GSH levels were lower in HIV-infected children with short stature (mean ± standard deviation [SD]: 0.639 µmol/mL ± 0.189) compared with HIV-infected children with normal height (mean ± SD: 0.860 µmol/mL ± 0.358; p < 0.05) and HIV-negative controls (mean ± SD: 0.990 µmol/mL ± 0.343; p < 0.05). Plasma levels of cholesterol, albumin, and vitamins A and E did not differ between the short-stature group and either the HIV-infected normal-height group or HIV-negative controls.

Conclusion These results demonstrate a GSH deficiency in HIV-infected children with short stature and support the hypothesis that GSH balance is important in growth among HIV-infected children.



Publication History

Received: 17 July 2020

Accepted: 13 December 2020

Article published online:
03 March 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 United Nations. The gap report. Accessed January 5, 2020 at: http://www.unaids.org/sites/default/files/media_asset/UNAIDS_Gap_report_en.pdf
  • 2 Centers for Disease Control and Prevention. HIV Surveillance Report: 2012; vol. 24. Diagnoses of HIV infection in the United States and dependent areas. Accessed January 5, 2020 at: https://www.cdc.gov/hiv/pdf/statistics_2012_HIV_Surveillance_Report_vol_24.pdf
  • 3 Domachowske JB. Pediatric human immunodeficiency virus infection. Clin Microbiol Rev 1996; 9 (04) 448-468
  • 4 Isanaka S, Duggan C, Fawzi WW. Patterns of postnatal growth in HIV-infected and HIV-exposed children. Nutr Rev 2009; 67 (06) 343-359
  • 5 Majaliwa ES, Mohn A, Chiarelli F. Growth and puberty in children with HIV infection. J Endocrinol Invest 2009; 32 (01) 85-90
  • 6 Tovo PA, de Martino M, Gabiano C. et al. Prognostic factors and survival in children with perinatal HIV-1 infection. The Italian Register for HIV Infections in Children. Lancet 1992; 339 (8804): 1249-1253
  • 7 Berhane R, Bagenda D, Marum L. et al. Growth failure as a prognostic indicator of mortality in pediatric HIV infection. Pediatrics 1997; 100 (01) E7
  • 8 Laue L, Pizzo PA, Butler K, Cutler Jr GB. Growth and neuroendocrine dysfunction in children with acquired immunodeficiency syndrome. J Pediatr 1990; 117 (04) 541-545
  • 9 Lepage P, Van de Perre P, Van Vliet G. et al. Clinical and endocrinologic manifestations in perinatally human immunodeficiency virus type 1--Infected children aged 5 years or older. Am J Dis Child 1991; 145 (11) 1248-1251
  • 10 Sellmeyer DE, Grunfeld C. Endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome. Endocr Rev 1996; 17 (05) 518-532
  • 11 Miller TL, Easley KA, Zhang W. et al; Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2 HIV) Study Group, National Heart, Lung, and Blood Institute, Bethesda, MD. Maternal and infant factors associated with failure to thrive in children with vertically transmitted human immunodeficiency virus-1 infection: the prospective, P2C2 human immunodeficiency virus multicenter study. Pediatrics 2001; 108 (06) 1287-1296
  • 12 Newell ML, Borja MC, Peckham C. European Collaborative Study. Height, weight, and growth in children born to mothers with HIV-1 infection in Europe. Pediatrics 2003; 111 (01) e52-e60
  • 13 Van Rossum AM, Gaakeer MI, Verweel S. et al. Endocrinologic and immunologic factors associated with recovery of growth in children with human immunodeficiency virus type 1 infection treated with protease inhibitors. Pediatr Infect Dis J 2003; 22 (01) 70-76
  • 14 Torres RA, Lewis W. Aging and HIV/AIDS: pathogenetic role of therapeutic side effects. Lab Invest 2014; 94 (02) 120-128
  • 15 Baruchel S, Wainberg MA. The role of oxidative stress in disease progression in individuals infected by the human immunodeficiency virus. J Leukoc Biol 1992; 52 (01) 111-114
  • 16 Pace GW, Leaf CD. The role of oxidative stress in HIV disease. Free Radic Biol Med 1995; 19 (04) 523-528
  • 17 Dröge W, Schulze-Osthoff K, Mihm S. et al. Functions of glutathione and glutathione disulfide in immunology and immunopathology. FASEB J 1994; 8 (14) 1131-1138
  • 18 Meister A, Anderson ME. Glutathione. Annu Rev Biochem 1983; 52: 711-760
  • 19 Viña J. Glutathione: Metabolism and Physiological Functions. 1st ed.. Boca Raton, FL: CRC Press; 1990
  • 20 Staal FJ, Roederer M, Herzenberg LA, Herzenberg LA. Intracellular thiols regulate activation of nuclear factor kappa B and transcription of human immunodeficiency virus. Proc Natl Acad Sci USA 1990; 87 (24) 9943-9947
  • 21 Duh EJ, Maury WJ, Folks TM, Fauci AS, Rabson AB. Tumor necrosis factor alpha activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-kappa B sites in the long terminal repeat. Proc Natl Acad Sci U S A 1989; 86 (15) 5974-5978
  • 22 Kumar A, Abbas W, Herbein G. TNF and TNF receptor superfamily members in HIV infection: new cellular targets for therapy?. Mediators Inflamm 2013; 2013: 484378
  • 23 Roederer M, Staal FJ, Raju PA, Ela SW, Herzenberg LA, Herzenberg LA. Cytokine-stimulated human immunodeficiency virus replication is inhibited by N-acetyl-L-cysteine. Proc Natl Acad Sci USA 1990; 87 (12) 4884-4888
  • 24 Kalebic T, Kinter A, Poli G, Anderson ME, Meister A, Fauci AS. Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N-acetylcysteine. Proc Natl Acad Sci USA 1991; 88 (03) 986-990
  • 25 Mihm S, Ennen J, Pessara U, Kurth R, Dröge W. Inhibition of HIV-1 replication and NF-kappa B activity by cysteine and cysteine derivatives. AIDS 1991; 5 (05) 497-503
  • 26 Staal FJ, Roederer M, Raju PA. et al. Antioxidants inhibit stimulation of HIV transcription. AIDS Res Hum Retroviruses 1993; 9 (04) 299-306
  • 27 Roederer M, Raju PA, Staal FJ, Herzenberg LA, Herzenberg LA. N-acetylcysteine inhibits latent HIV expression in chronically infected cells. AIDS Res Hum Retroviruses 1991; 7 (06) 563-567
  • 28 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 (05) 1967-1972
  • 29 Buhl R, Jaffe HA, Holroyd KJ. et al. Systemic glutathione deficiency in symptom-free HIV-seropositive individuals. Lancet 1989; 2 (8675): 1294-1298
  • 30 Aukrust P, Svardal AM, Müller F, Lunden B, Berge RK, Frøland SS. Decreased levels of total and reduced glutathione in CD4+ lymphocytes in common variable immunodeficiency are associated with activation of the tumor necrosis factor system: possible immunopathogenic role of oxidative stress. Blood 1995; 86 (04) 1383-1391
  • 31 Walmsley SL, Winn LM, Harrison ML, Uetrecht JP, Wells PG. Oxidative stress and thiol depletion in plasma and peripheral blood lymphocytes from HIV-infected patients: toxicological and pathological implications. AIDS 1997; 11 (14) 1689-1697
  • 32 Aukrust P, Müller F, Svardal AM, Ueland T, Berge RK, Frøland SS. Disturbed glutathione metabolism and decreased antioxidant levels in human immunodeficiency virus-infected patients during highly active antiretroviral therapy--potential immunomodulatory effects of antioxidants. J Infect Dis 2003; 188 (02) 232-238
  • 33 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) 1307-1311
  • 34 Morris D, Guerra C, Donohue C, Oh H, Khurasany M, Venketaraman V. Unveiling the mechanisms for decreased glutathione in individuals with HIV infection. Clin Dev Immunol 2012; 2012: 734125
  • 35 Cribbs SK, Guidot DM, Martin GS, Lennox J, Brown LA. Anti-retroviral therapy is associated with decreased alveolar glutathione levels even in healthy HIV-infected individuals. PLoS One 2014; 9 (02) e88630
  • 36 Morris D, Ly J, Chi PT. et al. Glutathione synthesis is compromised in erythrocytes from individuals with HIV. Front Pharmacol 2014; 5: 73
  • 37 Roederer M, Staal FJ, Osada H, Herzenberg LA, Herzenberg LA. CD4 and CD8 T cells with high intracellular glutathione levels are selectively lost as the HIV infection progresses. Int Immunol 1991; 3 (09) 933-937
  • 38 Staal FJ, Roederer M, Israelski DM. et al. Intracellular glutathione levels in T cell subsets decrease in HIV-infected individuals. AIDS Res Hum Retroviruses 1992; 8 (02) 305-311
  • 39 Aukrust P, Svardal AM, Müller F, Lunden B, Nordøy I, Frøland SS. Markedly disturbed glutathione redox status in CD45RA+CD4+ lymphocytes in human immunodeficiency virus type 1 infection is associated with selective depletion of this lymphocyte subset. Blood 1996; 88 (07) 2626-2633
  • 40 Rodriguez JF, Cordero J, Chantry C. et al. Plasma glutathione concentrations in children infected with human immunodeficiency virus. Pediatr Infect Dis J 1998; 17 (03) 236-241
  • 41 Hamill PV, Drizd TA, Johnson CL, Reed RB, Roche AF, Moore WM. Physical growth: National Center for Health Statistics percentiles. Am J Clin Nutr 1979; 32 (03) 607-629
  • 42 Centers for Disease Control (CDC). Classification system for human immunodeficiency virus (HIV) infection in children under 13 years of age. MMWR Morb Mortal Wkly Rep 1987; 36 (15) 225-230 , 235–236
  • 43 Vogt BL, Richie Jr JP. Fasting-induced depletion of glutathione in the aging mouse. Biochem Pharmacol 1993; 46 (02) 257-263
  • 44 Kleinman WA, Komninou D, Leutzinger Y. et al. Protein glutathiolation in human blood. Biochem Pharmacol 2003; 65 (05) 741-746
  • 45 Milne DB, Botnen J. Retinol, alpha-tocopherol, lycopene, and alpha- and beta-carotene simultaneously determined in plasma by isocratic liquid chromatography. Clin Chem 1986; 32 (05) 874-876
  • 46 Scheffe H. The Analysis of Variance. New York: John Wiley & Sons; 1999
  • 47 Muscat JE, Kleinman W, Colosimo S. et al. Enhanced protein glutathiolation and oxidative stress in cigarette smokers. Free Radic Biol Med 2004; 36 (04) 464-470
  • 48 McLean AE, Armstrong GR, Beales D. Effect of D- or L-methionine and cysteine on the growth inhibitory effects of feeding 1% paracetamol to rats. Biochem Pharmacol 1989; 38 (02) 347-352
  • 49 Keusch GT, Farthing MJ. Nutritional aspects of AIDS. Annu Rev Nutr 1990; 10: 475-501
  • 50 Miller TL. Nutritional aspects of HIV-infected children receiving highly active antiretroviral therapy. AIDS 2003; 17 (Suppl. 01) S130-S140
  • 51 Grunfeld C, Feingold KR. Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. N Engl J Med 1992; 327 (05) 329-337
  • 52 Dass PD, Bermes Jr. EW, Holmes EW. Renal and hepatic output of glutathione in plasma and whole blood. Biochim Biophys Acta 1992; 1156 (01) 99-102
  • 53 Svardal AM, Mansoor MA, Ueland PM. Determination of reduced, oxidized, and protein-bound glutathione in human plasma with precolumn derivatization with monobromobimane and liquid chromatography. Anal Biochem 1990; 184 (02) 338-346
  • 54 Roederer M, Ela SW, Staal FJ, Herzenberg LA, Herzenberg LA. N-acetylcysteine: a new approach to anti-HIV therapy. AIDS Res Hum Retroviruses 1992; 8 (02) 209-217
  • 55 Morris D, Guerra C, Khurasany M. et al. Glutathione supplementation improves macrophage functions in HIV. J Interferon Cytokine Res 2013; 33 (05) 270-279
  • 56 Nguyen D, Hsu JW, Jahoor F, Sekhar RV. Effect of increasing glutathione with cysteine and glycine supplementation on mitochondrial fuel oxidation, insulin sensitivity, and body composition in older HIV-infected patients. J Clin Endocrinol Metab 2014; 99 (01) 169-177