DOI QR코드

DOI QR Code

Genetic defects in the nef gene are associated with Korean Red Ginseng intake: monitoring of nef sequence polymorphisms over 20 years

  • Cho, Young-Keol (Department of Microbiology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Jung-Eun (Department of Microbiology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Woo, Jun-Hee (Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine)
  • Received : 2015.12.18
  • Accepted : 2016.02.19
  • Published : 2017.04.15

Abstract

Background: The presence of gross deletions in the human immunodeficiency virus nef gene ($g{\Delta}nef$) is associated with long-term nonprogression of infected patients. Here, we investigated how quickly genetic defects in the nef gene are associated with Korean Red Ginseng (KRG) intakein 10 long-term slow progressors. Methods: This study was divided into three phases over a 20-yr period; baseline, KRG intake alone, and KRG plus highly active antiretroviral therapy (ART). nef gene amplicons were obtained using reverse transcription polymerase chain reaction (PCR) and nested PCR from 10 long-term slow progressors (n = 1,396), and nested PCR from 36 control patients (n = 198), and 28 ART patients (n = 157), and these were then sequenced. The proportion of $g{\Delta}nef$, premature stop codons, and not in-frame insertion or deletion of a nucleotide was compared between three phases, control, and ART patients. Results: The proportion of defective nef genes was significantly higher in on-KRG patients (15.6%) than in baseline (5.7%), control (5.6%), on-KRG plus ART phase (7.8%), and on-ART patients (6.6%; p < 0.01). Small in-frame deletions or insertions were significantly more frequent among patients treated with KRG alone compared with controls (p < 0.01). Significantly fewer instances of genetic defects were detected in samples taken during the KRG plus ART phase (7.8%; p < 0.01). The earliest defects detected were $g{\Delta}nef$ and small in-frame deletions after 7 mo and 67 mo of KRG intake, respectively. Conclusion: KRG treatment might induce genetic defects in the nef gene. This report provides new insight into the importance of genetic defects in the pathogenesis of AIDS.

Keywords

References

  1. Palella Jr FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. New Engl J Med 1998;338:853-60. https://doi.org/10.1056/NEJM199803263381301
  2. Hatano H, Delwart EL, Norris PJ, Lee TH, Neilands TB, Kelley CF, Hunt PW, Hoh R, Linnen JM, Martin JN, et al. Evidence of persistent low-level viremia in long-term ART-suppressed, HIV-infected individuals. AIDS 2010;24:2535-9. https://doi.org/10.1097/QAD.0b013e32833dba03
  3. Hunt PW. HIV and inflammation: mechanisms and consequences. Curr HIV/AIDS Rep 2012;9:139-47. https://doi.org/10.1007/s11904-012-0118-8
  4. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006;12:1365-71. https://doi.org/10.1038/nm1511
  5. Cho YK, Lim JY, Jung YS, Oh SK, Lee HJ, Sung H. High frequency of grossly deleted nef genes in HIV-1 infected long-term slow progressors treated with Korean Red Ginseng. Curr HIV Res 2006;4:447-57. https://doi.org/10.2174/157016206778560072
  6. Cho YK, Jung YS. High frequency of gross deletions in the 5' LTR/gag regions in HIV type 1-infected long-term survivors treated with Korean Red Ginseng. AIDS Res Hum Retroviruses 2008;24:181-93. https://doi.org/10.1089/aid.2007.0143
  7. Yayeh T, Jung KH, Jeong HY, Park JH, Song YB, Kwak YS, Kang HS, Cho JY, Oh JW, Kim SK, et al. Korean Red Ginseng saponin fraction downregulates proinflammatory mediators in LPS stimulated RAW264.7 cells and protects mice against endotoxic shock. J Ginseng Res 2012;36:263-9. https://doi.org/10.5142/jgr.2012.36.3.263
  8. Smolinski AT, Pestka JJ. Modulation of lipopolysaccharide-induced proinflammatory cytokine production in vitro and in vivo by the herbal constituents apigenin (chamomile), ginsenoside Rb1 (ginseng) and parthenolide (feverfew). Food Chem Toxicol 2003;41:1381-90. https://doi.org/10.1016/S0278-6915(03)00146-7
  9. Byeon SE, Lee J, Kim JH, Yang WS, Kwak YS, Kim SY, Choung ES, Rhee MH, Cho JY. Molecular mechanism of macrophage activation by red ginseng acidic polysaccharide from Korean Red Ginseng. Mediators Inflamm 2012. http://dx.doi.org/10.1155/2012/732860.
  10. Baek KS, Hong YD, Kim Y, Sung NY, Yang S, Lee KM, Park JY, Park JS, Rho HS, Shin SS, et al. Anti-inflammatory activity of AP-SF, a ginsenoside-enriched fraction, from Korean ginseng. J Ginseng Res 2015;39:155-61. https://doi.org/10.1016/j.jgr.2014.10.004
  11. Lee SM, Bae BS, Park HW, Ahn NG, Cho BG, Cho YL, Kwak YS. Characterization of Korean Red Ginseng (Panax ginseng Meyer): history, preparation method, and chemical composition. J Ginseng Res 2015;39:384-91. https://doi.org/10.1016/j.jgr.2015.04.009
  12. Deacon NJ, Tsykin A, Solomon A, Smith K, Ludford-Menting M, Hooker DJ, McPhee DA, Greenway AL, Ellett A, Chatfield C, et al. Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science 1995;270:988-91. https://doi.org/10.1126/science.270.5238.988
  13. Kirchhoff F, Greenough TC, Brettler DB, Sullivan JL, Desrosiers RC. Absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. New Engl J Med 1995;332:228-32. https://doi.org/10.1056/NEJM199501263320405
  14. Learmont JC, Geczy AF, Mills J, Ashton LJ, Raynes-Greenow CH, Garsia RJ, Dyer WB, McIntyre L, Oelrichs RB, Rhodes DI, et al. Immunologic and virologic status after 14 to 18 years of infectionwith an attenuated strain ofHIV-1.A report from the Sydney Blood Bank Cohort. New Engl J Med 1999;340:1715-22. https://doi.org/10.1056/NEJM199906033402203
  15. Rhodes DI, Ashton L, Solomon A, Carr A, Cooper D, Kaldor J, Deacon N. Characterization of three nef-defective human immunodeficiency virus type 1 strains associated with long-term nonprogression. J Virol 2000;74:10581-8. https://doi.org/10.1128/JVI.74.22.10581-10588.2000
  16. Salvi R, Garbuglia AR, Caro AD, Pulciani S, Montella F, Benedetto A. Grossly defective nef gene sequences in a human immunodeficiency virus type 1-seropositive long-term nonprogressor. J Virol 1998;72:3646-57.
  17. Miura T, Brockman MA, Brumme CJ, Brumme ZL, Carlson JM, Pereyra F, Trocha A, Addo MM, Block BL, Rothchild AC, et al. Genetic characterization of human immunodeficiency virus type 1 in elite controllers: lack of gross genetic defects or common amino acid changes. J Virol 2008;82:8422-30. https://doi.org/10.1128/JVI.00535-08
  18. Pushker R, Jacque JM, Shields DC. Meta-analysis to test the association of HIV-1 nef amino acid differences and deletions with disease progression. J Virol 2010;84:3644-53. https://doi.org/10.1128/JVI.01959-09
  19. Kirchhoff F, Easterbrook PJ, Douglas N, Troop M, Greenough TC, Weber J, Carl S, Sullivan JL, Daniels RS. Sequence variations in human immunodeficiency virus type 1 Nef are associated with different stages of disease. J Virol 1999;73:5497-508.
  20. Cho YK, Lee HJ, Kim YB, Oh WI, Kim YK. Sequence analysis of C3-V3 region of human immunodeficiency virus type 1 gp120 and its correlation with clinical significance: the effect of long-term intake of Korean Red Ginseng on env gene variation. J Korean Soc Microbiol 1997;32:611-23.
  21. Cho YK, Sung H, Lee HJ, Joo CH, Cho GJ. Long-term intake of Korean Red Ginseng in HIV-1 infected patients: development of resistance mutation to zidovudine is delayed. Int Immunophamacol 2001;1:1295-305. https://doi.org/10.1016/S1567-5769(01)00061-3
  22. Cho YK, Sung HS, Kim TK, Lim JY, Jung YS, Kang SM. Korean Red Ginseng significantly slows CD4 T cell depletion over 10 years in HIV-1 infected patients: association with HLA. J Ginseng Res 2004;28:173-82. https://doi.org/10.5142/JGR.2004.28.4.173
  23. Cho YK, Jung YS. Dosage and duration effects of Korean Red Ginseng intake on frequency of gross deletions in the nef gene. J Ginseng Res 2010;34:219-25. https://doi.org/10.5142/jgr.2010.34.3.219
  24. Cho YK, Jung YS, Sung H. Frequent gross deletion in the HIV type 1 nef gene in hemophiliacs treatedwith Korean Red Ginseng: inhibition of detection by highly active antiretroviral therapy. AIDS Res Hum Retroviruses 2009;25:419-24. https://doi.org/10.1089/aid.2008.0178
  25. Cho YK, Jung Y, Sung H, Joo CH. Frequent genetic defects in the HIV-1 50LTR/gag gene in hemophiliacs treated with Korean Red Ginseng: decreased detection of genetic defects by highly active antiretroviral therapy. J Ginseng Res 2011;35:413-20. https://doi.org/10.5142/jgr.2011.35.4.413
  26. Cho YK, Kim JE, Foley BT. Phylogenetic analysis of near full-length HIV-1 type 1 genomic sequences from 21 Korean individuals. AIDS Res Hum Retroviruses 2013;29:738-43. https://doi.org/10.1089/aid.2012.0298
  27. Cho YK, Kim BR, Kim JE. Frequent genetic defects in long-term survivors for more than 26 years in the absence of antiretroviral therapy in Korea: its association with ginseng treatment. Retrovirology 2013;10(Suppl. 1):14. https://doi.org/10.1186/1742-4690-10-14
  28. Cho YK, Kim JE, Kim BR. Frequent gross deletions in pol gene in 10 HIV-1 infected patients treated with Korean red ginseng for 3 years: dosage dependency. Retrovirology 2013;10(Suppl. 1):15. https://doi.org/10.1186/1742-4690-10-15
  29. Cho YK, Kim BR, Kim JE, Woo JH, Foley BT. First report on a T69-ins insertion in CRF06_cpx HIV-1. AIDS Res Hum Retroviruses 2013;29:1079-84. https://doi.org/10.1089/aid.2013.0013
  30. Cho YK, Kim JE, Foley BT. Phylogenetic analysis of the earliest nef gene from hemophiliacs and local controls in Korea. Biores Open Access 2012;1:41-9. https://doi.org/10.1089/biores.2012.0215
  31. Kim BR, Kim JE, Sung H, Cho YK. Long-term follow up of HIV-infected Korean hemophiliacs, after infection from a common source of virus. Haemophilia 2015;21:e1-11. https://doi.org/10.1111/hae.12527
  32. Brambilla A, Turchetto L, Gatti A, Bovolenta C, Veglia F, Santagostino E, Gringeri A, Clementi M, Poli G, Bagnarelli P, et al. Defective nef alleles in a cohort of hemophiliacs with progressing and nonprogressing HIV-1 infection. Virology 1999;259:349-68. https://doi.org/10.1006/viro.1999.9783
  33. Cho YK, Kim BR, Chang MS, Kim JE. Effects of Korean Red Ginseng and ART on vif gene in 10 long-term slow progressors over 20 years: high frequency of deletions and G-to-A hypermutation. Evid Based Complement Alternat Med 2013. http://dx.doi.org/10.1155/2013/871648.
  34. Alexander L, Weiskopf E, Greenough TC, Gaddis NC, Auerbach MR, Malim MH, O'Brien SJ, Walker BD, Sullivan JL, Desrosiers RC. Unusual polymorphisms in human immunodeficiency virus type 1 associated with nonprogressive infection. J Virol 2000;74:4361-76. https://doi.org/10.1128/JVI.74.9.4361-4376.2000
  35. Sung HS, Kang SM, Lee MS, Kim TG, Cho YK. Korean Red Ginseng slows depletion of CD4 T cells in human immunodeficiency virus type 1-infected patients. Clin Diagn Lab Immunol 2005;12:497-501.
  36. Zhang H, Lu Z, Tan GT, Qiu S, Farnsworth NR, Pezzuto JM, Fong HHS. Polyacetyleneginsenoside-Ro, a novel triterpene saponin from Panax ginseng. Tetrahedron Lett 2002;43:973-7. https://doi.org/10.1016/S0040-4039(01)02310-3
  37. Lam SK, Ng TB. Sanchi ginseng (Panax notoginseng) with inhibitory effects on human immunodeficiency virus-1 reverse transcriptase. Life Sci 2002;70:3049-58. https://doi.org/10.1016/S0024-3205(02)01557-6
  38. Wang HX, Ng TB. Quinqueginsin, a novel protein with anti-human immunodeficiency virus, antifungal, ribonuclease and cell-free translation-inhibitory activities from American ginseng roots. Biochem Biophys Res Commun 2000;269:203-8. https://doi.org/10.1006/bbrc.2000.2114
  39. Blankson JN, Bailey JR, Thayil S, Yang HC, Lassen K, Lai J, Gandhi SK, Siliciano JD, Williams TM, Siliciano RF. Isolation and characterization of replication-competent human immunodeficiency virus type 1 from a subset of elite suppressors. J Virol 2007;81:2508-18. https://doi.org/10.1128/JVI.02165-06
  40. Kang KA, Piao MJ, Kim KC, Zheng J, Yao CW, Cha JW, Kim HS, Kim DH, Bae SC, Hyun JW. Compound K, a metabolite of ginseng saponin, inhibits colorectal cancer cell growth and induces apoptosis through inhibition of histone deacetylase activity. Int J Oncol 2013;43:1907-14. https://doi.org/10.3892/ijo.2013.2129

Cited by

  1. High Prevalence of Non-B HIV-1 Subtypes in Overseas Sailors and Prostitutes in Korea vol.34, pp.4, 2017, https://doi.org/10.1089/aid.2017.0238
  2. Genetic Analysis of the Full-Length gag Gene from the Earliest Korean Subclade B of HIV-1: An Outbreak among Korean Hemophiliacs vol.11, pp.6, 2017, https://doi.org/10.3390/v11060545
  3. Pharmacological effects of ginseng on infectious diseases vol.27, pp.5, 2017, https://doi.org/10.1007/s10787-019-00630-4
  4. Sequence Length of HIV-1 Subtype B Increases over Time: Analysis of a Cohort of Patients with Hemophilia over 30 Years vol.13, pp.5, 2017, https://doi.org/10.3390/v13050806