Human Genetic Variation and HIV/AIDS in Papua New Guinea: Time to Connect the Dots
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Purpose of Review
Human genetic polymorphisms known to influence HIV acquisition and disease progression occur in Papua New Guinea (PNG). However, no genetic association study has been reported so far. In this article, we review research findings, with a view to stimulate genotype-to-phenotype research.
PNG, a country in Oceania, has a high prevalence of HIV and many sexually transmitted infections. While limited data is available from this country regarding the distribution of human genetic polymorphisms known to influence clinical outcomes of HIV/AIDS, genetic association studies are lacking. Our studies, in the past decade, have revealed that polymorphisms in chemokine receptor-ligand (CCR2-CCR5, CXCL12), innate immune (Toll-like receptor, β-defensin), and antiretroviral drug-metabolism enzyme (CYP2B6, UGT2B7) genes are prevalent in PNG.
Although our results need to be validated in further studies, it is urgent to pursue large-scale, comprehensive genetic association studies that include these as well as additional genetic polymorphisms.
KeywordsCCR5 CYP2B6 HIV/AIDS. Human genetic variation Papua New Guinea
I dedicate this review to my respected friend and guide Dr. Mark Stoneking (Max Planck Institute for Evolutionary Anthropology, Germany), who has inspired me through his worldwide work on human genetics.
I have undoubtedly been influenced, in the present work, by the advice and assistance which I have received from my teachers, friends, and fellow workers. Such help is impossible to assess, or even to define. Though nameless here, they are not forgotten and I offer my sincere gratitude to them. Nevertheless, I take full responsibility for all the views expressed in this article, and if I have fallen into errors, the fault is mine, and not attributable to those who have helped me.
This work was supported by a Development Award from the Center for AIDS Research, University Hospitals Case Medical Center, Cleveland, OH, U.S.A. (NIH grant #AI36219); an Infectious Diseases Research Support from STERIS Corporation, Mentor, OH, U.S.A. and a Large Pilot Grant from the Case Western Reserve University/Cleveland Clinic CTSA grant #UL1RR024989 (National Center for Research Resources, NIH). Financial support was also provided by the Fogarty International Center (NIH, D43TW007377).
Compliance with Ethical Standards
Conflict of Interest
The author declares that he has no competing interests.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by the author.
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- 11.Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science. 1996;273(5283):1856–62.CrossRefGoogle Scholar
- 13.Zimmerman PA, Buckler-White A, Alkhatib G, Spalding T, Kubofcik J, Combadiere C, et al. Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk. Mol Med. 1997;3(1):23–36.CrossRefGoogle Scholar
- 14.• Smolen-Dzirba J, Rosinska M, Janiec J, Beniowski M, Cycon M, Bratosiewicz-Wasik J, et al. HIV-1 infection in persons homozygous for CCR5-delta32 allele: the next case and the review. AIDS Rev. 2017;19(4):219–30 This paper describes the latest person homozygous for CCR5 ∆32, who was infected with subtype B HIV-1.PubMedGoogle Scholar
- 15.•• Mehlotra RK, Zimmerman PA, Weinberg A. Defensin gene variation and HIV/AIDS: a comprehensive perspective needed. J Leukoc Biol. 2016;99(5):687–92. https://doi.org/10.1189/jlb.6RU1215-560R This article provides reasons to study all possible defensin gene polymorphisms collectivly in order to gain better insights into their relationship with HIV/AIDS outcomes.CrossRefPubMedGoogle Scholar
- 21.•• Neary M, Owen A. Pharmacogenetic considerations for HIV treatment in different ethnicities: an update. Expert Opin Drug Metab Toxicol. 2017;13(11):1169–81. https://doi.org/10.1080/17425255.2017.1391214 This article presents findings that would aid in the understanding of the extent and impact of pharmacogenetic variants in different populations, and the consequences this has for achieving sustained virological response to antiretroviral therapy.CrossRefPubMedGoogle Scholar
- 24.Vallely A, Ryan CE, Allen J, Sauk JC, Simbiken CS, Wapling J, et al. High prevalence and incidence of HIV, sexually transmissible infections and penile foreskin cutting among sexual health clinic attendees in Papua New Guinea. Sex Health. 2014;11(1):58–66. https://doi.org/10.1071/SH13197.CrossRefPubMedGoogle Scholar
- 25.•• Vallely LM, Toliman P, Ryan C, Rai G, Wapling J, Tomado C, et al. Prevalence and risk factors of Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and other sexually transmissible infections among women attending antenatal clinics in three provinces in Papua New Guinea: a cross-sectional survey. Sex Health. 2016;13(5):420–7. https://doi.org/10.1071/SH15227 This paper provides a comprehensive account of many sexually transmitted infections in PNG.CrossRefPubMedGoogle Scholar
- 26.•• Gare J, Kelly-Hanku A, Ryan CE, David M, Kaima P, Imara U, et al. Factors influencing antiretroviral adherence and virological outcomes in people living with HIV in the highlands of Papua New Guinea. PLoS One. 2015;10(8):e0134918. https://doi.org/10.1371/journal.pone.0134918 This paper describes important findings related to ART use, adherence, and outcomes in the highland areas of PNG.CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Wand H, Siba P. Prevalence and correlates of HIV infection among sex workers in Papua New Guinea: first results from the Papua New Guinea and Australia Sexual Health Improvement Project (PASHIP). AIDS Behav. 2015;19(12):2194–203. https://doi.org/10.1007/s10461-015-1096-9.CrossRefPubMedGoogle Scholar
- 30.Kelly-Hanku A, Vallely A, Man WY, Wilson D, Law G, Gray R. A systematic review of heterosexual anal intercourse and its role in the transmission of HIV and other sexually transmitted infections in Papua New Guinea. BMC Public Health. 2013;13:1108. https://doi.org/10.1186/1471-2458-13-1108.CrossRefPubMedPubMedCentralGoogle Scholar
- 34.•• Lavu E, Kave E, Mosoro E, Markby J, Aleksic E, Gare J, et al. High levels of transmitted HIV drug resistance in a study in Papua New Guinea. PLoS One. 2017;12(2):e0170265. https://doi.org/10.1371/journal.pone.0170265 This paper describes latest findings related to ART resistance in PNG.CrossRefPubMedPubMedCentralGoogle Scholar
- 38.Su B, Jin L, Hu F, Xiao J, Luo J, Lu D, et al. Distribution of two HIV-1-resistant polymorphisms (SDF1-3′A and CCR2-64I) in East Asian and world populations and its implication in AIDS epidemiology. Am J Hum Genet. 1999;65(4):1047–53. https://doi.org/10.1086/302568.CrossRefPubMedPubMedCentralGoogle Scholar
- 40.•• Mehlotra RK, Hall NB, Bruse SE, John B, Blood Zikursh MJ, Stein CM, et al. CCR2, CCR5, and CXCL12 variation and HIV/AIDS in Papua New Guinea. Infect Genet Evol. 2015;36:165–73. https://doi.org/10.1016/j.meegid.2015.09.014 This study describes, for the first time, the prevalence of CCR5 haplotypes in PNG.CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Li J, Menard V, Benish RL, Jurevic RJ, Guillemette C, Stoneking M, et al. Worldwide variation in human drug-metabolism enzyme genes CYP2B6 and UGT2B7: implications for HIV/AIDS treatment. Pharmacogenomics. 2012;13(5):555–70. https://doi.org/10.2217/pgs.11.160.CrossRefPubMedPubMedCentralGoogle Scholar
- 45.Mummidi S, Bamshad M, Ahuja SS, Gonzalez E, Feuillet PM, Begum K, et al. Evolution of human and non-human primate CC chemokine receptor 5 gene and mRNA. Potential roles for haplotype and mRNA diversity, differential haplotype-specific transcriptional activity, and altered transcription factor binding to polymorphic nucleotides in the pathogenesis of HIV-1 and simian immunodeficiency virus. J Biol Chem. 2000;275(25):18946–61. https://doi.org/10.1074/jbc.M000169200.CrossRefPubMedGoogle Scholar
- 46.Gonzalez E, Dhanda R, Bamshad M, Mummidi S, Geevarghese R, Catano G, et al. Global survey of genetic variation in CCR5, RANTES, and MIP-1a: impact on the epidemiology of the HIV-1 pandemic. Proc Natl Acad Sci U S A. 2001;98(9):5199–204. https://doi.org/10.1073/pnas.091056898.CrossRefPubMedPubMedCentralGoogle Scholar
- 47.Coloccini RS, Dilernia D, Ghiglione Y, Turk G, Laufer N, Rubio A, et al. Host genetic factors associated with symptomatic primary HIV infection and disease progression among Argentinean seroconverters. PLoS One. 2014;9(11):e113146. https://doi.org/10.1371/journal.pone.0113146.CrossRefPubMedPubMedCentralGoogle Scholar
- 48.Jaumdally SZ, Picton A, Tiemessen CT, Paximadis M, Jaspan HB, Gamieldien H, et al. CCR5 expression, haplotype and immune activation in protection from infection in HIV-exposed uninfected individuals in HIV-serodiscordant relationships. Immunology. 2017;151(4):464–73. https://doi.org/10.1111/imm.12743.CrossRefPubMedPubMedCentralGoogle Scholar
- 52.Beima-Sofie KM, Bigham AW, Lingappa JR, Wamalwa D, Mackelprang RD, Bamshad MJ, et al. Toll-like receptor variants are associated with infant HIV-1 acquisition and peak plasma HIV-1 RNA level. AIDS. 2013;27(15):2431–9. https://doi.org/10.1097/QAD.0b013e3283629117.CrossRefPubMedPubMedCentralGoogle Scholar
- 57.Soriano-Sarabia N, Vallejo A, Ramirez-Lorca R, Rodriguez Mdel M, Salinas A, Pulido I, et al. Influence of the Toll-like receptor 9 1635A/G polymorphism on the CD4 count, HIV viral load, and clinical progression. J Acquir Immune Defic Syndr. 2008;49(2):128–35. https://doi.org/10.1097/QAI.0b013e318184fb41.CrossRefPubMedGoogle Scholar
- 61.Manning L, Cutts J, Stanisic DI, Laman M, Carmagnac A, Allen S, et al. A Toll-like receptor-1 variant and its characteristic cellular phenotype is associated with severe malaria in Papua New Guinean children. Genes Immun. 2016;17(1):52–9. https://doi.org/10.1038/gene.2015.50.CrossRefPubMedGoogle Scholar
- 62.• Willie B, Gare J, King CL, Zimmerman PA, Mehlotra RK. A preliminary assessment of Toll-like receptor and b-defensin gene polymorphisms in Papua New Guinea - what does it mean for HIV/AIDS? PNG Med J. 2017; In press. This study provides a preliminary, but first, description of b-defensin copy number variation in PNG.Google Scholar
- 68.Jansen PA, Rodijk-Olthuis D, Hollox EJ, Kamsteeg M, Tjabringa GS, de Jongh GJ, et al. b-defensin-2 protein is a serum biomarker for disease activity in psoriasis and reaches biologically relevant concentrations in lesional skin. PLoS One. 2009;4(3):e4725. https://doi.org/10.1371/journal.pone.0004725.CrossRefPubMedPubMedCentralGoogle Scholar
- 72.Mehlotra RK, Dazard JE, John B, Zimmerman PA, Weinberg A, Jurevic RJ. Copy number variation within human beta-defensin gene cluster influences progression to AIDS in the Multicenter AIDS Cohort Study. J AIDS Clin Res. 2012;3(10). https://doi.org/10.4172/2155-6113.1000184.
- 73.Abujaber R, Shea PR, McLaren PJ, Lakhi S, Gilmour J, Allen S, et al. No evidence for association of beta-defensin genomic copy number with HIV susceptibility, HIV load during clinical latency, or progression to AIDS. Ann Hum Genet. 2017;81(1):27–34. https://doi.org/10.1111/ahg.12182.CrossRefPubMedGoogle Scholar
- 74.Hardwick RJ, Machado LR, Zuccherato LW, Antolinos S, Xue Y, Shawa N, et al. A worldwide analysis of beta-defensin copy number variation suggests recent selection of a high-expressing DEFB103 gene copy in East Asia. Hum Mutat. 2011;32(7):743–50. https://doi.org/10.1002/humu.21491.CrossRefPubMedPubMedCentralGoogle Scholar
- 77.•• Aia P, Kal M, Lavu E, John LN, Johnson K, Coulter C, et al. The burden of drug-resistant tuberculosis in Papua New Guinea: results of a large population-based survey. PLoS One. 2016;11(3):e0149806. https://doi.org/10.1371/journal.pone.0149806 This study provides first comprehensive account of drug-resistant tuberculosis in PNG.CrossRefPubMedPubMedCentralGoogle Scholar
- 79.Ward BA, Gorski JC, Jones DR, Hall SD, Flockhart DA, Desta Z. The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther. 2003;306(1):287–300. https://doi.org/10.1124/jpet.103.049601.CrossRefPubMedGoogle Scholar
- 81.Hofmann MH, Blievernicht JK, Klein K, Saussele T, Schaeffeler E, Schwab M, et al. Aberrant splicing caused by single nucleotide polymorphism c.516G>T [Q172H], a marker of CYP2B6*6, is responsible for decreased expression and activity of CYP2B6 in liver. J Pharmacol Exp Ther. 2008;325(1):284–92. https://doi.org/10.1124/jpet.107.133306.CrossRefPubMedGoogle Scholar
- 82.Mehlotra RK, Cheruvu VK, Blood Zikursh MJ, Benish RL, Lederman MM, Salata RA, et al. Chemokine (C-C motif) receptor 5-2459 genotype in patients receiving highly active antiretroviral therapy: race-specific influence on virologic success. J Infect Dis. 2011;204(2):291–8. https://doi.org/10.1093/infdis/jir262.CrossRefPubMedPubMedCentralGoogle Scholar
- 85.• Duarte H, Cruz JP, Aniceto N, Ribeiro AC, Fernandes A, Paixao P, et al. Population approach to efavirenz therapy. J Pharm Sci. 2017;106(10):3161–6. https://doi.org/10.1016/j.xphs.2017.06.004 This study provides further results to suggest why in CYP2B6*6 / *6 (or 516TT) homozygous individuals an efavirenz dose adjustment is necessary.CrossRefPubMedGoogle Scholar
- 88.Belanger AS, Caron P, Harvey M, Zimmerman PA, Mehlotra RK, Guillemette C. Glucuronidation of the antiretroviral drug efavirenz by UGT2B7 and an in vitro investigation of drug-drug interaction with zidovudine. Drug Metab Dispos. 2009;37(9):1793–6. https://doi.org/10.1124/dmd.109.027706.CrossRefPubMedPubMedCentralGoogle Scholar
- 89.Innocenti F, Liu W, Fackenthal D, Ramirez J, Chen P, Ye X, et al. Single nucleotide polymorphism discovery and functional assessment of variation in the UDP-glucuronosyltransferase 2B7 gene. Pharmacogenet Genomics. 2008;18(8):683–97. https://doi.org/10.1097/FPC.0b013e3283037fe4.CrossRefPubMedPubMedCentralGoogle Scholar
- 91.Haas DW, Kwara A, Richardson DM, Baker P, Papageorgiou I, Acosta EP, et al. Secondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes. J Antimicrob Chemother. 2014;69(8):2175–82. https://doi.org/10.1093/jac/dku110.CrossRefPubMedPubMedCentralGoogle Scholar
- 95.John E, Christiansen FT, Mueller I, Schofield L, Senitzer D, Siba P, et al. Distinct distribution of killer-cell immunoglobulin-like receptor genes in the Mugil and Ilaita areas of Papua New Guinea. Tissue Antigens. 2012;79(4):263–71. https://doi.org/10.1111/j.1399-0039.2012.01848.x.CrossRefPubMedGoogle Scholar
- 96.•• Tucci JD, Pumuye PP, Helsby NA, Barratt DT, Pokeya PP, Hombhanje F, et al. Pharmacogenomics in Papua New Guineans: unique profiles and implications for enhancing drug efficacy while improving drug safety. Pharmacogenet Genomics. 2018;28(6):153–64. https://doi.org/10.1097/FPC.0000000000000335 This is the first comprehensive account of pharmacogenetic variation related to infectious diseases in PNG.CrossRefPubMedGoogle Scholar
- 97.• Bergstrom A, Oppenheimer SJ, Mentzer AJ, Auckland K, Robson K, Attenborough R, et al. A Neolithic expansion, but strong genetic structure, in the independent history of New Guinea. Science. 2017;357(6356):1160–3. https://doi.org/10.1126/science.aan3842 This study provides genome-wide data related to Papua New Guineans.CrossRefPubMedPubMedCentralGoogle Scholar