Journal of NeuroVirology

, Volume 23, Issue 4, pp 511–519 | Cite as

Genetics of HIV-associated sensory neuropathy and related pain in Africans

  • Huguette Gaelle Ngassa MbendaEmail author
  • Antonia Wadley
  • Zane Lombard
  • Catherine Cherry
  • Patricia Price
  • Peter Kamerman


Despite the use of safer antiretroviral medications, the rate of HIV-associated sensory neuropathy (HIV-SN), the most common neurological complication of HIV, remains high. This condition is often painful and has a negative effect on quality of life. Up to 90% of those with HIV-SN experience pain for which there is no effective analgesic treatment. Genetic factors are implicated, but there is a lack of a comprehensive body of research for African populations. This knowledge gap is even more pertinent as Africans are most affected by HIV. However, recent studies performed in Southern African populations have identified genes displaying potential as genetic markers for HIV-SN and HIV-SN-associated pain in Africans. Here, we review the published studies to describe current knowledge of genetic risk factors for this disease in Africa.


HIV neuropathy Pain Genetics Africa 



The authors are grateful to the School of Physiology, Faculty of Health Sciences, University of Witwatersrand for the intramural facilities. HGNM extends her sincere thanks to the URC and BFRG of the University for providing her a postdoctoral fellowship, and AW to the Hillel Friedland Trust for Fellowship funding. The authors gratefully acknowledge the contribution to this work of the Victorian Operational Infrastructure Support Program received by the Burnet Institute.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Affandi JS, Price P, Imran D et al (2008) Can we predict neuropathy risk before stavudine prescription in a resource-limited setting? AIDS Res Hum Retrovir 24:1281–1284CrossRefPubMedGoogle Scholar
  2. Angelini C, Bello L, Spinazzi M et al (2009) Mitochondrial disorders of the nuclear genome. Acta Myol XXVIII:16–23Google Scholar
  3. Arulkumaran N, Unwin RJ, Tam FW (2011) A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases. Expert Opin Investig Drugs 20:897–915CrossRefPubMedPubMedCentralGoogle Scholar
  4. Batini C, Coia V, Battaggia C et al (2006) Phylogeography of the human mitochondrial L1c haplogroup: genetic signatures of the prehistory of Central Africa. Mol Phyl Evol 43:635–644CrossRefGoogle Scholar
  5. Beggs S, Trang T, Salter MW (2012) P2X4R+ microglia drive neuropathic pain. Nat Neurosci 15:1068–1073CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bhatia NS, Chow FC (2016) Neurologic complications in treated HIV-1 infection. Curr Neurol Neurosci Rep 16:62CrossRefPubMedGoogle Scholar
  7. Canter JA, Kallianpur AR, Parl FF et al (2005) Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women. Cancer Res 65:8028–8033CrossRefPubMedGoogle Scholar
  8. Canter JA, Haas DW, Kallianpur AR et al (2008) The mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy. Pharmacogenomics J 8:71–77CrossRefPubMedGoogle Scholar
  9. Canter JA, Robbins GK, Selph D et al (2010) African mitochondrial DNA subhaplogroups and peripheral neuropathy during antiretroviral therapy. J Infect Dis 201:1703–1707CrossRefPubMedPubMedCentralGoogle Scholar
  10. Cettomai D, Kwasa J, Kendi C et al (2010) Utility of quantitative sensory testing and screening tools in identifying HIV-associated peripheral neuropathy in Western Kenya: pilot testing. PLoS One 5:e14256CrossRefPubMedPubMedCentralGoogle Scholar
  11. Chen Y-S, Torroni A, Excoffier L et al (1995) Analysis of mtDNA variation in African populations reveals the most ancient of all human continent-specific haplogroups. Am J Hum Genet 57:133–149PubMedPubMedCentralGoogle Scholar
  12. Chen G, Du WD, Cao HM (2007) Mitochondrial DNA mutations and related human diseases. Yi Chuan 29:1299–1308CrossRefPubMedGoogle Scholar
  13. Cherry C, Wesselingh S, Lal L et al (2005) Evaluation of a clinical screening tool for HIV-associated sensory neuropathies. Neurology 65:1778–1781CrossRefPubMedGoogle Scholar
  14. Cherry CL, Rosenow A, Affandi JS et al (2008) Cytokine genotype suggests a role for inflammation in nucleoside analog-associated sensory neuropathy (NRTI-SN) and predicts an individual’s NRTI-SN risk. AIDS Res Hum Retrovir 24:117–123CrossRefPubMedGoogle Scholar
  15. Cherry CL, Affandi JS, Imran D et al (2009) Age and height predict neuropathy risk in patients with HIV prescribed stavudine. Neurology 73:315–320CrossRefPubMedGoogle Scholar
  16. Cherry C, Affandi J, Brew BJ, et al (2011) Ethnicity is an independent predictor of neuropathy risk in HIV patients. Presented at the 18th Conference on Retroviruses and Opportunistic Infections. MA, USA, 27 February–2 March 2011Google Scholar
  17. Cherry CL, Wadley AL, Kamerman PR (2016) Diagnosing and treating HIV-associated sensory neuropathy: a global perspective. Pain Manag 6:191–199CrossRefPubMedGoogle Scholar
  18. Chew CS, Cherry CL, Imran D et al (2011) Tumour necrosis factor haplotypes associated with sensory neuropathy in Asian and Caucasian human immunodeficiency virus patients. Tissue Antigens 77:126–130CrossRefPubMedGoogle Scholar
  19. Chew CSN, Wadley AL, Lombard Z et al (2013) TNF haplotypes in a southern African population resemble those seen in Caucasians and Asians. Genes Immun 14:268–270CrossRefPubMedGoogle Scholar
  20. Clifford DB, Simpson DM, Brown S et al (2012) NGX-4010 C119 Study Group. A randomized, double-blind, controlled study of NGX-4010, a capsaicin 8% dermal patch, for the treatment of painful HIV-associated distal sensory polyneuropathy. J Acquir Immune Defic Syndr 59:126–133CrossRefPubMedGoogle Scholar
  21. Conrad DF, Jakobsson M, Coop G et al (2006) A worldwide survey of haplotype variation and linkage disequilibrium in the human genome. Nat Genet 38:1251–1260CrossRefPubMedGoogle Scholar
  22. Costigan M, Belfer I, Griffin RS et al (2010) Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1. Brain 133:2519–2527CrossRefPubMedPubMedCentralGoogle Scholar
  23. Darvishi K, Sharma S, Bhat AK et al (2007) Mitochondrial DNA G10398A polymorphism imparts maternal haplogroup N a risk for breast and esophageal cancer. Cancer Lett 249:249–255CrossRefPubMedGoogle Scholar
  24. Datta S, Majumder M, Biswas NK et al (2007) Increased risk of oral cancer in relation to common Indian mitochondrial polymorphisms and autosomal GSTP1 locus. Cancer 110:1991–1999CrossRefPubMedGoogle Scholar
  25. Distante S, Robson KJ, Graham-Campbell J et al (2004) The origin and spread of the HFE-C282Y haemochromatosis mutation. Hum Genet 115:269–279CrossRefPubMedGoogle Scholar
  26. Ellis RJ, Rosario D, Clifford DB, CHARTER Study Group et al (2010) Continued high prevalence and adverse clinical impact of human immunodeficiency virus-associated sensory neuropathy in the era of combination antiretroviral therapy: the CHARTER Study. Arch Neurol 67:552–558CrossRefPubMedPubMedCentralGoogle Scholar
  27. Erhardt A, Lucae S, Unschuld PG et al (2007) Association of polymorphisms in P2X7R and CaMKKb with anxiety disorders. J Affect Disord 101:159–168CrossRefPubMedGoogle Scholar
  28. Ferrari S, Vento S, Monaco S et al (2006) Human immunodeficiency virus-associated peripheral neuropathies. Mayo Clin Proc 81:213–219CrossRefPubMedGoogle Scholar
  29. Galantino MLA, Kietrys DM, Parrott JS et al (2014) Quality of life and self-reported lower extremity function in adults with HIV-related distal sensory polyneuropathy. Phys Ther 94:1455–1466CrossRefPubMedGoogle Scholar
  30. Gong QY, Chen Y (2015) Correlation between P2X7 receptor gene polymorphisms and gout. Rheumatol Int 35(8):1307–1310CrossRefPubMedGoogle Scholar
  31. Goullee HA, Wadley AL, Cherry CL et al (2016) Polymorphisms in CAMKK2 may predict sensory neuropathy in African HIV patients. J Neuro-Oncol 22:508–517Google Scholar
  32. Gurdasani D, Carstensen T, Tekola-Ayele F et al (2015) The African genome variation project shapes medical genetics in Africa. Nature 517:327–332CrossRefPubMedGoogle Scholar
  33. Hendry LM, Wadley AL, Cherry CL et al (2016) TNF block gene variants associated with pain intensity in black-southern Africans with HIV-associated sensory neuropathy. Clin J Pain 32:45–50CrossRefPubMedGoogle Scholar
  34. Hendry L, Lombard Z, Wadley A et al (2013) KCNS1, but not GCH1, is associated with pain intensity in a black southern African population with HIV associated sensory neuropathy: a genetic association study. J Acquir Immune Defic Syndr 63:2730CrossRefGoogle Scholar
  35. Holzinger ER, Hulgan T, Ellis RJ, Grant I for the CHARTER Group et al (2012) Mitochondrial DNA variation and HIV-associated sensory neuropathy in CHARTER. J Neurovirol 18:511–520CrossRefPubMedPubMedCentralGoogle Scholar
  36. Hulgan T, Haas DW, Haines JL et al (2005) Mitochondrial haplogroups and peripheral neuropathy during antiretroviral therapy: an adult AIDS clinical trials group study. AIDS 19:1341–1349CrossRefPubMedGoogle Scholar
  37. Jakobsson M, Scholz SW, Scheet P et al (2008) Genotype, haplotype and copy-number variation in worldwide human populations. Nature 451:998–1003CrossRefPubMedGoogle Scholar
  38. Kallianpur AR, Hulgan T, Canter JA et al (2006) Hemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy. AIDS 20:1503–1513CrossRefPubMedGoogle Scholar
  39. Kamerman PR, Wadley AL, Cherry CL (2012a) HIV-associated sensory neuropathy: risk factors and genetics. Curr Pain Headache Rep 16:226–236CrossRefPubMedGoogle Scholar
  40. Kamerman PR, Moss PJ, Weber J et al (2012b) Pathogenesis of HIV-associated sensory neuropathy: evidence from in vivo and in vitro experimental models. J Peripher Nerv Syst 17:19–31CrossRefPubMedGoogle Scholar
  41. Kamerman PR (2016) HIV-neuropathy: down, but not out.
  42. Kandiah PA, Atadzhanov M, Kvalsund MP et al (2010) Evaluating the diagnostic capacity of a single-question neuropathy screen (SQNS) in HIV positive Zambian adults. J Neurol Neurosurg Psychiatry 81:1380–1381CrossRefPubMedGoogle Scholar
  43. Kokubo M, Nishio M, Ribar TJ et al (2009) BDNF-mediated cerebellar granule cell development is impaired in mice null for CaMKK2 or CaMKIV. J Neurosci 29:8901–8913CrossRefPubMedPubMedCentralGoogle Scholar
  44. Kumar N, Sharma G, Kaur G et al (2012) Major histocompatibility complex class I chain related gene-A microsatellite polymorphism shows secondary association with type 1 diabetes and celiac disease in North Indians. Tissue Antigens 80:356–362CrossRefPubMedGoogle Scholar
  45. Lim TKY, Rone MB, Lee S et al (2015) Mitochondrial and bioenergetic dysfunction in trauma-induced painful peripheral neuropathy. Mol Pain 11:58CrossRefPubMedPubMedCentralGoogle Scholar
  46. Lismont C, Nordgren M, Van Veldhoven PP et al (2015) Redox interplay between mitochondria and peroxisomes. Front Cell Dev Biol 3:35CrossRefPubMedPubMedCentralGoogle Scholar
  47. Lucey BP, Clifford DB, Creighton J et al (2011) Relationship of depression and catastrophizing to pain, disability, and medication adherence in patients with HIV-associated sensory neuropathy. AIDS Care 23:921–928CrossRefPubMedPubMedCentralGoogle Scholar
  48. Lucotte G, Dieterlen F (2003) A European allele map of the C282Y mutation of hemochromatosis: Celtic versus Viking origin of the mutation? Blood Cells Mol Dis 31:262–267CrossRefPubMedGoogle Scholar
  49. Manchia M, Cullis J, Turecki G et al (2013) The impact of phenotypic and genetic heterogeneity on results of genome wide association studies of complex diseases. PLoS One 8:e76295CrossRefPubMedPubMedCentralGoogle Scholar
  50. Maritz J, Benatar M, Dave JA et al (2010) HIV neuropathy in South Africans: frequency, characteristics, and risk factors. Muscle Nerve 41:599–606PubMedGoogle Scholar
  51. Martinez A, Fernandez-Arquero M, Pascual-Salcedo D et al (2000) Primary association of tumor necrosis factor-region genetic markers with susceptibility to rheumatoid arthritis. Arthritis Rheum 43:1366–1370CrossRefPubMedGoogle Scholar
  52. Mattson MP, Liu D (2003) Mitochondrial potassium channels and uncoupling proteins in synaptic plasticity and neuronal cell death. Biochem Biophys Res Commun 304:539–549CrossRefPubMedGoogle Scholar
  53. Mehta SA, Ahmed A, Kariuki BW et al (2010) Implementation of a validated peripheral neuropathy screening tool in patients receiving antiretroviral therapy in Mombasa, Kenya. Am J Trop Med Hyg 83:565–570CrossRefPubMedPubMedCentralGoogle Scholar
  54. Mills EJ, Bakanda C, Birungi J et al (2011) Original research life expectancy of persons receiving combination antiretroviral therapy in low-income countries: a cohort analysis from Uganda. Ann Intern Med 155:206–216CrossRefGoogle Scholar
  55. Neurological Disorders (2007) Public health challenges. World Health Organization. Geneva: World Health OrganizationGoogle Scholar
  56. Phillips TJC, Cherry CL, Cox S et al (2010) Pharmacological treatment of painful HIV-associated sensory neuropathy: a systematic review and meta-analysis of randomised controlled trials. PLoS One 5:e14433CrossRefPubMedPubMedCentralGoogle Scholar
  57. Phillips TJC, Brown M, Ramirez JD et al (2014) Sensory, psychological, and metabolic dysfunction in HIV-associated peripheral neuropathy: a cross-sectional deep profiling study. Pain 155:1846–1860CrossRefPubMedPubMedCentralGoogle Scholar
  58. Pillay P, Wadley AL, Cherry CL et al (2015) Pharmacological treatment of painful HIV-associated sensory neuropathy. S Afr Med J 105:769–772CrossRefPubMedGoogle Scholar
  59. Rai E, Sharma S, Koul A et al (2007) Interaction between the UCP2-866G/A, mtDNA 10398G/A and PGC1alpha p.Thr394Thr and p.Gly482Ser polymorphisms in type 2 diabetes susceptibility in North Indian population. Hum Genet 122:535–540CrossRefPubMedGoogle Scholar
  60. Reich DE, Cargill M, Bolk S et al (2001) Linkage disequilibrium in the human genome. Nature 411:199–204CrossRefPubMedGoogle Scholar
  61. Rosa A, Brehm A (2011) African human mtDNA phylogeography at-a-glance. J Anthropol Sci 89:25–58PubMedGoogle Scholar
  62. Rudofsky G Jr, Schroedter A, Schlotterer A et al (2006) Functional polymorphisms of UCP2 and UCP3 are associated with a reduced prevalence of diabetic neuropathy in patients with type 1 diabetes. Diabetes Care 29:89–94CrossRefPubMedGoogle Scholar
  63. Saraste M (1999) Oxidative phosphorylation at the fin de siècle. Science 283:1488–1493CrossRefPubMedGoogle Scholar
  64. Saylor D, Dickens AM, Sacktor N et al (2016) HIV-associated neurocognitive disorder-pathogenesis and prospects for treatment. Nat Rev Neurol 12:234–248CrossRefPubMedPubMedCentralGoogle Scholar
  65. Scott JW, Park E, Rodriguiz RM et al (2015) Autophosphorylation of CaMKK2 generates autonomous activity that is disrupted by a T85S mutation linked to anxiety and bipolar disorder. Sci Rep 5:14436CrossRefPubMedPubMedCentralGoogle Scholar
  66. Sinxadi PZ, Dave JA, Samuels DC et al (2013) Mitochondrial genomics and antiretroviral therapy-associated metabolic complications in HIV-infected black South Africans: a pilot study. AIDS Res Hum Retrovir 29:1031–1039CrossRefPubMedPubMedCentralGoogle Scholar
  67. Smyth K, Affandi JS, McArthur JC et al (2007) Prevalence of and risk factors for HIV-associated neuropathy in Melbourne, Australia 1993–2006. HIV Med 8:367–373CrossRefPubMedGoogle Scholar
  68. Tegeder I, Costigan M, Griffin RS et al (2006) GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med 12:1269–1277CrossRefPubMedGoogle Scholar
  69. Teo Y-Y, Small KS, Kwiatkowski DP (2010) Methodological challenges of genome-wide association analysis in Africa. Nat Rev Genet 11:149–160CrossRefPubMedPubMedCentralGoogle Scholar
  70. Tishkoff SA, Verrelli BC (2003) Role of evolutionary history on haplotype block structure in the human genome: implication for disease mapping. Curr Opin Genet Dev 13:569–575CrossRefPubMedGoogle Scholar
  71. Tishkoff SA, Reed FA, Friedlaender FR et al (2009) The genetic structure and history of Africans and African Americans. Science 324:1035–1044CrossRefPubMedPubMedCentralGoogle Scholar
  72. Toomajian C, Kreitman M (2002) Sequence variation and haplotype structure at the human HFE locus. Genetics 161:1609–1623PubMedPubMedCentralGoogle Scholar
  73. Torroni A, Wallace DC (1994) Mitochondrial DNA variation in human populations and implications for detection of mitochondrial DNA mutations of pathological significance. J Bioenerg Biomembr 26:261–271CrossRefPubMedGoogle Scholar
  74. Torroni A, Huoponen K, Francalacci P et al (1996) Classification of European mtDNAs from an analysis of three European populations. Genet 144:1835–1850Google Scholar
  75. Tsuda M, Masuda T, Tozaki-Saitoh H et al (2013) P2X4 receptors and neuropathic pain. Front Cell Neurosci 7:191CrossRefPubMedPubMedCentralGoogle Scholar
  76. Tyor WR, Wesselingh SL, Griffin JW et al (1995) Unifying hypothesis for the pathogenesis of HIV-associated dementia complex, vacuolar myelopathy, and sensory neuropathy. J Acquir Immune Defic Syndr Hum Retrovirol 9:379–388CrossRefPubMedGoogle Scholar
  77. UNAIDS (2014) The gap report 2014.Google Scholar
  78. Valente FP, Tan CRT, Temple SE et al (2009) The evolution and diversity of TNF block haplotypes in European, Asian and Australian aboriginal populations. Genes Immun 10:607–615CrossRefPubMedGoogle Scholar
  79. Van Hecke O, Kamerman PR, Attal N et al (2015) Neuropathic pain phenotyping by international consensus (NeuroPPIC) for genetic studies: a NeuPSIG systematic review, Delphi survey, and expert panel recommendations. Pain 156:2337–2353CrossRefPubMedPubMedCentralGoogle Scholar
  80. Van Oosterhout JJ, Mallewa J, Kaunda S et al (2012) Stavudine toxicity in adult longer-term ART patients in Blantyre, Malawi. PLoS One 14:e42029CrossRefGoogle Scholar
  81. Van Sighem AI, Gras LAJ, Reiss P et al (2010) Life expectancy of recently diagnosed asymptomatic HIV-infected patients approaches that of uninfected individuals. AIDS 24:1527–1535CrossRefPubMedGoogle Scholar
  82. Wadley AL, Cherry CL, Price P et al (2011) HIV neuropathy risk factors and symptom characterization in stavudine-exposed South Africans. J Pain Symptom Manag 41:700–706CrossRefGoogle Scholar
  83. Wadley AL, Lombard Z, Cherry CL et al (2012) Analysis of a previously identified “pain protective” haplotype and individual polymorphisms in the GCH1 gene in Africans with HIV-associated sensory neuropathy: a genetic association study. J Acquir Immune Defic Syndr 60:20–23CrossRefPubMedGoogle Scholar
  84. Wadley AL, Lombard Z, Cherry CL et al (2013a) Polymorphisms in uncoupling protein genes UCP2 and UCP3 are not associated with HIV-associated sensory neuropathy in African individuals. J Peripher Nerv Syst 18:94–96CrossRefPubMedGoogle Scholar
  85. Wadley AL, Kamerman PR, Chew CSN et al (2013b) A polymorphism in IL4 may associate with sensory neuropathy in African HIV patients. Mol Immunol 55:197–199CrossRefPubMedGoogle Scholar
  86. Wadley AL, Hendry LM, Kamerman PR et al (2015) Role of TNF block genetic variants in HIV-associated sensory neuropathy in black southern Africans. Eur J Hum Genet 23:363–368CrossRefPubMedGoogle Scholar
  87. Watson E, Forster P, Richards M et al (1997) Mitochondrial footprints of human expansions in Africa. Am J Hum Genet 61:691–704CrossRefPubMedPubMedCentralGoogle Scholar
  88. Woldeamanuel YW, Kamerman PR, Veliotes DGA et al (2016) Development, validation, and field-testing of an instrument for clinical assessment of HIV-associated neuropathy and neuropathic pain in resource-restricted and large population study settings. PLoS One 11:e0164994CrossRefPubMedPubMedCentralGoogle Scholar
  89. World Health Organization (2010) Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach (2010 version).
  90. World Health Organization (2014) Global update on the health sector response to HIV.
  91. Ye K, Cao C, Lin X et al (2015) Natural selection on HFE in Asian populations contributes to enhanced non-heme iron absorption. BMC Genet 16:61CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2017

Authors and Affiliations

  • Huguette Gaelle Ngassa Mbenda
    • 1
    Email author
  • Antonia Wadley
    • 1
  • Zane Lombard
    • 2
    • 3
  • Catherine Cherry
    • 1
    • 4
  • Patricia Price
    • 1
    • 5
  • Peter Kamerman
    • 1
    • 5
  1. 1.School of Physiology, Faculty of Health SciencesUniversity of the WitwatersrandJohannesburgSouth Africa
  2. 2.Division of Human Genetics, Faculty of Health Sciences, School of PathologyUniversity of the WitwatersrandJohannesburgSouth Africa
  3. 3.National Health Laboratory ServiceJohannesburgSouth Africa
  4. 4.Center for Biomedical Research, Burnet Institute; Department of Infectious DiseasesAlfred Hospital and Monash UniversityMelbourneAustralia
  5. 5.Faculty of Health Sciences, School of Biomedical SciencesCurtin UniversityPerthAustralia

Personalised recommendations