Current HIV/AIDS Reports

, Volume 7, Issue 2, pp 53–59

Systems Biology-Based Approaches to Understand HIV-Exposed Uninfected Women

  • Adam Burgener
  • J. Sainsbury
  • F. A. Plummer
  • T. Blake Ball


Worldwide HIV infects women more frequently than men, and it is clear that not all exposed to HIV become infected. Several populations of HIV-exposed uninfected (EU) women have been identified, including discordant couples and sex workers. Understanding what provides natural protection in EU women is critical in vaccine or microbicide development. However, correlates of protection in these women are still unclear. Most studies have used classical methods, examining single genes or cellular factors, a mainstay for traditional immunobiology. This reductionist approach may be limited in the information it can provide. Novel technologies are now available that allow us to take a “systems biology” approach, which allows the study of a complex biological system and identifies factors that may provide protection against HIV infection. Herein we report developments in discovery-based systems biology approaches in EU women and how this broadens our understanding of natural protection against HIV-1.


HIV/AIDS Proteomics Transcriptomics Systems biology HIV resistance Biomarkers Mucosal immunology 


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    UNAIDS: 2008 Report on the Global AIDS Epidemic. 2008.Google Scholar
  2. 2.
    Quinn TC, Overbaugh J: HIV/AIDS in women: an expanding epidemic. Science 2005, 308:1582–1583.CrossRefPubMedGoogle Scholar
  3. 3.
    Shattock RJ, Moore JP: Inhibiting sexual transmission of HIV-1 infection. Nat Rev Microbiol 2003, 1:25–34.CrossRefPubMedGoogle Scholar
  4. 4.
    Samson M, Libert F, Doranz BJ, et al.: Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996, 382:722–725.CrossRefPubMedGoogle Scholar
  5. 5.
    Stranford SA, Skurnick J, Louria D, et al.: Lack of infection in HIV-exposed individuals is associated with a strong CD8(+) cell noncytotoxic anti-HIV response. Proc Natl Acad Sci U S A 1999, 96:1030–1035.CrossRefPubMedGoogle Scholar
  6. 6.
    Boulet S, Sharafi S, Simic N, et al.: Increased proportion of KIR3DS1 homozygotes in HIV-exposed uninfected individuals. AIDS 2008, 22:595–599.CrossRefPubMedGoogle Scholar
  7. 7.
    Ball TB, Ji H, Kimani J, et al.: Polymorphisms in IRF-1 associated with resistance to HIV-1 infection in highly exposed uninfected Kenyan sex workers. AIDS 2007, 21:1091–1101.CrossRefPubMedGoogle Scholar
  8. 8.
    Wichukchinda N, Kitamura Y, Rojanawiwat A, et al.: The polymorphisms in DC-SIGNR affect susceptibility to HIV type 1 infection. AIDS Res Hum Retroviruses 2007, 23:686–692.CrossRefPubMedGoogle Scholar
  9. 9.
    Miyazawa M, Lopalco L, Mazzotta F, et al.: The “immunologic advantage” of HIV-exposed seronegative individuals. AIDS 2009, 23:161–175.CrossRefPubMedGoogle Scholar
  10. 10.
    Iqbal SM, Ball TB, Kimani J, et al.: Elevated T cell counts and RANTES expression in the genital mucosa of HIV-1-resistant Kenyan commercial sex workers. J Infect Dis 2005, 192:728–738.CrossRefPubMedGoogle Scholar
  11. 11.
    Hirbod T, Reichard C, Hasselrot K, et al.: HIV-1 neutralizing activity is correlated with increased levels of chemokines in saliva of HIV-1-exposed uninfected individuals. Curr HIV Res 2008, 6:28–33.CrossRefPubMedGoogle Scholar
  12. 12.
    Kaul R, Trabattoni D, Bwayo JJ, et al.: HIV-1-specific mucosal IgA in a cohort of HIV-1-resistant Kenyan sex workers. AIDS 1999, 13:23–29.CrossRefPubMedGoogle Scholar
  13. 13.
    Horton RE, Ball TB, Wachichi C, et al.: Cervical HIV-specific IgA in a population of commercial sex workers correlates with repeated exposure but not resistance to HIV. AIDS Res Hum Retroviruses 2008, 25:83–92.CrossRefGoogle Scholar
  14. 14.
    Valore EV, Park CH, Igreti SL, et al.: Antimicrobial components of vaginal fluid. Am J Obstet Gynecol 2002, 187:561–568.CrossRefPubMedGoogle Scholar
  15. 15.
    Cole AM: Innate host defense of human vaginal and cervical mucosae. Curr Top Microbiol Immunol 2006, 306:199–230.CrossRefPubMedGoogle Scholar
  16. 16.
    Venkataraman N, Cole AL, Svoboda P, et al.: Cationic polypeptides are required for anti-HIV-1 activity of human vaginal fluid. J Immunol 2005, 175:7560–7567.PubMedGoogle Scholar
  17. 17.
    Zhang L, Yu W, He T, et al.: Contribution of human alpha-defensin 1, 2, and 3 to the anti-HIV-1 activity of CD8 antiviral factor. Science 2002, 298:995–1000.CrossRefPubMedGoogle Scholar
  18. 18.
    Cocchi F, DeVico AL, Garzino-Demo A, et al.: Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 1995, 270:1811–1815.CrossRefPubMedGoogle Scholar
  19. 19.
    Crombie R, Silverstein RL, MacLow C, et al.: Identification of a CD36-related thrombospondin 1-binding domain in HIV-1 envelope glycoprotein gp120: relationship to HIV-1-specific inhibitory factors in human saliva. J Exp Med 1998, 187:25–35.CrossRefPubMedGoogle Scholar
  20. 20.
    Shaw JL, Smith CR, Diamandis EP: Proteomic analysis of human cervico-vaginal fluid. J Proteome Res 2007, 6:2859–2865.CrossRefPubMedGoogle Scholar
  21. 21.
    Kitano H: Systems biology: a brief overview. Science 2002, 295:1662–1664.CrossRefPubMedGoogle Scholar
  22. 22.
    Wang Z, Gerstein M, Snyder M: RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 2009, 10:57–63.CrossRefPubMedGoogle Scholar
  23. 23.
    Clark TA, Schweitzer TXC, Staples MK, et al.: Discovery of tissue-specific exons using comprehensive human exon microarrays. Genome Biology 2007, 8:R64.CrossRefPubMedGoogle Scholar
  24. 24.
    Velculescu VE, Zhang L, Vogelstein B, et al.: Serial analysis of gene expression. Science 1995, 270:484–487.CrossRefPubMedGoogle Scholar
  25. 25.
    Kodzius R, Kojima M, Nishiyori H, et al.: CAGE: cap analysis of gene expression. Nature Methods 2006, 3:211–222.CrossRefPubMedGoogle Scholar
  26. 26.
    Brenner S, Johnson M, Bridgham J, et al.: Gene expression analysis by massively parallel signature sequencing (MPSS) on microbead arrays. Nat Biotechnol 2000, 18:630–634.CrossRefPubMedGoogle Scholar
  27. 27.
    Mortazavi A, Williams BA, McCue K, et al.: Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nature Methods 2008, 5:621–628.CrossRefPubMedGoogle Scholar
  28. 28.
    Cicala C, Arthos J, Selig SM, et al.: HIV envelope induces a cascade of cell signals in non-proliferating target cells that favor virus replication. Proc Natl Acad Sci U S A 2002, 99:9380–9385.CrossRefPubMedGoogle Scholar
  29. 29.
    Harman AN, Kraus M, Bye CR, et al.: HIV-1-infected dendritic cells show 2 phases of gene expression changes, with lysosomal enzyme activity decreased during the second phase. Blood 2009, 114:85–94.CrossRefPubMedGoogle Scholar
  30. 30.
    • Missé D, Yssel H, Trabattoni D, et al.: IL-22 participates in an innate anti-HIV-1 host-resistance network through acute-phase protein induction. J Immunol 2007, 178:407–415. This article investigates global gene expression of EU women, identifying PRDX2 and IL-22 as genes that are overexpressed, including the A-SAA protein in blood plasma.Google Scholar
  31. 31.
    Geiden-Lynn R, Kursar M, Brown NV, et al.: HIV-1 antiviral activity of recombinant natural killer cell enhancing factors, NKEF-A and NKEF-B, members of the peroxiredoxin family. J Biol Chem 2003, 278:1569–1574.CrossRefGoogle Scholar
  32. 32.
    Bantscheff M, Schirle M, Sweetman G, et al.: Quantitative mass spectrometry in proteomics: a critical review. Anal Bioanal Chem 2007, 389:1017–1031.CrossRefPubMedGoogle Scholar
  33. 33.
    Domon B, Aebersold R: Mass spectrometry and protein analysis. Science 2006, 312:212–217.CrossRefPubMedGoogle Scholar
  34. 34.
    Fowke KR, Nagelkerke NJ, Kimani J, et al.: Resistance to HIV-1 infection among persistently seronegative prostitutes in Nairobi, Kenya. Lancet 1996, 348:1347–1351.CrossRefPubMedGoogle Scholar
  35. 35.
    • Burgener A, Boutilier J, Wachihi C, et al.: Identification of differentially expressed proteins in the cervical mucosa of HIV-1-resistant sex workers. J Proteome Res 2008, 7:4446–4454. This study reveals fundamental differences in protein expression in the cervical secretions of highly exposed uninfected women, showing they over-express serpin antiproteases and express fewer inflammatory immune mediators, such as complement components.Google Scholar
  36. 36.
    Burgener A, Ahmed R, Mesa C, et al.: HIV-1-resistant commercial sex workers overexpress antiproteases and antiviral factors in their cervical mucosa. Unpublished data 2009.Google Scholar
  37. 37.
    Wu WW, Wang G, Baek SJ, et al.: Comparative study of three proteomic quantitative methods, DIGE, cICAT, and iTRAQ, using 2D gel- or LC-MALDI TOF/TOF. J Proteome Res 2006, 5:651–658.CrossRefPubMedGoogle Scholar
  38. 38.
    • Iqbal SM, Ball TB, Levinson P, et al.: Elevated elafin/trappin-2 in the female genital tract is associated with protection against HIV acquisition. AIDS 2009, 23:1669–1677. This article identifies a serine protease inhibitor (elafin/trappin-2) to be overexpressed in the genital secretions of EU women in multiple SW cohorts. This protein was associated statistically with protection against HIV-1 infection.Google Scholar
  39. 39.
    Mangan MS, Kaiserman D, Bird PI: The role of serpins in vertebrate immunity. Tissue Antigens 2008, 72:1–10.CrossRefPubMedGoogle Scholar
  40. 40.
    Galliano MF, Toulza E, Jonca N, et al.: Binding of alpha2ML1 to the low density lipoprotein receptor-related protein 1 (LRP1) reveals a new role for LRP1 in the human epidermis. PLoS ONE 2008, 3:e2729.CrossRefPubMedGoogle Scholar
  41. 41.
    Li Q, Zhou XD, Xu XY, et al.: Recombinant human elafin protects airway epithelium integrity during inflammation. Mol Biol Rep 2009 Oct 13 (Epub ahead of print).Google Scholar
  42. 42.
    Benarafa C, Priebe GP, Remold-O’Donnell E: The neutrophil serine protease inhibitor serpinb1 preserves lung defense functions in Pseudomonas aeruginosa infection. J Exp Med 2007, 204:1901–1909.CrossRefPubMedGoogle Scholar
  43. 43.
    Schick C, Kamachi Y, Bartuski AJ, et al.: Squamous cell carcinoma antigen 2 is a novel serpin that inhibits the chymotrypsin-like proteinases cathepsin G and mast cell chymase. J Biol Chem 1997, 272:1849–1855.CrossRefPubMedGoogle Scholar
  44. 44.
    Moriuchi H, Moriuchi M, Fauci AS: Cathepsin G, a neutrophil-derived serine protease, increases susceptibility of macrophages to acute human immunodeficiency virus type 1 infection. J Virol 2000, 74:6849–6855.CrossRefPubMedGoogle Scholar
  45. 45.
    Congote LF: The C-terminal 26-residue peptide of serpin A1 is an inhibitor of HIV-1. Biochem Biophys Res Commun 2006, 343:617–622.CrossRefPubMedGoogle Scholar
  46. 46.
    Elmaleh DR, Brown NV, Geiben-Lynn R: Anti-viral activity of human antithrombin III. Int J Mol Med 2005, 16:191–200.PubMedGoogle Scholar
  47. 47.
    Ghosh M, Shen Z, Fahey JV, et al.: Trappin-2/elafin: a novel innate anti-human immunodeficiency virus-1 molecule of the human female reproductive tract. Immunology 2009 Jul 18 (Epub ahead of print).Google Scholar
  48. 48.
    Nagalakshmi ML, Rascle A, Zurawski S, et al.: Interleukin-22 activates STAT3 and induces IL-10 by colon epithelial cells. Int Immunopharmacol 2004, 4:679–691.CrossRefPubMedGoogle Scholar
  49. 49.
    Stoiber H, Pruenster M, Ammann CG, et al.: Complement-opsonized HIV: the free rider on its way to infection. Mol Immunol 2005, 42:153–160.CrossRefPubMedGoogle Scholar
  50. 50.
    Kerr FK, Thomas AR, Wijeyewickrema LC, et al.: Elucidation of the substrate specificity of the MASP-2 protease of the lectin complement pathway and identification of the enzyme as a major physiological target of the serpin, C1-inhibitor. Mol Immunol 2008, 45:670–677.CrossRefPubMedGoogle Scholar
  51. 51.
    Persidsky Y, Heilman D, Haorah J, et al.: Rho-mediated regulation of tight junctions during monocyte migration across the blood-brain barrier in HIV-1 encephalitis (HIVE). Blood 2006, 107:4770–4780.CrossRefPubMedGoogle Scholar
  52. 52.
    Chen X, Niyonsaba F, Ushio H, et al.: Synergistic effect of antibacterial agents human beta-defensins, cathelicidin LL-37 and lysozyme against Staphylococcus aureus and Escherichia coli. J Dermatol Sci 2005, 40:123–132.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Adam Burgener
    • 1
  • J. Sainsbury
    • 1
  • F. A. Plummer
    • 1
  • T. Blake Ball
    • 1
  1. 1.National Laboratory for HIV ImmunologyPublic Health Agency of CanadaWinnipegCanada

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