Current HIV/AIDS Reports

, Volume 6, Issue 1, pp 20–28 | Cite as

HIV infection of the genital mucosa in women



The vast majority of new HIV infections are acquired via the genital and rectal mucosa. Here, we provide an overview of our current knowledge of how HIV establishes local infection, with an emphasis on viral invasion through the female genital tract. Studies using human explant tissues and in vivo animal studies have improved our understanding of the cellular and molecular pathways of infection; this information could be harnessed to design effective HIV vaccines and microbicides.


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References and Recommended Reading

  1. 1.
    Pendergrass PB, Belovicz MW, Reeves CA: Surface area of the human vagina as measured from vinyl polysiloxane casts. Gynecol Obstet Invest 2003, 55:110–113.PubMedCrossRefGoogle Scholar
  2. 2.
    Miller CJ, Li Q, Abel K, et al.: Propagation and dissemination of infection after vaginal transmission of simian immunodeficiency virus. J Virol 2005, 79:9217–9227.PubMedCrossRefGoogle Scholar
  3. 3.
    Kell PD, Barton SE, Edmonds DK, Boag FC: HIV infection in a patient with Meyer-Rokitansky-Kuster-Hauser syndrome. J R Soc Med 1992, 85:706–707.PubMedGoogle Scholar
  4. 4.
    Miller CJ, Alexander NJ, Vogel P, et al.: Mechanism of genital transmission of SIV: a hypothesis based on transmission studies and the location of SIV in the genital tract of chronically infected female rhesus macaques. J Med Primatol 1992, 21:64–68.PubMedGoogle Scholar
  5. 5.
    Padian NS, van der Straten A, Ramjee G, et al.: Diaphragm and lubricant gel for prevention of HIV acquisition in southern African women: a randomised controlled trial. Lancet 2007, 370:251–261.PubMedCrossRefGoogle Scholar
  6. 6.
    Joag SV, Adany I, Li Z, et al.: Animal model of mucosally transmitted human immunodeficiency virus type 1 disease: intravaginal and oral deposition of simian/human immunodeficiency virus in macaques results in systemic infection, elimination of CD4+ T cells, and AIDS. J Virol 1997, 71:4016–4023.PubMedGoogle Scholar
  7. 7.
    Howell AL, Edkins RD, Rier SE, et al.: Human immunodeficiency virus type 1 infection of cells and tissues from the upper and lower human female reproductive tract. J Virol 1997, 71:3498–3506.PubMedGoogle Scholar
  8. 8.
    Kaizu M, Weiler AM, Weisgrau KL, et al.: Repeated intravaginal inoculation with cell-associated simian immunodeficiency virus results in persistent infection of nonhuman primates. J Infect Dis 2006, 194:912–916.PubMedCrossRefGoogle Scholar
  9. 9.
    Khanna KV, Whaley KJ, Zeitlin L, et al.: Vaginal transmission of cell-associated HIV-1 in the mouse is blocked by a topical, membrane-modifying agent. J Clin Invest 2002, 109:205–211.PubMedGoogle Scholar
  10. 10.
    Zhu T, Wang N, Carr A, et al.: Genetic characterization of human immunodeficiency virus type 1 in blood and genital secretions: evidence for viral compartmentalization and selection during sexual transmission. J Virol 1996, 70:3098–3107.PubMedGoogle Scholar
  11. 11.
    Gupta P, Collins KB, Ratner D, et al.: Memory CD4(+) T cells are the earliest detectable human immunodeficiency virus type 1 (HIV-1)-infected cells in the female genital mucosal tissue during HIV-1 transmission in an organ culture system. J Virol 2002, 76:9868–9876.PubMedCrossRefGoogle Scholar
  12. 12.
    Maher D, Wu X, Schacker T, et al.: HIV binding, penetration, and primary infection in human cervicovaginal tissue. Proc Natl Acad Sci U S A 2005, 102:11504–11509.PubMedCrossRefGoogle Scholar
  13. 13.
    Ibata B, Parr EL, King NJ, Parr MB: Migration of foreign lymphocytes from the mouse vagina into the cervicovaginal mucosa and to the iliac lymph nodes. Biol Reprod 1997, 56:537–543.PubMedCrossRefGoogle Scholar
  14. 14.
    Phillips DM, Tan X, Perotti ME, Zacharopoulos VR: Mechanism of monocyte-macrophage-mediated transmission of HIV. AIDS Res Hum Retroviruses 1998, 14(Suppl 1):S67–S70.PubMedGoogle Scholar
  15. 15.
    Alfsen A, Yu H, Magerus-Chatinet A, et al.: HIV-1-infected blood mononuclear cells form an integrin- and agrin-dependent viral synapse to induce efficient HIV-1 transcytosis across epithelial cell monolayer. Mol Biol Cell 2005, 16:4267–4279.PubMedCrossRefGoogle Scholar
  16. 16.
    Van Herrewege Y, Michiels J, Waeytens A, et al.: A dual chamber model of female cervical mucosa for the study of HIV transmission and for the evaluation of candidate HIV microbicides. Antiviral Res 2007, 74:111–124.PubMedCrossRefGoogle Scholar
  17. 17.
    Dezzutti CS, Guenthner PC, Cummins JE Jr, et al.: Cervical and prostate primary epithelial cells are not productively infected but sequester human immunodeficiency virus type 1. J Infect Dis 2001, 183:1204–1213.PubMedCrossRefGoogle Scholar
  18. 18.
    Wu Z, Chen Z, Phillips DM: Human genital epithelial cells capture cell-free human immunodeficiency virus type 1 and transmit the virus to CD4+ cells: implications for mechanisms of sexual transmission. J Infect Dis 2003, 188:1473–1482.PubMedCrossRefGoogle Scholar
  19. 19.
    Bomsel M: Transcytosis of infectious human immunodeficiency virus across a tight human epithelial cell line barrier. Nat Med 1997, 3:42–47.PubMedCrossRefGoogle Scholar
  20. 20.
    Bobardt MD, Chatterji U, Selvarajah S, et al.: Cell-free human immunodeficiency virus type 1 transcytosis through primary genital epithelial cells. J Virol 2007, 81:395–405.PubMedCrossRefGoogle Scholar
  21. 21.
    Greenhead P, Hayes P, Watts PS, et al.: Parameters of human immunodeficiency virus infection of human cervical tissue and inhibition by vaginal virucides. J Virol 2000, 74:5577–5586.PubMedCrossRefGoogle Scholar
  22. 22.
    Hladik F, Sakchalathorn P, Ballweber L, et al.: Initial events in establishing vaginal entry and infection by human immunodeficiency virus type-1. Immunity 2007, 26:257–270.PubMedCrossRefGoogle Scholar
  23. 23.
    Furuta Y, Eriksson K, Svennerholm B, et al.: Infection of vaginal and colonic epithelial cells by the human immunodeficiency virus type 1 is neutralized by antibodies raised against conserved epitopes in the envelope glycoprotein gp120. Proc Natl Acad Sci U S A 1994, 91:12559–12563.PubMedCrossRefGoogle Scholar
  24. 24.
    Stoddard E, Cannon G, Ni H, et al.: gp340 expressed on human genital epithelia binds HIV-1 envelope protein and facilitates viral transmission. J Immunol 2007, 179:3126–3132.PubMedGoogle Scholar
  25. 25.
    Munch J, Standker L, Adermann K, et al.: Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide. Cell 2007, 129:263–275.PubMedCrossRefGoogle Scholar
  26. 26.
    Hu J, Gardner MB, Miller CJ: Simian immunodeficiency virus rapidly penetrates the cervicovaginal mucosa after intravaginal inoculation and infects intraepithelial dendritic cells. J Virol 2000, 74:6087–6095.PubMedCrossRefGoogle Scholar
  27. 27.
    Miller CJ, McChesney M, Moore PF: Langerhans cells, macrophages and lymphocyte subsets in the cervix and vagina of rhesus macaques. Lab Invest 1992, 67:628–634.PubMedGoogle Scholar
  28. 28.
    Yeaman GR, Asin S, Weldon S, et al.: Chemokine receptor expression in the human ectocervix: implications for infection by the human immunodeficiency virus-type I. Immunology 2004, 113:524–533.PubMedCrossRefGoogle Scholar
  29. 29.
    Tschachler E, Groh V, Popovic M, et al.: Epidermal Langerhans cells—a target for HTLV-III/LAV infection. J Invest Dermatol 1987, 88:233–237.PubMedCrossRefGoogle Scholar
  30. 30.
    Kawamura T, Cohen SS, Borris DL, et al.: Candidate microbicides block HIV-1 infection of human immature Langerhans cells within epithelial tissue explants. J Exp Med 2000, 192:1491–1500.PubMedCrossRefGoogle Scholar
  31. 31.
    Collins KB, Patterson BK, Naus GJ, et al.: Development of an in vitro organ culture model to study transmission of HIV-1 in the female genital tract. Nat Med 2000, 6:475–479.PubMedCrossRefGoogle Scholar
  32. 32.
    Hu Q, Frank I, Williams V, et al.: Blockade of attachment and fusion receptors inhibits HIV-1 infection of human cervical tissue. J Exp Med 2004, 199:1065–1075.PubMedCrossRefGoogle Scholar
  33. 33.
    Turville SG, Cameron PU, Handley A, et al.: Diversity of receptors binding HIV on dendritic cell subsets. Nat Immunol 2002, 3:975–983.PubMedCrossRefGoogle Scholar
  34. 34.
    Geijtenbeek TB, Kwon DS, Torensma R, et al.: DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 2000, 100:587–597.PubMedCrossRefGoogle Scholar
  35. 35.
    Jameson B, Baribaud F, Pohlmann S, et al.: Expression of DC-SIGN by dendritic cells of intestinal and genital mucosae in humans and rhesus macaques. J Virol 2002, 76:1866–1875.PubMedCrossRefGoogle Scholar
  36. 36.
    Pope M, Gezelter S, Gallo N, et al.: Low levels of HIV-1 infection in cutaneous dendritic cells promote extensive viral replication upon binding to memory CD4+ T cells. J Exp Med 1995, 182:2045–2056.PubMedCrossRefGoogle Scholar
  37. 37.
    Gummuluru S, Rogel M, Stamatatos L, Emerman M: Binding of human immunodeficiency virus type 1 to immature dendritic cells can occur independently of DC-SIGN and mannose binding C-type lectin receptors via a cholesteroldependent pathway. J Virol 2003, 77:12865–12874.PubMedCrossRefGoogle Scholar
  38. 38.
    Boggiano C, Manel N, Littman DR: Dendritic cell-mediated trans-enhancement of human immunodeficiency virus type 1 infectivity is independent of DC-SIGN. J Virol 2007, 81:2519–2523.PubMedCrossRefGoogle Scholar
  39. 39.
    de Witte L, Nabatov A, Pion M, et al.: Langerin is a natural barrier to HIV-1 transmission by Langerhans cells. Nat Med 2007, 13:367–371.PubMedCrossRefGoogle Scholar
  40. 40.
    Johansson EL, Rudin A, Wassen L, Holmgren J: Distribution of lymphocytes and adhesion molecules in human cervix and vagina. Immunology 1999, 96:272–277.PubMedCrossRefGoogle Scholar
  41. 41.
    Hladik F, Lentz G, Delpit E, et al.: Coexpression of CCR5 and IL-2 in human genital but not blood T cells: implications for the ontogeny of the CCR5+ Th1 phenotype. J Immunol 1999, 163:2306–2313.PubMedGoogle Scholar
  42. 42.
    Zhang L, He T, Talal A, et al.: In vivo distribution of the human immunodeficiency virus/simian immunodeficiency virus coreceptors: CXCR4, CCR3, and CCR5. J Virol 1998, 72:5035–5045.PubMedGoogle Scholar
  43. 43.
    Zhang Z, Schuler T, Zupancic M, et al.: Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science 1999, 286:1353–1357.PubMedCrossRefGoogle Scholar
  44. 44.
    Veazey RS, Marx PA, Lackner AA: Vaginal CD4+ T cells express high levels of CCR5 and are rapidly depleted in simian immunodeficiency virus infection. J Infect Dis 2003, 187:769–776.PubMedCrossRefGoogle Scholar
  45. 45.
    Zhang ZQ, Wietgrefe SW, Li Q, et al.: Roles of substrate availability and infection of resting and activated CD4+ T cells in transmission and acute simian immunodeficiency virus infection. Proc Natl Acad Sci U S A 2004, 101:5640–5645.PubMedCrossRefGoogle Scholar
  46. 46.
    Cummins JE Jr, Guarner J, Flowers L, et al.: Preclinical testing of candidate topical microbicides for anti-human immunodeficiency virus type 1 activity and tissue toxicity in a human cervical explant culture. Antimicrob Agents Chemother 2007, 51:1770–1779.PubMedCrossRefGoogle Scholar
  47. 47.
    Hladik F, Lentz G, Akridge RE, et al.: Dendritic cell-T-cell interactions support coreceptor-independent human immunodeficiency virus type 1 transmission in the human genital tract. J Virol 1999, 73:5833–5842.PubMedGoogle Scholar
  48. 48.
    Tuttle DL, Harrison JK, Anders C, et al.: Expression of CCR5 increases during monocyte differentiation and directly mediates macrophage susceptibility to infection by human immunodeficiency virus type 1. J Virol 1998, 72:4962–4969.PubMedGoogle Scholar
  49. 49.
    Spira AI, Marx PA, Patterson BK, et al.: Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques. J Exp Med 1996, 183:215–225.PubMedCrossRefGoogle Scholar
  50. 50.
    Bobardt MD, Saphire AC, Hung HC, et al.: Syndecan captures, protects, and transmits HIV to T lymphocytes. Immunity 2003, 18:27–39.PubMedCrossRefGoogle Scholar
  51. 51.
    Marechal V, Prevost MC, Petit C, et al.: Human immunodeficiency virus type 1 entry into macrophages mediated by macropinocytosis. J Virol 2001, 75:11166–11177.PubMedCrossRefGoogle Scholar
  52. 52.
    Sharova N, Swingler C, Sharkey M, Stevenson M: Macrophages archive HIV-1 virions for dissemination in trans. Embo J 2005, 24:2481–2489.PubMedCrossRefGoogle Scholar
  53. 53.
    Nestle FO, Nickoloff BJ: Deepening our understanding of immune sentinels in the skin. J Clin Invest 2007, 117:2382–2385.PubMedCrossRefGoogle Scholar
  54. 54.
    Wu L, KewalRamani VN: Dendritic-cell interactions with HIV: infection and viral dissemination. Nat Rev Immunol 2006, 6:859–868.PubMedCrossRefGoogle Scholar
  55. 55.
    Prakash M, Kapembwa MS, Gotch F, Patterson S: Chemokine receptor expression on mucosal dendritic cells from the endocervix of healthy women. J Infect Dis 2004, 190:246–250.PubMedCrossRefGoogle Scholar
  56. 56.
    Bhoopat L, Eiangleng L, Rugpao S, et al.: In vivo identification of Langerhans and related dendritic cells infected with HIV-1 subtype E in vaginal mucosa of asymptomatic patients. Mod Pathol 2001, 14:1263–1269.PubMedCrossRefGoogle Scholar
  57. 57.
    Harada H, Goto Y, Ohno T, et al.: Proliferative activation up-regulates expression of CD4 and HIV-1 co-receptors on NK cells and induces their infection with HIV-1. Eur J Immunol 2007, 37:2148–2155.PubMedCrossRefGoogle Scholar
  58. 58.
    Rappocciolo G, Piazza P, Fuller CL, et al.: DC-SIGN on B lymphocytes is required for transmission of HIV-1 to T lymphocytes. PLoS Pathog 2006, 2:e70.PubMedCrossRefGoogle Scholar
  59. 59.
    Leon B, Lopez-Bravo M, Ardavin C: Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against Leishmania. Immunity 2007, 26:519–531.PubMedCrossRefGoogle Scholar
  60. 60.
    McDonald D, Wu L, Bohks SM, et al.: Recruitment of HIV and its receptors to dendritic cell-T cell junctions. Science 2003, 300:1295–1297.PubMedCrossRefGoogle Scholar
  61. 61.
    Hladik F, McElrath MJ: Setting the stage: host invasion by HIV. Nat Rev Immunol 2008, 8:447–457.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2009

Authors and Affiliations

  1. 1.Fred Hutchinson Cancer Research CenterSeattleUSA

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