Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Inhibiting sexual transmission of HIV-1 infection

Nature Reviews Microbiology volume 1, pages 25–34 (2003)Cite this article

Key Points

  • The sexual transmission of HIV-1 is mediated by exposure to HIV-1-infected cells and/or infectious virus in mucosal secretions or semen.

  • The stratified mucosal epithelium and the endocervical epithelium form effective barriers against HIV-1 or HIV-1-infected cells; however, breaches in the integrity of these barriers are frequent, increasing susceptibility to infection. Once the epithelial barriers have been breached, HIV-1 can target cells in the underlying epithelial layers, including T cells, dendritic cells and macrophages.

  • Fundamental research into the mechanisms of HIV-1 binding and entry into host cells has facilitated the logical identification of suitable and logical targets for microbicides that are aimed at inhibiting the sexual transmission of HIV-1.

  • The development of topical microbicides that inhibit HIV-1 attachment to, and fusion with, host cells is being investigated as a strategy to prevent infection of mucosal tissue. Such microbicides can target either the virus itself, or the host cells that the virus infects.

  • Effective microbicide candidates that target the virus must target conserved features. Some microbicides, such as nonoxynol-9, target the viral membrane; however, these compounds can also damage the host cell membrane, and in fact nonoxynol-9 has been shown to increase the risk of HIV-1 transmission. The viral membrane is therefore problematic as a target.

  • More specific microbicide candidates include those that target the viral envelope glycoprotein (Env). Compounds being investigated include monoclonal antibodies (mAbs; for example, b12, 2G12 and 2F5); proteins (for example, PRO-542) and peptides (for example, T-20, licensed as Enfuvirtide, and T-1249, now in Phase 1 trials) that specifically target the gp120 or gp41 moieties of the Env protein; long-chain anionic polymers, such as dextrin-2-sulphate and cellulose acetate phlatate, that target positively charged regions of gp120, mainly around the V3 loop; and compounds such as cyanovirin-N that target the glycan residues that are associated with gp120.

  • Research into microbicidal agents that target the cell have focused mainly on targeting the cellular receptors for HIV-1, that is, the mannose C-type lectin receptors, such as (but not exclusively) DC-SIGN; CD4; and the CCR5 and CXCR4 co-receptors, using mAbs, modified chemokines and small-molecule inhibitors. Microbicides aimed at inhibiting HIV-1 binding to cellular receptors must reach the target cells with at least the same efficiency as HIV-1 and be maintained at a concentration high enough to provide protection. As entry inhibitors target specific regions of the Env protein, which shows a high degree of sequence divergence, combinations of inhibitors could be used to achieve breadth of coverage.

Abstract

The worldwide infection rate for HIV-1 is estimated to be 14,000 per day, but only now, more than 20 years into the epidemic, are the immediate events between exposure to infectious virus and the establishment of infection becoming clear. Defining the mechanisms of HIV-1 transmission, the target cells involved and how the virus attaches to and fuses with these cells, could reveal ways to block the sexual spread of the virus. In this review, we will discuss how our increasing knowledge of the ways in which HIV-1 is transmitted is shaping the development of new, more sophisticated intervention strategies based on the application of vaginal or rectal microbicides.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Potential mechanisms for HIV-1 transmission across mucosal epithelium.
Figure 2: Ectocervical squamous epithelium.
Figure 3: Endocervical epithelial cells.
Figure 4: Potential mechanisms of action for microbicide compounds.
Figure 5: Potential viral targets for microbicide compounds.

Similar content being viewed by others

References

  1. UN AIDS. AIDS Epidemic Update, (2002).

  2. Vittinghoff, E. et al. Per-contact risk of human immunodeficiency virus transmission between male sexual partners. Am. J. Epidemiol. 150, 306–311 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Padian, N., Shiboski, S., Glass, S. & Vittinghoff, E. Heterosexual transmission of human immunodeficiency virus (HIV) in northern California: results of a ten-year study. Am. J. Epidemiol. 146, 350–357 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Gray, R. H. et al. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet 357, 1149–1153 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Auvert, B. et al. Ecological and individual level analysis of risk factors for HIV infection in four urban populations in sub-Saharan Africa with different levels of HIV infection. AIDS 15, S15–S30 (2001).

    Article  PubMed  Google Scholar 

  6. de Vincenzi, I. A longitudinal study of human immunodeficiency virus transmission by heterosexual partners. European Study Group on Heterosexual Transmission of HIV. N. Engl. J. Med. 331, 341–346 (1994).

    Article  CAS  PubMed  Google Scholar 

  7. Nicolosi, A. et al. The efficiency of male-to-female and female-to-male sexual transmission of the human immunodeficiency virus: a study of 730 stable couples. Italian Study Group on HIV Heterosexual Transmission. Epidemiology 5, 570–575 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Mastro, T. D., Satten, G. A., Nopkesorn, T., Sangkharomya, S. & Longini, I. M. Jr Probability of female-to-male transmission of HIV-1 in Thailand. Lancet 343, 204–207 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Halperin, D. T. Heterosexual anal intercourse: prevalence, cultural factors, and HIV infection and other health risks, Part I. AIDS Patient Care STDs. 13, 717–730 (1999). Highlights differences in the prevalence of anal intercourse amongst women and emphasises the need for rectal as well as vaginal microbicides.

    Article  CAS  PubMed  Google Scholar 

  10. Baleta, A. Concern voiced over 'dry sex' practices in South Africa. Lancet 352, 1292 (1998). An in-depth review on the present understanding of the mechanisms of vaginal HIV-1 transmission, based on in vitro , animal and in vivo studies.

    Article  CAS  PubMed  Google Scholar 

  11. Miller, C. J. & Shattock, R. J. Target cells in vaginal HIV transmission. Microbes Infect. 5, 59–67 (2003). An interesting paper looking at the relationship between viral load and HIV transmission in Africa. It shows equivalent HIV-1 transmission rates from men–women and women–men.

    Article  CAS  PubMed  Google Scholar 

  12. Quinn, T. C. et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. N. Engl. J. Med. 342, 921–929 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Eron, J. J. Jr et al. The effects of protease inhibitor therapy on human immunodeficiency virus type 1 levels in semen (AIDS clinical trials group protocol 850). J. Infect. Dis. 181, 1622–1628 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Cu-Uvin, S. et al. Effect of highly active antiretroviral therapy on cervicovaginal HIV-1 RNA. AIDS 14, 415–421 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Kalichman, S. C. et al. Human immunodeficiency virus in semen and plasma: investigation of sexual transmission risk behavioral correlates. AIDS Res. Hum. Retroviruses 17, 1695–1703 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Tachet, A. et al. Detection and quantification of HIV-1 in semen: identification of a subpopulation of men at high potential risk of viral sexual transmission. AIDS 13, 823–831 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Wawer, M. J. et al. HIV-1 transmission per coital act, by stage of HIV infection in the HIV+ index partner, in discordant couples, Rakai, Uganda. 10th Conference on Retroviruses and Opportunistic Infections, [online] (cited 12 Aug 2003), <http://www.retroconference.org/2003/Abstract/Abstract.aspx?AbstractID=2233> (2003).

  18. Zhang, L. Q. et al. Selection for specific sequences in the external envelope protein of human immunodeficiency virus type 1 upon primary infection. J. Virol. 67, 3345–3356 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fiore, A. J. et al. Biological phenotype of HIV-1 and transmission. AIDS 9, 822–823 (1995).

    Article  PubMed  Google Scholar 

  20. Van't Wout, A. et al. Macrophage-tropic variants initiate human immunodeficiency virus type-1 infection after sexual, parenteral and vertical transmission. J. Clin. Invest. 94, 2060–2067 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tatt, I. D., Barlow, K. L., Nicoll, A. & Clewley, J. P. The public health significance of HIV-1 subtypes. AIDS 15, S59–S71 (2001).

    Article  PubMed  Google Scholar 

  22. Morris, L. & Williamson, C. Host and viral factors that impact on HIV–1 transmission and disease progression in South Africa. S. Afr. Med. J. 91, 212–215 (2001).

    CAS  PubMed  Google Scholar 

  23. Shattock, R. J., Griffin, G. E. & Gorodeski, G. I. In vitro models of mucosal HIV transmission. Nature Med. 6, 607–608 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. King, B. F. The permeability of nonhuman primate vaginal epithelium: a freeze-fracture and tracer-perfusion study. J. Ultrastruct. Res. 83, 99–110 (1983).

    Article  CAS  PubMed  Google Scholar 

  25. Robboy, S. J., Prade, M. & Cunha, G. in Histology for Pathologists (ed. Sternberg, S. S.) 881–892 (Raven Press, New York, 1992).

    Google Scholar 

  26. Smith, S. M., Baskin, G. B. & Marx, P. A. Estrogen protects against vaginal simian immunodeficiency virus. J. Infect. Dis. 182, 708–715 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Marx, P. A. et al. Progesterone implants vaginal transmission and early virus load. Nature Med. 2, 1084–1089 (1996). Shows that experimental thinning of the vaginal epithelium increases the efficiency by which SIV infects macaques after vaginal inoculation.

    Article  CAS  PubMed  Google Scholar 

  28. Dezzutti, C. S. et al. Cervical and prostate primary epithelial cells are not productively infected but sequester human immunodeficiency virus type 1. J. Infect. Dis. 183, 1204–1213 (2001). Shows that genital epithelial cells are resistant to HIV-1 infection and do not transcytose viral particles, although they may bind infectious virions (see also reference 35).

    Article  CAS  PubMed  Google Scholar 

  29. Novell, M. K., Benrudi, G. I. & Thompson, R. J. Investigation of microtrauma after sexual intercourse. J. Reprod. Med. 29, 269–271 (1984).

    Google Scholar 

  30. Cold, C. J. & Taylor, J. R. The prepuce. BJU Int. 83, S34–S44 (1999).

    Article  Google Scholar 

  31. Van Howe, R. S. Does circumcision influence sexually transmitted diseases?: a literature review. BJU Int. 83, S52–S62 (1999). Reference 30 and 31 discuss the possible role of the foreskin in HIV-1 transmission.

    Article  Google Scholar 

  32. Strathdee, S. A., Hogg, R. S., O'Shaughnessy, M. V., Montaner, J. S. & Schechter, M. T. A decade of research on the natural history of HIV infection: Part 2. Cofactors. Clin. Invest. Med. 19, 121–130 (1996).

    CAS  PubMed  Google Scholar 

  33. Baeten, J. M. et al. Selenium deficiency is associated with shedding of HIV-1-infected cells in the female genital tract. J. Acquir. Immune Defic. Syndr. 26, 360–364 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Mostad, S. B. et al. Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina. Lancet 350, 922–927 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Greenhead, P. et al. Parameters of human immunodeficiency virus infection of human cervical tissue and inhibition by vaginal virucides. J. Virol. 74, 5577–5586 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Coombs, R. W., Reichelderfer, P. S. & Landay, A. L. Recent observations on HIV type-1 infection in the genital tract of men and women. AIDS 17, 455–480 (2003). A thorough review of HIV-1 infection of the genital tract and the factors that influence HIV-1 shedding.

    Article  PubMed  Google Scholar 

  37. Moriyama, A. et al. Secretory leukocyte protease inhibitor (SLPI) concentrations in cervical mucus of women with normal menstrual cycle. Mol. Hum. Reprod. 5, 656–661 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Agace, W. W. et al. Constitutive expression of stromal derived factor-1 by mucosal epithelia and its role in HIV transmission and propagation. Curr. Biol. 10, 325–328 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Amerongen, H. M. et al. Transepithelial transport of HIV-1 by intestinal M cells: a mechanism for transmission of AIDS. J. Acquir. Immune Defic. Syndr. 4, 760–765 (1991).

    CAS  PubMed  Google Scholar 

  40. Neutra, M. R. Interaction of viruses and microparticles with apical membranes of M cells: implications for human immunodeficiency virus transmission. J. Infect. Dis. 179, S441–S443 (1999).

    Article  PubMed  Google Scholar 

  41. Bomsel, M. Trancytosis of infectious human immunodeficiency virus across a tight human epithelial cell line barrier. Nature Med. 3, 42–47 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Phillips, D. M. The role of cell-to-cell transmission in HIV infection. AIDS 8, 719–731 (1994).

    Article  CAS  PubMed  Google Scholar 

  43. Chenine, A. et al. Primary intestinal epithelial cells can be infected with laboratory-adapted strain HIV type 1 NDK but not with clinical primary isolates. AIDS Res. Hum. Retroviruses 14, 1235–1238 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Delezay, O. et al. Co-expression of CXCR4/fusin and galactosylceramide in the human intestinal epithelial cell line HT-29. AIDS 11, 1311–1318 (1997).

    Article  CAS  PubMed  Google Scholar 

  45. Khanna, K. V. et al. Vaginal transmission of cell-associated HIV-1 in the mouse is blocked by a topical, membrane-modifying agent. J. Clin. Invest. 109, 205–211 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Romani, N. et al. Migration of dendritic cells into lymphatics — the Langerhans cell example: routes, regulation and relevance. Int. Rev. Cytol. 207, 237–270 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Zaitseva, M. et al. Expression and function of CCR5 and CXCR4 on human Langerhans cells and macrophages: implications for HIV primary infection. Nature. Med. 12, 1369–1375 (1997).

    Article  Google Scholar 

  48. Kawamura, T. et al. Candidate microbicides block HIV-1 infection of human immature Langerhans cells within epithelial tissue explants. J. Exp. Med. 192, 1491–1500 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Patterson, B. K. et al. Repertoire of chemokine receptor expression in the female genital tract: implications for human immunodeficiency virus transmission. Am. J. Pathol. 153, 481–490 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Veazey, R. S., Marx, P. A. & Lackner, A. A. Vaginal CD4+ T cells express high levels of CCR5 and are rapidly depleted in simian immunodeficiency virus infection. J. Infect. Dis. 187, 769–776 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Stone, A. Microbicides: a new approach to preventing HIV and other sexually transmitted infections. Nature Rev. Drug Discov. 1, 977–985 (2002).

    Article  CAS  Google Scholar 

  52. Turpin, J.A. Considerations and development of topical microbicides to inhibit the sexual transmission of HIV. Expert Opin. Investig. Drugs. 11, 1077–1097 (2002). References 51 and 52 review the wide range of potential microbicide candidates under development.

    Article  CAS  PubMed  Google Scholar 

  53. Bourinbaiar, A. S. & Lee-Huang, S. L. Comparative in vitro study of contraceptive agents with anti-HIV activity: Gramicidin, nonoxynol-9, and gossypol. Contraception 49, 131–137 (1994).

    Article  CAS  PubMed  Google Scholar 

  54. Van Damme, L. et al. COL-1492 Study Group. Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial. Lancet 360, 971–977 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Poignard, P., Ollman Saphire, E., Parren, P. W. H. I. & Burton, D. R. Gp120: Biologic aspects of structural features. Annu. Rev. Immunol. 19, 253–274 (2001). A review on the structure and function of the HIV-1 envelope glycoproteins that puts the activity of Env-targeting inhibitors into context.

    Article  CAS  PubMed  Google Scholar 

  56. Bugelski, P. J., Ellens, H., Hart, T. K. & Kirsh, R. L. Soluble CD4 and dextran sulphate mediate release of gp120 from HIV-1: Implications for clinical trials. J. Acquir. Immune Defic. Syndr. 4, 923–924 (1991).

    CAS  PubMed  Google Scholar 

  57. Neurath, A. R., Strick, N., Jiang, S., Li, Y. Y. & Debnath, A. K. Anti-HIV-1 activity of cellulose acetate phthalate: Synergy with soluble CD4 and induction of 'dead end' gp41 six–helix bundles. BMC Infect. Dis. 2, 6 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Walker, B. D. & Korber, B. T. Immune control of HIV: the obstacles of HLA and viral diversity. Nature Immunol. 2, 473–475 (2001).

    Article  CAS  Google Scholar 

  59. Doms, R. W. Beyond receptor expression: The influence of receptor conformation, density, and affinity in HIV-1 infection. Virology 276, 229–237 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Reeves, J. D. et al. Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics. Proc. Natl Acad. Sci. USA 99, 16249–16254 (2002). References 59 and 60 review the HIV-1 fusion process and outline many of the parameters that affect the efficiency of entry-inhibitor action.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Trkola, A. et al. Cross-clade neutralization of primary isolates of human immunodeficiency virus type 1 by human monoclonal antibodies and tetrameric CD4 IgG. J. Virol. 69, 6609–6617 (1995). An early paper that showed that selected human mAbs and a CD4-based agent can have broad neutralizing activity against diverse primary isolates in vitro

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Parren, P. W. H. I. & Burton, D. R. The antiviral activity of antibodies in vitro and in vivo. Adv. Immunol. 77, 195–262 (2001). A definitive review on how antibodies inhibit viral infection, HIV–1 infection in particular.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zwick, M. B. et al. Neutralization synergy of human immunodeficiency virus type 1 primary isolates by cocktails of broadly neutralizing antibodies. J. Virol. 75, 12198–12208 (2001). The most detailed study yet performed on the potential and limitations of synergy between HIV-1 neutralizing antibodies in vitro.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. O'Hara, B. M. & Olson, W. C. HIV entry inhibitors in clinical development. Curr. Opin. Pharmacol. 2, 523–528 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Scanlan, C. N. et al. The broadly neutralizing anti-human immunodeficiency virus type 1 antibody 2G12 recognizes a cluster of α1→2 mannose residues on the outer face of gp120. J. Virol. 76, 7306–7321 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sanders, R. W. et al. The mannose-dependent epitope for neutralizing antibody 2G12 on human immunodeficiency virus type 1 glycoprotein gp120. J. Virol. 76, 7293–7305 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Trkola, A. et al. CD4-dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5. Nature 384, 184–187 (1996).

    Article  CAS  PubMed  Google Scholar 

  68. Kilby, J. M. et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nature Med. 4, 1302–1307 (1998). The first paper that showed that an entry inhibitor could have a significant effect on viral load in HIV-1-infected people.

    Article  CAS  PubMed  Google Scholar 

  69. Baldwin, C. E., Sanders, R. W. & Berkhout, B. Inhibiting HIV-1 entry with fusion inhibitors. Curr. Med. Chem. 10, 1773–1782 (2003).

    Article  Google Scholar 

  70. Melikyan, G. B. et al. Evidence that the transition of HIV-1 gp41 into a six-helix bundle, not the bundle configuration, induces membrane fusion. J. Cell Biol. 151, 413–423 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Gallo, S. A., Puri, A. & Blumenthal, R. HIV-1 gp41 six-helix bundle formation occurs rapidly after the engagement of gp120 by CXCR4 in the HIV-1 Env-mediated fusion process. Biochemistry 40, 12231–12236 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Root, M. J. & Hamer, D. H. Targeting therapeutics to an exposed and conserved binding element of the HIV-1 fusion protein. Proc. Natl Acad. Sci. USA 100, 5016–5023 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Moulard, M. et al. Selective interactions of polyanions with basic surfaces on human immunodeficiency virus type 1 gp120. J. Virol. 74, 1948–1960 (2000). A detailed investigation of the mechanism of action of sulphated polysaccharides, including compounds that are now in large-scale clinical trials as candidate microbicides.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Shattock, R. J. & Doms, R. W. AIDS models: Microbicides could learn from vaccines. Nature Med. 8, 425 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Kwong, P., Wyatt, R., Sattentau, Q. J., Sodroski, J. & Hendrickson, W. A. Oligomeric modeling and electrostatic analysis of the gp120 envelope glycoprotein of human immunodeficiency virus. J. Virol. 74, 1961–1972 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bewley, C. A. Solution structure of a cyanovirin-N:Manα1-2Manα complex: Structural basis for high-affinity carbohydrate-mediated binding to gp120. Structure 9, 31–40 (2001).

    Article  Google Scholar 

  77. Dey, B. et al. Multiple antiviral activities of cyanovirin-N: blocking of human immunodeficiency virus type 1 gp120 interaction with CD4 and coreceptor and inhibition of diverse enveloped viruses. J. Virol. 74, 4562–4569 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Pohlmann, S., Baribaud, F. & Doms, R. W. DC-SIGN and DC-SIGNR: helping hands for HIV. Trends Immunol. 22, 643–646 (2001). This review provides a detailed description of how targeting DC-SIGN might be a relevant strategy for the prevention of HIV-1 sexual transmission.

    Article  CAS  PubMed  Google Scholar 

  79. Baribaud, F., Pohlmann, S. & Doms, R. W. The role of DC-SIGN and DC-SIGNR in HIV and SIV attachment, infection, and transmission. Virology 286, 1–6 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Kwon, D. S., Gregorio, G., Bitton, N., Hendrickson, W. A. & Littman, D. R. DC-SIGN mediated internalization of HIV is required for trans-enhancement of T cell infection. Immunity 16, 135–144 (2002). In vitro studies that help to outline the mechanism by which DC-SIGN might act to facilitate the sexual transmission of HIV-1 in vivo.

    Article  CAS  PubMed  Google Scholar 

  81. Jameson, B. et al. Expression of DC-SIGN by dendritic cells of intestinal and genital mucosae in humans and rhesus macaques. J. Virol. 76, 1866–1875 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Baribaud, F., Doms, R. W. & Pohlmann, S. The role of DC-SIGN and DC-SIGNR in HIV and Ebola virus infection: can potential therapeutics block virus transmission and dissemination? Expert Opin. Ther. Targets 6, 1–9 (2002).

    Article  Google Scholar 

  83. Turville, S.G. et al. Diversity of receptors binding HIV on dendritic cell subsets. Nature Immunol. 3, 975–983 (2002). This paper shows that several different CLRs, not just DC-SIGN, can act as attachment factors for HIV-1 on DCs.

    Article  CAS  Google Scholar 

  84. Hong, P. W. et al. Human immunodeficiency virus envelope (gp120) binding to DC-SIGN and primary dendritic cells is carbohydrate dependent but does not involve 2G12 or cyanovirin binding sites: Implications for structural analyses of gp120-DC SIGN binding. J. Virol. 76, 2855–12865 (2002).

    Article  CAS  Google Scholar 

  85. Lin, G. et al. Differential N-linked glycosylation of human immunodeficiency virus and Ebola virus envelope glycoproteins modulates interactions with DC-SIGN and DC-SIGNR. J. Virol. 77, 1337–1346 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Moore, J. P. & Sweet, R. W. The HIV gp120-CD4 interaction: A target for pharmacological or immunological intervention? Perspect. Drug Discov. Design 1, 235–250 (1993).

    Article  CAS  Google Scholar 

  87. Sattentau, Q. J. & Weiss, R. A. The CD4 antigen: physiological ligand and HIV receptor. Cell 52, 631–632 (1988).

    Article  CAS  PubMed  Google Scholar 

  88. Healey, D. et al. Novel anti-CD4 monoclonal antibodies separate HIV infection and fusion of CD4+ cells from virus binding. J. Exp. Med. 172, 1233–1242 (1990).

    Article  CAS  PubMed  Google Scholar 

  89. Burkly, L. C. et al. Inhibition of HIV entry by a CD4 domain 2 specific monoclonal antibody: Dissecting the basis for its inhibitory effect on HIV-induced cell fusion. J. Immunol. 149, 1779–1787 (1992).

    CAS  PubMed  Google Scholar 

  90. Moore, J. P., Sattentau, Q. J., Klasse, P. J. & Burkly, L. C. A monoclonal antibody to CD4 domain 2 blocks soluble CD4-induced conformational changed in the envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) and HIV-1 infection of CD4+ cells. J. Virol. 66, 4784–4793 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Reimann, K. A., Khunkhun, R., Lin, W., Gordon, W. & Fung, M. A humanized, nondepleting anti-CD4 antibody that blocks virus entry inhibits virus replication in Rhesus monkeys chronically infected with simian immunodeficiency virus. AIDS Res. Hum. Retrovirus 18, 747–755 (2002).

    Article  CAS  Google Scholar 

  92. Dragic, T. An overview of the determinants of CCR5 and CXCR4 co receptor function. J. Gen. Virol. 82, 1807–1814 (2001). This reference provides a more detailed summary of the development of entry inhibitors than has been given in this review.

    Article  CAS  PubMed  Google Scholar 

  93. Pierson, T. C. & Doms, R. W. HIV-1 entry inhibitors: new targets, novel therapies. Immunol. Lett. 85, 113–118 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Moore, J. P. and Stevenson, M. New targets for inhibitors of HIV-1 replication. Nature Rev. Mol. Cell Biol. 1, 40–49 (2000).

    Article  CAS  Google Scholar 

  95. Wu, L. et al. Interaction of chemokine receptor CCR5 with its ligands: multiple domains for HIV-1 gp120 binding and a single domain for chemokine binding. J. Exp. Med. 186, 1373–1381 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Trkola, A. et al. Potent, broad-spectrum inhibition of human immunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO 140. J. Virol. 75, 579–588 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Simmons, G. et al. Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist. Science 276, 276–279 (1997).

    Article  CAS  PubMed  Google Scholar 

  98. Torre, V. S. et al. Variable sensitivity of CCR5-tropic human immunodeficiency virus type 1 isolates to inhibition by RANTES analogs. J. Virol. 74, 4868–4876 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Rusconi, S. et al. Combination of CCR5 and CXCR4 inhibitors in therapy of human immunodeficiency virus type 1 infection: In vitro studies of mixed virus infections. J. Virol. 74, 9328–9332 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kawamura, T. et al. R5 HIV productively infects Langerhans cells, and infection levels are regulated by compound CCR5 polymorphisms. Proc. Natl Acad. Sci. USA. 100, 8401–8406 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kazmierski, W. et al. Recent progress in discovery of small-molecule CCR5 chemokine receptor ligands as HIV-1 inhibitors. Bioorg. Med. Chem. 11, 2663–2676 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Strizki, J. M. et al. SCH-C (SCH 351125), an orally bioavailable small molecule antagonist of the chemokine receptor CCR5 is a potent inhibitor of HIV-1 infection in vitro and in vivo. Proc. Natl Acad. Sci. USA 98, 12718–12723 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Trkola, A. et al. HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use. Proc. Natl Acad. Sci. USA 99, 395–400 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Donzella, G. A. et al. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nature Med. 4, 72–77 (1998).

    Article  CAS  PubMed  Google Scholar 

  105. Sabbe, R. et al. Donor- and ligand-dependent differences in C-C chemokine receptor expression. J. Virol. 75, 661–671 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Nagashima, K. A. et al. Human immunodeficiency virus type 1 entry inhibitors PRO 542 and T 20 are potently synergistic in blocking virus-cell and cell-cell fusion. J. Infect. Dis. 183, 1121–1125 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Tremblay, C. L. et al. Anti-human immunodeficiency virus interactions of SCH-C (SCH 351125), a CCR5 antagonist, with other antiretroviral agents in vitro. Antimicrob. Agents Chemother. 46, 1336–1339 (2002). References 106 and 107 show that entry inhibitors can act synergistically, at least in vitro.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Veazey, R. S. et al. Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120. Nature Med. 9, 343–346 (2003). This paper shows that a specific inhibitor of HIV-1 entry, the b12 mAb, can act to prevent the vaginal transmission of an R5 SHIV in the macaque model.

    Article  CAS  PubMed  Google Scholar 

  109. Gupta, P. et al. High viral load in semen of human immunodeficiency virus type I-infected men at all stages of disease and its reduction by therapy by protease and non-nucleoside reverse transcriptase inhibitors. J. Virol. 31, 6271–6275 (1997).

    Article  Google Scholar 

  110. Schillberg, S., Fischer, R. & Emans, N. Molecular farming of recombinant antibodies in plants. Cell Mol. Life Sci. 60, 433–445 (2003).

    Article  CAS  PubMed  Google Scholar 

  111. Sherwood, J. K., Zeitlin, L., Whaley, K. J., Cone, R. A. & Saltzman, M. Controlled release of antibodies for long-term topical passive immunoprotection of female mice against genital herpes. Nature Biotechnol. 14, 468–471 (1996).

    Article  CAS  Google Scholar 

  112. Dean, M. et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Science 273, 1856–1862 (1996).

    Article  CAS  PubMed  Google Scholar 

  113. Liu, R. et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86, 367–377 (1996).

    Article  CAS  PubMed  Google Scholar 

  114. Berger, E. A., Murphy, P. M. & Farber, J. M. Chemokine receptors as HIV-1 coreceptors: Roles in viral entry, tropism, and disease. Annu. Rev. Immunol. 17, 657–700 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. Geijtenbeek, T. B. et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100, 587–597 (2000).

    Article  CAS  PubMed  Google Scholar 

  116. Pope, M. Mucosal dendritic cells and immunodeficiency viruses. J. Infect. Dis. 179, S427–S430 (1999).

    Article  PubMed  Google Scholar 

  117. King, N. J., Parr, E. L. & Parr, M. B. Migration of lymphoid cells from vaginal epithelium to iliac lymph nodes in relation to vaginal infection by herpes simplex virus type 2. J. Immunol. 160, 1173–1180 (1998).

    CAS  PubMed  Google Scholar 

  118. Liao, Z., Roos, J. W. & Hildreth, J. E. Increased infectivity of HIV type 1 particles bound to cell surface and solid-phase ICAM-1 and VCAM-1 through acquired adhesion molecules LFA-1 and VLA-4. AIDS Res. Hum. Retroviruses 16, 355–366 (2000).

    Article  CAS  PubMed  Google Scholar 

  119. Ugolini, S. et al. Inhibition of virus attachment to CD4+ target cells is a major mechanism of T cell line-adapted HIV-1 neutralization. J. Exp. Med. 186, 1287–1298 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Layne, S. P., Merges, M. J., Dembo, M. B., Spouge, J. L. & Nara, P. L. HIV requires multiple gp120 molecules for CD4-mediated infection. Nature 346, 277–279 (1990).

    Article  CAS  PubMed  Google Scholar 

  121. Kuhmann, S. E., Platt, E. J., Kozak, S. L. & Kabat, D. J. Cooperation of multiple CCR5 coreceptors is required for infections by human immunodeficiency virus type 1. Virology 7, 7005–7015 (2000).

    Article  Google Scholar 

  122. Wyatt, R. & Sodroski, J. The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. Science 280, 1884–1888 (1998). An overview of the structure of the HIV-1 envelope glycoproteins, with an emphasis on the core of the gp120 subunit.

    Article  CAS  PubMed  Google Scholar 

  123. Chan, D. C., Fass, D., Berger, J. M. & Kim, P. S. Core structure of gp41 from the HIV envelope glycoprotein. Cell 89, 263–273 (1997). This paper discusses the function of the gp41 glycoprotein during receptor-mediated fusion.

    Article  CAS  PubMed  Google Scholar 

  124. Doms, R. W. and Moore, J. P. HIV-1 membrane fusion: Targets of opportunity. J. Cell Biol. 151, F9–F14 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Swingler, S. et al. HIV-1 Nef mediates lymphocyte chemotaxis and activation by infected macrophages. Nature Med. 5, 997–103 (1999).

    Article  CAS  PubMed  Google Scholar 

  126. Izmailova, E. et al. HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages. Nature Med. 9, 191–197 (2003). References 125 and 126 provide evidence that HIV-1 infection of mucosal macrophages and dendritic cells might exacerbate localized infection through recruitment of activated T cells.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge the help of P. Greenhead and R. Moss for electron microscopy.

Author information

Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Infectious Diseases, St. George's Hospital Medical School, London, UK

    Robin J. Shattock

  2. Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, USA

    John P. Moore

Authors
  1. Robin J. Shattock
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John P. Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robin J. Shattock.

Related links

Related links

DATABASES

LocusLink

CCR5

CD4

CLRs

CXCR4

SLPI

Glossary

DISCORDANT COUPLES

Two sexual partners in, usually, a stable monogamous relationship, in which one person is HIV-infected and the other is not.

ACUTE INFECTION

An initial infection that is associated with a high viral load — often resolving with seroconversion, 3–6 months after infection.

X4 VIRUSES

HIV-1 strains that use the CXCR4 chemokine receptor as a co-receptor to enter target cells.

R5 VIRUSES

HIV-1 strains that use the CCR5 chemokine receptor as a co-receptor to enter target cells

STRATIFIED SQUAMOUS EPITHELIUM

An epithelium consisting of several layers of keratin-containing cells, in which the surface cells are flattened and scale-like and the deeper cells are polyhedral in form.

DESMOSOME

A junction between the cell membranes of neighbouring cells, which consists of associated intracellular microfilaments and intercellular mucopolysaccharides and are important in cell-to-cell adhesion.

COLUMNAR EPITHELIUM

An epithelium that is formed of a single layer of cells, which are taller than they are wide.

TIGHT JUNCTION

A specialized intercellular junction in which the two plasma membranes are separated by only 1–2 nm. They are found near the apical surface of cells in simple epithelia and prevents fluid moving through the intercellular gap.

CERVICAL OS

The 'mouth' or 'opening' of the endocervical canal into the vaginal vault.

CERVICAL ECTOPY

An outgrowth of endocervical columnar epithelium—that is usually restricted to the endocervical canal — onto the exocervical surface at the top of the vaginal vault.

M CELLS

Specialized epithelial cells that deliver samples of luminal material from the lumen into organized lymphoid tissue by transepithelial vesicular transport. They are classically found in the gastrointestinal tract, but absent from the genital epithelia.

LANGERHANS CELLS

Dendritic, antigen-presenting cells that contains characteristic racket-shaped granules, known as birbeck granules, and which expressing the CD1a antigen. Principally found in the stratified squamous epithelium.

PYKNOTIC NUCLEI

Nuclei that have contracted contents — a feature that is visible with deep staining and is a sign of cell death.

DC-SIGN

DC-specific intercellular adhesion molecule (ICAM)-grabbing non-integrin.

RANTES

A CC-chemokine that binds to and activates signal transduction by several chemokine receptors, including CCR5, and that has modest inhibitory activity against HIV-1 entry through the same receptor.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shattock, R., Moore, J. Inhibiting sexual transmission of HIV-1 infection. Nat Rev Microbiol 1, 25–34 (2003). https://doi.org/10.1038/nrmicro729

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro729

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing