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:

Transmission, acute HIV-1 infection and the quest for strategies to prevent infection

Nature Medicine volume 9, pages 847–852 (2003) Cite this article

Save article
View saved research

Abstract

By the acute stage of HIV-1 infection, the immune system already faces daunting challenges. Research on mucosal barriers and the events immediately after heterosexual transmission that precede this acute stage could facilitate the development of effective microbicides and vaccines.

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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

Figure 1: HIV-1 lymphatic tissue reservoirs and the potential obstacles that the immune system faces.

Katie Ris

Figure 2: Overview of sexual transmission to women and acute infection.

Katie Ris

Figure 3: Close-up view of virus crossing the barrier and initial propagation and dissemination of infection.

Katie Ris

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news in related subjects.

References

  1. World Health Organization (WHO). AIDS epidemic update: December 2002 (WHO, Geneva, 2002).

  2. Annan, K.A. In Africa, AIDS has a woman's face. New York Times 29 December (2002), p.9.

  3. Miller, C.J. et al. Genital mucosal transmission of simian immunodeficiency virus: animal model for heterosexual transmission of human immunodeficiency virus. J. Virol. 63, 4277–4284 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Miller, C.J. et al. In vivo replication capacity rather than in vitro macrophage tropism predicts efficiency of vaginal transmission of simian immunodeficiency virus or simian/human immunodeficiency virus in rhesus macaques. J. Virol. 72, 3248–3258 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Haase, A.T. Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues. Annu. Rev. Immunol. 17, 625–656 (1999).

    CAS  PubMed  Google Scholar 

  6. Tenner-Racz, K. et al. HTLV-III/LAV viral antigens in lymph nodes of homosexual men with persistent generalized lymphadenopathy and AIDS. Am. J. Pathol. 123, 9–15 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Biberfeld, P. et al. HTLV-III expression in infected lymph nodes and relevance to pathogenesis of lymphadenopathy. Am. J. Pathol. 125, 436–442 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Pantaleo, G. et al. Lymphoid organs function as major reservoirs for human immunodeficiency virus. Proc. Natl. Acad. Sci. USA 88, 9838–9842 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Fox, C.H. et al. Lymphoid germinal centers are reservoirs of human immunodeficiency virus type 1 RNA. J. Infect. Dis. 164, 1051–1057 (1993).

    Google Scholar 

  10. Pantaleo, G. et al. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 362, 355–358 (1993).

    CAS  PubMed  Google Scholar 

  11. Embretson, J. et al. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 362, 359–362 (1993).

    CAS  PubMed  Google Scholar 

  12. Schacker, T. et al. Rapid accumulation of HIV in lymphatic tissue reservoirs during acute and early HIV infection: implications for timing of antiretroviral therapy. J. Infect. Dis. 181, 354–357 (2000).

    CAS  PubMed  Google Scholar 

  13. Racz, P. et al. The spectrum of morphologic changes in lymph nodes from patients with AIDS or AIDS-related complex. Prog. Allergy 37, 81–181 (1985).

    Google Scholar 

  14. Cooper, D.A. et al. Acute AIDS retrovirus infection. Definition of a clinical illness associated with seroconversion. Lancet 1, 537–540 (1985).

    CAS  PubMed  Google Scholar 

  15. Ho, D.D. et al. Primary human T-lymphotropic virus type III infection. Ann. Intern. Med. 103, 880–883 (1985).

    CAS  PubMed  Google Scholar 

  16. Schacker, T.W., Hughes, J.P., Shea, T., Coombs, R.W. & Corey, L. Biological and virologic characteristics of primary HIV infection. Ann. Intern. Med. 128, 613–620 (1998).

    CAS  PubMed  Google Scholar 

  17. Kahn, J.O. & Walker, B.D. Acute human immunodeficiency virus type 1 infection. N. Engl. J. Med. 339, 33–39 (1998).

    CAS  PubMed  Google Scholar 

  18. Kinloch-de Loes, S. et al. Symptomatic primary infection due to human immunodeficiency virus type 1: review of 31 cases. Clin. Infect. Dis. 17, 59–65 (1993).

    CAS  PubMed  Google Scholar 

  19. Lavreys, L. et al. Primary human immunodeficiency virus type 1 infection: clinical manifestations among women in Monbasa, Kenya. Clin. Infect. Dis. 30, 486–490 (2000).

    CAS  PubMed  Google Scholar 

  20. Zhang, Z.-Q. et al. Sexual transmission and propagation of simian and human immunodeficiency viruses in two distinguishable populations of CD4+ T cells. Science 286, 1353–1357 (1999).

    CAS  PubMed  Google Scholar 

  21. Cavert, W. et al. Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science 276, 960–964 (1997).

    CAS  PubMed  Google Scholar 

  22. Wei, X. et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373, 117–122 (1995).

    CAS  PubMed  Google Scholar 

  23. Ho, D.D. et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123–126 (1995).

    CAS  PubMed  Google Scholar 

  24. Little, S.J., McLean, A.R., Spina, C.A., Richman, D.D. & Havlir, D.V. Viral dynamics of acute HIV-1 infection. J. Exp. Med. 190, 841–850 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Koup, R.A. et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J. Virol. 68, 4650–4655 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Douek, D.C. et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 417, 95–98 (2002).

    CAS  PubMed  Google Scholar 

  27. Lewis, J. et al. Development of a neutralizing antibody response during acute primary human immunodeficiency virus type 1 infection and the emergence of antigenic variants. J. Virol. 72, 8943–8951 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Richman, D.D., Wrin, T., Little, S.J. & Petropoulos, C.J. Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc. Natl. Acad. Sci. USA 100, 4144–4149 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Goulder, P.J.R. et al. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat. Med. 3, 212–217 (1997).

    CAS  PubMed  Google Scholar 

  30. Borrow, P. et al. Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat. Med. 3, 205–211 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Price, D.A. et al. Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection. Proc. Natl. Acad. Sci. USA 94, 1890–1895 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Allen, T.M. et al. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nat. Med. 407, 386–390 (2000).

    CAS  Google Scholar 

  33. Chun, T.-W. et al. Quantitation of latent tissue reservoirs and total body load in HIV-1 infection. Nature 387, 183–188 (1997).

    CAS  PubMed  Google Scholar 

  34. Haase, A.T. et al. Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science 274, 985–989 (1996).

    CAS  PubMed  Google Scholar 

  35. Persaud, D., Zhou, Y., Siliciano, J.M. & Siliciano, R.F. Latency in human immunodeficiency virus type 1 infection: no easy answers. J. Virol. 77, 1659–1665 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Heath, S.L., Tew, J.G., Szakal, A.K. & Burton, G.F. Follicular dendritic cells and human immunodeficiency virus infectivity. Nature 377, 740–744 (1995).

    CAS  PubMed  Google Scholar 

  37. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  39. Deng, H.K. et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature 381, 661–666 (1996).

    CAS  PubMed  Google Scholar 

  40. Alkhatib, G. et al. CC CKR5: A RANTES, MIP-1α, MIP-1β receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272, 1955–1958 (1996).

    CAS  PubMed  Google Scholar 

  41. Berger, E.A. et al. A new classification for HIV-1. Nature 391, 240 (1998).

    CAS  PubMed  Google Scholar 

  42. Schuitemaker, H. et al. Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus populations. J. Virol. 66, 1354–1360 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Paxton, W.A. et al. Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposures. Nat. Med. 2, 412–417 (1996).

    CAS  PubMed  Google Scholar 

  44. 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).

    CAS  PubMed  Google Scholar 

  45. 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, 1856–1861 (1996).

    CAS  PubMed  Google Scholar 

  46. Marx, P.A. et al. Progesterone implants enhance SIV vaginal transmission and early virus load. Nat. Med. 2, 1084–1089 (1996).

    CAS  PubMed  Google Scholar 

  47. Hu, J., Gardner, M.B. & Miller, C.J. Simian immunodeficiency virus rapidly penetrates the cervicovaginal mucosa after intravaginal inoculation and infects intraepithelial dendritic cells. J. Virol. 74, 6087–6095 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Martin, H.L. et al. Vaginal lactobacilli, microbial flora, and risk of human immunodeficiency virus type 1 and sexually transmitted disease acquisition. J. Infect. Dis. 180, 1863–1868 (1999).

    CAS  PubMed  Google Scholar 

  49. Sweankambo, N. et al. HIV-1 infection associated with abnormal vaginal flora morphology and bacterial vaginosis. Lancet 350, 546–550 (1997).

    Google Scholar 

  50. Cohn, M.A. et al. Chronic inflammation with increased human immunodeficiency virus (HIV) RNA expression in the vaginal epithelium of HIV-infected Thai women. J. Infect. Dis. 184, 410–417 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  52. Moss, G.B. et al. Association of cervical ectopy with heterosexual transmission of human immunodeficiency virus: results of a study of couples in Nairobi, Kenya. J. Infect. Dis. 164, 588–591 (1991).

    CAS  PubMed  Google Scholar 

  53. Bomsel, M. Transcytosis of infectious human immunodeficiency virus across a tight human epithelial cell line barrier. Nat. Med. 1, 42–47 (1997).

    Google Scholar 

  54. Bomsel, M. et al. Intracellular neutralization of HIV transcytosis across tight epithelial barriers by anti-HIV envelope protein dIgA or IgM. Immunity 9, 277–287 (1998).

    CAS  PubMed  Google Scholar 

  55. Belec, L. et al. Cervicovaginal secretory antibodies to human immunodeficiency virus type 1 (HIV-1) that block viral transcytosis through tight epithelial barriers in highly exposed HIV-1-seronegative African women. J. Infect. Dis. 184, 1412–1422 (2001).

    CAS  PubMed  Google Scholar 

  56. Veazey, R.S. et al. Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120. Nat. Med. 9, 343–346 (2003).

    CAS  PubMed  Google Scholar 

  57. Meng, G. et al. Primary intestinal epithelial cells selectively transfer R5 HIV-1 to CCR5+ cells. Nat. Med. 2, 150–156 (2002).

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  59. Frank, I. & Pope, M. The enigma of dendritic cell-immunodeficiency virus interplay. Curr. Mol. Med. 2, 229–248 (2002).

    CAS  PubMed  Google Scholar 

  60. Lee, B. et al. cis Expression of DC-SIGN allows for more efficient entry of human and simian immunodeficiency viruses via CD4 and a coreceptor. J. Virol. 75, 12028–12038 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Turville, S.G. et al. Diversity of receptors binding HIV on dendritic cell subsets. Nat. Immunol. 3, 975–983 (2002).

    CAS  PubMed  Google Scholar 

  62. Spira, A.I. 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. 183, 215–225 (1996).

    CAS  PubMed  Google Scholar 

  63. Gupta, P. 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. 76, 9868–9876 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Collins, K.B., Patterson, B.K., Naus, G.J., Landers, D.V. & Gupta, P. Development of an in vitro organ culture model to study transmission of HIV-1 in the female genital tract. Nat. Med. 6, 475–479 (2000).

    CAS  PubMed  Google Scholar 

  65. Granelli-Piperno, A., Delgado, E., Finkel, V., Paxton, W. & Steinman, R.M. Immature dendritic cells selectively replicate macrophagetropic (M-tropic) human immunodeficiency virus type 1, while mature cells efficiently transmit both M- and T-tropic virus to T cells. J. Virol. 72, 2733–2737 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Reece, J.C. et al. HIV-1 selection by epidermal dendritic cells during transmission across human skin. J. Exp. Med. 187, 1623–1631 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. McDonald, D. et al. Recruitment of HIV and its receptors to dendritic cell–T cell junctions. Science 300, 1295–1297 (2003).

    CAS  PubMed  Google Scholar 

  68. Pope, M. et al. Conjugates of dendritic cells and memory T lymphocytes from skin facilitate productive infection with HIV-1. Cell 78, 389–398 (1994).

    CAS  PubMed  Google Scholar 

  69. Pope, M., Gezelter, S., Gallo, N., Hoffman, L. & Steinman, R.M. Low levels of HIV-1 infection in cutaneous dendritic cells promote extensive viral replication upon binding to memory CD4+ T cells. J. Exp. Med. 182, 2045–2056 (1995).

    CAS  PubMed  Google Scholar 

  70. Schuitemaker, H. et al. Monocytotropic human immunodeficiency virus 1 (HIV-1) variants detectable in all stages of HIV infection lack T-cell line tropism and syncytium-inducing ability in primary T-cell culture. J. Virol. 65, 356–363 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Hirsch, V.M. et al. Vpx is required for dissemination and pathogenesis of SIVSM PBj: Evidence of macrophage-dependent viral amplification. Nat. Med. 4, 1401–1408 (1998).

    CAS  PubMed  Google Scholar 

  72. Swingler, S. et al. HIV-1 Nef mediates lymphocyte chemotaxis and activation by infected macrophages. Nat. Med. 5, 997–1003 (1999).

    CAS  PubMed  Google Scholar 

  73. Swingler, S. et al. HIV-1 Nef intersects the CD40L signaling pathway in macrophages to promote resting cell infection. Nature (in the press).

  74. Messmer, D. et al. Endogenously expressed nef uncouples cytokine and chemokine production from membrane phenotypic maturation in dendritic cells. J. Immunol. 169, 4172–4182 (2002).

    CAS  PubMed  Google Scholar 

  75. Sol-Foulon, N. et al. HIV-1 Nef-induced upregulation of DC-SIGN in dendritic cells promotes lymphocyte clustering and viral spread. Immunity 16, 145–155 (2002).

    CAS  PubMed  Google Scholar 

  76. Izmailova, E. et al. HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages. Nat. Med. 9, 191–197 (2003).

    CAS  PubMed  Google Scholar 

  77. Schwartz, E.J. et al. Effect of target cell availability on HIV-1 production in vitro. AIDS 16, 341–345 (2002).

    CAS  PubMed  Google Scholar 

  78. DeBoer, R.J. & Perelson, A.S. Target cell limited and immune control models of HIV infection: a comparison. J. Theor. Biol. 190, 201–214 (1998).

    CAS  Google Scholar 

  79. Reilly, C., Schacker, T., Haase, A., Wietgrefe, S. & Krason, D. The clustering of infected SIV cells in lymphatic tissue. J. Am. Stat. Assn. 97, 943–954 (2002).

    Google Scholar 

  80. Reinhart, T.A. et al. Tracking members of the simian immunodeficiency virus deltaB670 quasispecies population in vivo at single-cell resolution. J. Virol. 72, 113–120 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Veazey, R.S. et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280, 427–431 (1998).

    CAS  PubMed  Google Scholar 

  82. 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).

    CAS  PubMed  Google Scholar 

  83. Joag, S.V. 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. 71, 4016–4023 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Mothé, B.R. et al. Dominance of CD8 responses specific for epitopes bound by a single major histocompatibility complex class I molecule during the acute phase of viral infection. J. Virol. 76, 875–884 (2002).

    PubMed  PubMed Central  Google Scholar 

  85. Miller, C.J. et al. Rhesus macaques previously infected with simian/human immunodeficiency virus are protected from vaginal challenge with pathogenic SIVmac239. J. Virol. 71, 1911–1921 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Amara, R.R. et al. Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 292, 69–74 (2001).

    CAS  PubMed  Google Scholar 

  87. Enose, Y. et al. Protection by intranasal immunization of a nef-deleted, nonpathogenic SHIV against intravaginal challenge with a heterologous pathogenic SHIV. Virology 298, 206–316 (2002).

    Google Scholar 

  88. Crotty, S. et al. Protection against simian immunodeficiency virus vaginal challenge by using Sabin poliovirus vectors. J. Virol. 75, 7435–7452 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Johnson, R.P. et al. Highly attenuated vaccine strains of simian immunodeficiency virus protect against vaginal challenge: inverse relationship of degree of protection with level of attenuation. J. Virol. 73, 4952–4961 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Joag, S.V. et al. Oral immunization of macaques with attenuated vaccine virus induces protection against vaginally transmitted AIDS. J. Virol. 72, 9069–9078 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhu, T. et al. Persistence of extraordinarily low levels of genetically homogeneous human immunodeficiency virus type 1 in exposed seronegative individuals. J. Virol. 77, 6108–6116 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Kaul, R. et al. Late seroconversion in HIV-resistant Nairobi prostitutes despite pre-existing HIV-specific CD8+ responses. J. Clin. Invest. 107, 341–349 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank C. O'Neill and T. Leonard for help with editing and preparing the manuscript and figures, and J.V. Carlis, T. Schacker and P.J. Southern for comments. M.P. is an Elizabeth Glaser Scientist of the Elizabeth Glaser Pediatric AIDS Foundation and is supported by grants AI52060, AI40877, HD41752 and AI52048 from the National Institutes of Health (NIH), and by the Rockefeller Foundation and the Elizabeth Glaser Pediatric AIDS Foundation. A.T.H. is Regents' Professor and Head of the Department of Microbiology at the University of Minnesota and is supported by grants CA 79458, AI28246, HD37356, AI48484 and RR00167 from the NIH, and by the University of Minnesota.

Author information

Authors and Affiliations

  1. Center for Biomedical Research, Population Council, 1230 York Avenue, New York, 10021, USA

    Melissa Pope

  2. Department of Microbiology, University of Minnesota, 420 Delaware Street SE, Minneapolis, 55455, Minnesota, USA

    Ashley T Haase

Authors
  1. Melissa Pope
    View author publications

    Search author on:PubMed Google Scholar

  2. Ashley T Haase
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Ashley T Haase.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pope, M., Haase, A. Transmission, acute HIV-1 infection and the quest for strategies to prevent infection. Nat Med 9, 847–852 (2003). https://doi.org/10.1038/nm0703-847

Download citation

  • Issue date:

  • DOI: https://doi.org/10.1038/nm0703-847

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