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:

Hide, shield and strike back: how HIV-infected cells avoid immune eradication

Key Points

  • HIV escapes the immune system by hiding inside cells. In resting cells, blocks to the initiation and elongation of viral transcription have been proposed.

  • Viral regulatory and accessory proteins contribute to immune escape.

  • The transcriptional transactivator Tat can inhibit antigen processing and presentation by MHC class I and class II molecules.

  • The viral 'negative effector' Nef can block the expression of MHC class I molecules, as well as trigger the apoptosis of effector T cells through interactions between FAS ligand and FAS.

  • The anti-apoptotic effects of Nef could contribute to the survival of infected cells.

Abstract

Viruses that induce chronic infections can evade immune responses. HIV is a prototype of this class of pathogen. Not only does it mutate rapidly and make its surface components difficult to access by neutralizing antibodies, but it also creates cellular hideouts, establishes proviral latency, removes cell-surface receptors and destroys immune effectors to escape eradication. A better understanding of these strategies might lead to new approaches in the fight against AIDS.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: The HIV genome, transcripts and proteins.
Figure 2: The replicative cycle of HIV.
Figure 3: The HIV long terminal repeat.
Figure 4: Mechanism of Tat transactivation.
Figure 5: Nef-induced downregulation of expression of MHC class I molecules and CD4.
Figure 6: HIV and apoptosis.

Similar content being viewed by others

References

  1. Cohen, O. J. & Fauci, A. S. Current strategies in the treatment of HIV infection. Adv. Intern. Med. 46, 207–246 (2001).

    CAS  PubMed  Google Scholar 

  2. Blankson, J. N., Persaud, D. & Siliciano, R. F. The challenge of viral reservoirs in HIV-1 infection. Annu. Rev. Med. 53, 557–593 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Pantaleo, G. et al. Role of lymphoid organs in the pathogenesis of human immunodeficiency virus (HIV) infection. Immunol. Rev. 140, 105–130 (1994).

    Article  CAS  PubMed  Google Scholar 

  4. Webster, R. G. 1918 Spanish influenza: the secrets remain elusive. Proc. Natl Acad. Sci. USA 96, 1164–1166 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Oldstone, M. B. Viral persistence: mechanisms and consequences. Curr. Opin. Microbiol. 1, 436–441 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Ploegh, H. L. Viral strategies of immune evasion. Science 280, 248–253 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Greene, W. C. & Peterlin, B. M. Charting HIV's remarkable voyage through the cell: basic science as a passport to future therapy. Nature Med. 8, 673–680 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Tang, H., Kuhen, K. L. & Wong-Staal, F. Lentivirus replication and regulation. Annu. Rev. Genet. 33, 133–170 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Frankel, A. D. & Young, J. A. HIV-1: fifteen proteins and an RNA. Annu. Rev. Biochem. 67, 1–25 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Doms, R. W. & Trono, D. The plasma membrane as a combat zone in the HIV battlefield. Genes Dev. 14, 2677–2688 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. 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). This paper reports the identification of DC-SIGN and characterization of its ability to carry and convey HIV to cells.

    Article  CAS  PubMed  Google Scholar 

  12. 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).

    Article  CAS  PubMed  Google Scholar 

  13. Gallay, P., Hope, T., Chin, D. & Trono, D. HIV-1 infection of nondividing cells through the recognition of integrase by the importin/karyopherin pathway. Proc. Natl Acad. Sci. USA 94, 9825–9830 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bukrinsky, M. I. et al. A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells. Nature 365, 666–669 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Heinzinger, N. K. et al. The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells. Proc. Natl Acad. Sci. USA 91, 7311–7315 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Miller, M. D., Farnet, C. M. & Bushman, F. D. Human immunodeficiency virus type 1 preintegration complexes: studies of organization and composition. J. Virol. 71, 5382–5390 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Jordan, A., Defechereux, P. & Verdin, E. The site of HIV-1 integration in the human genome determines basal transcriptional activity and response to Tat transactivation. EMBO J. 20, 1726–1738 (2001). This article describes how the site of integration of HIV has an important effect on viral replication, transcription and Tat-mediated transactivation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schroder, A. et al. HIV-1 integration in the human genome favors active genes and local hotspots. Cell 110, 521 (2002). HIV integration favours active genes in the host genome.

    Article  CAS  PubMed  Google Scholar 

  19. Stevenson, M., Stanwick, T. L., Dempsey, M. P. & Lamonica, C. A. HIV-1 replication is controlled at the level of T-cell activation and proviral integration. EMBO J. 9, 1551–1560 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zack, J. A. et al. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell 61, 213–222 (1990).

    Article  CAS  PubMed  Google Scholar 

  21. Zack, J. A., Haislip, A. M., Krogstad, P. & Chen, I. S. Incompletely reverse-transcribed human immunodeficiency virus type 1 genomes in quiescent cells can function as intermediates in the retroviral life cycle. J. Virol. 66, 1717–1725 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Korin, Y. D. & Zack, J. A. Progression to the G1b phase of the cell cycle is required for completion of human immunodeficiency virus type 1 reverse transcription in T cells. J. Virol. 72, 3161–3168 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Korin, Y. D. & Zack, J. A. Nonproductive human immunodeficiency virus type 1 infection in nucleoside-treated G0 lymphocytes. J. Virol. 73, 6526–6532 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Pierson, T. C. et al. Intrinsic stability of episomal circles formed during human immunodeficiency virus type 1 replication. J. Virol. 76, 4138–4144 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Stevenson, M. et al. Molecular basis of cell-cycle-dependent HIV-1 replication. Implications for control of virus burden. Adv. Exp. Med. Biol. 374, 33–45 (1995).

    Article  CAS  PubMed  Google Scholar 

  26. Unutmaz, D., KewalRamani, V. N., Marmon, S. & Littman, D. R. Cytokine signals are sufficient for HIV-1 infection of resting human T lymphocytes. J. Exp. Med. 189, 1735–1746 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ducrey-Rundquist, O., Guyader, M. & Trono, D. Modalities of interleukin-7-induced human immunodeficiency virus permissiveness in quiescent T lymphocytes. J. Virol. 76, 9103–9111 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jones, K. A. & Peterlin, B. M. Control of RNA initiation and elongation at the HIV-1 promoter. Annu. Rev. Biochem. 63, 717–743 (1994).

    Article  CAS  PubMed  Google Scholar 

  29. Taube, R., Fujinaga, K., Wimmer, J., Barboric, M. & Peterlin, B. M. Tat transactivation: a model for the regulation of eukaryotic transcriptional elongation. Virology 264, 245–253 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Kao, S. Y., Calman, A. F., Luciw, P. A. & Peterlin, B. M. Anti-termination of transcription within the long terminal repeat of HIV-1 by Tat gene product. Nature 330, 489–493 (1987). The first demonstration that Tat affects the rate of elongation, rather than the initiation of transcription. Abortive transcripts were detected also in this study.

    Article  CAS  PubMed  Google Scholar 

  31. Wei, P., Garber, M. E., Fang, S. M., Fischer, W. H. & Jones, K. A. A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA. Cell 92, 451–462 (1998). The identification of CYCT1 as the binding partner and P-TEFb as the co-activator of Tat.

    Article  CAS  PubMed  Google Scholar 

  32. Price, D. H. P-TEFb, a cyclin-dependent kinase controlling elongation by RNA polymerase II. Mol. Cell. Biol. 20, 2629–2634 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chao, S. H. et al. Flavopiridol inhibits P-TEFb and blocks HIV-1 replication. J. Biol. Chem. 275, 28345–28348 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Barboric, M., Nissen, R. M., Kanazawa, S., Jabrane-Ferrat, N. & Peterlin, B. M. NF-κB binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II. Mol. Cell 8, 327–337 (2001). A demonstration that RelA from NF-κB binds P-TEFb also.

    Article  CAS  PubMed  Google Scholar 

  35. Harrich, D., Hsu, C., Race, E. & Gaynor, R. B. Differential growth kinetics are exhibited by human immunodeficiency virus type 1 TAR mutants. J. Virol. 68, 5899–5910 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Pomerantz, R. J., Seshamma, T. & Trono, D. Efficient replication of human immunodeficiency virus type 1 requires a threshold level of Rev: potential implications for latency. J. Virol. 66, 1809–1813 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Cullen, B. R. Retroviruses as model systems for the study of nuclear RNA export pathways. Virology 249, 203–210 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Nguyen, D. H. & Hildreth, J. E. Evidence for budding of human immunodeficiency virus type 1 selectively from glycolipid-enriched membrane lipid rafts. J. Virol. 74, 3264–3272 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Strack, B., Calistri, A., Accola, M. A., Palu, G. & Gottlinger, H. G. A role for ubiquitin ligase recruitment in retrovirus release. Proc. Natl Acad. Sci. USA 97, 13063–13068 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Garrus, J. E. et al. Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. Cell 107, 55–65 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Martin-Serrano, J., Zang, T. & Bieniasz, P. D. HIV-1 and Ebola virus encode small peptide motifs that recruit Tsg101 to sites of particle assembly to facilitate egress. Nature Med. 7, 1313–1319 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. VerPlank, L. et al. Tsg101, a homologue of ubiquitin-conjugating (E2) enzymes, binds the L domain in HIV type 1 Pr55(Gag). Proc. Natl Acad. Sci. USA 98, 7724–7729 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Esser, M. T. et al. Differential incorporation of CD45, CD80 (B7-1), CD86 (B7-2) and major histocompatibility complex class I and II molecules into human immunodeficiency virus type 1 virions and microvesicles: implications for viral pathogenesis and immune regulation. J. Virol. 75, 6173–6182 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zheng, Y. H., Plemenitas, A., Linnemann, T., Fackler, O. T. & Peterlin, B. M. Nef increases infectivity of HIV via lipid rafts. Curr. Biol. 11, 875–879 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Guyader, M., Kiyokawa, E., Abrami, L., Turelli, P. & Trono, D. Role for human immunodeficiency virus type 1 membrane cholesterol in viral internalization. J. Virol. 76, 10356–10364 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  48. Schnittman, S. M. et al. The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4. Science 245, 305–308 (1989). One of the first demonstrations that a greater number of cells contain viral DNA than contain viral RNA in the periphery of infected individuals.

    Article  CAS  PubMed  Google Scholar 

  49. Emiliani, S. et al. A point mutation in the HIV-1 Tat responsive element is associated with postintegration latency. Proc. Natl Acad. Sci. USA 93, 6377–6381 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Emiliani, S. et al. Mutations in the Tat gene are responsible for human immunodeficiency virus type 1 postintegration latency in the U1 cell line. J. Virol. 72, 1666–1670 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Seshamma, T., Bagasra, O., Trono, D., Baltimore, D. & Pomerantz, R. J. Blocked early-stage latency in the peripheral blood cells of certain individuals infected with human immunodeficiency virus type 1. Proc. Natl Acad. Sci. USA 89, 10663–10667 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Adams, M. et al. Cellular latency in human immunodeficiency virus-infected individuals with high CD4 levels can be detected by the presence of promoter-proximal transcripts. Proc. Natl Acad. Sci. USA 91, 3862–3866 (1994). This study shows that there is proviral transcriptional latency in the absence of HAART in the peripheral-blood lymphocytes of infected individuals.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chun, T. W. et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl Acad. Sci. USA 94, 13193–13197 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Finzi, D. et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295–1300 (1997).

    Article  CAS  PubMed  Google Scholar 

  55. Wong, J. K. et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278, 1291–1295 (1997). References 53–55 describe the persistence of the viral reservoir despite HAART.

    Article  CAS  PubMed  Google Scholar 

  56. Ku, C. C., Murakami, M., Sakamoto, A., Kappler, J. & Marrack, P. Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 288, 675–678 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Sprent, J. & Surh, C. D. T-cell memory. Annu. Rev. Immunol. 20, 551–579 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Furtado, M. R. et al. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. N. Engl. J. Med. 340, 1614–1622 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Ramratnam, B. et al. The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy. Nature Med. 6, 82–85 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Sharkey, M. E. et al. Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy. Nature Med. 6, 76–81 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Brack-Werner, R. Astrocytes: HIV cellular reservoirs and important participants in neuropathogenesis. AIDS 13, 1–22 (1999).

    Article  CAS  PubMed  Google Scholar 

  62. Nunnari, G. et al. Residual HIV-1 disease in seminal cells of HIV-1-infected men on suppressive HAART: latency without on-going cellular infections. AIDS 16, 39–45 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Herrmann, C. H., Carroll, R. G., Wei, P., Jones, K. A. & Rice, A. P. Tat-associated kinase, TAK, activity is regulated by distinct mechanisms in peripheral-blood lymphocytes and promonocytic cell lines. J. Virol. 72, 9881–9888 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Nguyen, V. T., Kiss, T., Michels, A. A. & Bensaude, O. 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature 414, 322–325 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Yang, Z., Zhu, Q., Luo, K. & Zhou, Q. The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature 414, 317–322 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Garber, M. E. et al. CDK9 autophosphorylation regulates high-affinity binding of the human immunodeficiency virus type 1 tat-P-TEFb complex to TAR RNA. Mol. Cell. Biol. 20, 6958–6969 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fong, Y. W. & Zhou, Q. Relief of two built-in autoinhibitory mechanisms in P-TEFb is required for assembly of a multicomponent transcription elongation complex at the human immunodeficiency virus type 1 promoter. Mol. Cell. Biol. 20, 5897–5907 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kiernan, R. E. et al. Interaction between cyclin T1 and SCF(SKP2) targets CDK9 for ubiquitination and degradation by the proteasome. Mol. Cell. Biol. 21, 7956–7970 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wada, T. et al. DSIF, a novel transcription elongation factor that regulates RNA polymerase II processivity, is composed of human Spt4 and Spt5 homologs. Genes Dev. 12, 343–356 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yamaguchi, Y. et al. NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation. Cell 97, 41–51 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Ivanov, D., Kwak, Y. T., Guo, J. & Gaynor, R. B. Domains in the SPT5 protein that modulate its transcriptional regulatory properties. Mol. Cell. Biol. 20, 2970–2983 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kim, J. B. & Sharp, P. A. Positive transcription elongation factor B phosphorylates hSPT5 and RNA polymerase II carboxyl-terminal domain independently of cyclin-dependent kinase-activating kinase. J. Biol. Chem. 276, 12317–12323 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Wu-Baer, F., Lane, W. S. & Gaynor, R. B. Role of the human homolog of the yeast transcription factor SPT5 in HIV-1 Tat-activation. J. Mol. Biol. 277, 179–197 (1998).

    Article  CAS  PubMed  Google Scholar 

  74. Kim, J. B., Yamaguchi, Y., Wada, T., Handa, H. & Sharp, P. A. Tat-SF1 protein associates with RAP30 and human SPT5 proteins. Mol. Cell. Biol. 19, 5960–5968 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yamaguchi, Y., Inukai, N., Narita, T., Wada, T. & Handa, H. Evidence that negative elongation factor represses transcription elongation through binding to a DRB sensitivity-inducing factor/RNA polymerase II complex and RNA. Mol. Cell. Biol. 22, 2918–2927 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Pomerantz, R. J., Trono, D., Feinberg, M. B. & Baltimore, D. Cells nonproductively infected with HIV-1 exhibit an aberrant pattern of viral RNA expression: a molecular model for latency. Cell 61, 1271–1276 (1990).

    Article  CAS  PubMed  Google Scholar 

  77. Addo, M. M. et al. The HIV-1 regulatory proteins Tat and Rev are frequently targeted by cytotoxic T lymphocytes derived from HIV-1-infected individuals. Proc. Natl Acad. Sci. USA 98, 1781–1786 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Schwartz, O., Marechal, V., Le Gall, S., Lemonnier, F. & Heard, J. M. Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nature Med. 2, 338–342 (1996).

    Article  CAS  PubMed  Google Scholar 

  79. Collins, K. L., Chen, B. K., Kalams, S. A., Walker, B. D. & Baltimore, D. HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391, 397–401 (1998). References 78 and 79 describe the decreased expression of MHC class I determinants by Nef and its consequences for cytotoxic T-lymphocyte (CTL) evasion.

    Article  CAS  PubMed  Google Scholar 

  80. Bijlmakers, M. J. & Ploegh, H. L. Putting together an MHC class I molecule. Curr. Opin. Immunol. 5, 21–26 (1993).

    Article  CAS  PubMed  Google Scholar 

  81. York, I. A. et al. A cytosolic herpes simplex virus protein inhibits antigen presentation to CD8+ T lymphocytes. Cell 77, 525–535 (1994).

    Article  CAS  PubMed  Google Scholar 

  82. Tortorella, D., Gewurz, B. E., Furman, M. H., Schust, D. J. & Ploegh, H. L. Viral subversion of the immune system. Annu. Rev. Immunol. 18, 861–926 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Swann, S. A. et al. HIV-1 Nef blocks transport of MHC class I molecules to the cell surface via a PI3-kinase-dependent pathway. Virology 282, 267–277 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Lama, J., Mangasarian, A. & Trono, D. Cell-surface expression of CD4 reduces HIV-1 infectivity by blocking Env incorporation in a Nef- and Vpu-inhibitable manner. Curr. Biol. 9, 622–631 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Aiken, C., Konner, J., Landau, N. R., Lenburg, M. E. & Trono, D. Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain. Cell 76, 853–864 (1994).

    Article  CAS  PubMed  Google Scholar 

  86. Bresnahan, P. A. et al. A dileucine motif in HIV-1 Nef acts as an internalization signal for CD4 downregulation and binds the AP-1 clathrin adaptor. Curr. Biol. 8, 1235–1238 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Craig, H. M., Pandori, M. W. & Guatelli, J. C. Interaction of HIV-1 Nef with the cellular dileucine-based sorting pathway is required for CD4 down-regulation and optimal viral infectivity. Proc. Natl Acad. Sci. USA 95, 11229–11234 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Piguet, V. et al. Mechanism of Nef-induced CD4 endocytosis: Nef connects CD4 with the mu chain of adaptor complexes. EMBO J. 17, 2472–2481 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Piguet, V. et al. Nef-induced CD4 degradation: a diacidic-based motif in Nef functions as a lysosomal targeting signal through the binding of β-COP in endosomes. Cell 97, 63–73 (1999).

    Article  CAS  PubMed  Google Scholar 

  90. Carroll, I. R., Wang, J., Howcroft, T. K. & Singer, D. S. HIV Tat represses transcription of the β2-microglobulin promoter. Mol. Immunol. 35, 1171–1178 (1998).

    Article  CAS  PubMed  Google Scholar 

  91. Greenberg, M. E., Lafrate, A. J. & Skowronski, J. The SH3 domain-binding surface and an acidic motif in HIV-1 Nef regulate trafficking of class I MHC complexes. EMBO J. 17, 2777–2789 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Le Gall, S. et al. Distinct trafficking pathways mediate Nef-induced and clathrin-dependent major histocompatibility complex class I down-regulation. J. Virol. 74, 9256–9266 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Crump, C. M. et al. PACS-1 binding to adaptors is required for acidic cluster motif-mediated protein traffic. EMBO J. 20, 2191–2201 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Piguet, V. et al. HIV-1 Nef protein binds to the cellular protein PACS-1 to downregulate class I major histocompatibility complexes. Nature Cell Biol. 2, 163–167 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. Gaffet, P., Jones, A. T. & Clague, M. J. Inhibition of calcium-independent mannose 6-phosphate receptor incorporation into trans-Golgi network-derived clathrin-coated vesicles by wortmannin. J. Biol. Chem. 272, 24170–24175 (1997).

    Article  CAS  PubMed  Google Scholar 

  96. Wan, L. et al. PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization. Cell 94, 205–216 (1998).

    Article  CAS  PubMed  Google Scholar 

  97. Blagoveschenskaya, A. D., Thomas, L., Feliciangeli, S. F., Hugh, C. -H. & Thomas, G. HIV-1 Nef downregulates MHC-I by a PACS-1- and PI3K-regulated ARF6 endocytic pathway. Cell 111, 853–866 (2002). Together with reference 94, this study provides a mechanistic insight into Nef-mediated sequestration of MHC class I determinants.

    Article  Google Scholar 

  98. Cohen, G. B. et al. The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells. Immunity 10, 661–671 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. Le Gall, S. et al. Nef interacts with the mu subunit of clathrin adaptor complexes and reveals a cryptic sorting signal in MHC I molecules. Immunity 8, 483–495 (1998).

    Article  CAS  PubMed  Google Scholar 

  100. Howcroft, T. K., Strebel, K., Martin, M. A. & Singer, D. S. Repression of MHC class I gene promoter activity by two-exon Tat of HIV. Science 260, 1320–1322 (1993).

    Article  CAS  PubMed  Google Scholar 

  101. Weissman, J. D. et al. HIV-1 tat binds TAFII250 and represses TAFII250-dependent transcription of major histocompatibility class I genes. Proc. Natl Acad. Sci. USA 95, 11601–11606 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Matsui, M., Warburton, R. J., Cogswell, P. C., Baldwin, A. S. Jr & Frelinger, J. A. Effects of HIV-1 Tat on expression of HLA class I molecules. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 11, 233–240 (1996).

    Article  CAS  PubMed  Google Scholar 

  103. Finkel, T. H. et al. Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nature Med. 1, 129–134 (1995).

    Article  CAS  PubMed  Google Scholar 

  104. Mueller, Y. M. et al. Increased CD95/Fas-induced apoptosis of HIV-specific CD8+ T cells. Immunity 15, 871–882 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Xu, X. N. et al. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T-cell receptor ζ-chain. J. Exp. Med. 189, 1489–1496 (1999). A description of how Nef activates the expression of FAS ligand and triggers apoptosis of CTLs that are directed against infected cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Champagne, P. et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410, 106–111 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Westendorp, M. O. et al. Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 375, 497–500 (1995).

    Article  CAS  PubMed  Google Scholar 

  108. Herbein, G. et al. Apoptosis of CD8+ T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4. Nature 395, 189–194 (1998).

    Article  CAS  PubMed  Google Scholar 

  109. Geleziunas, R., Xu, W., Takeda, K., Ichijo, H. & Greene, W. C. HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell. Nature 410, 834–838 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Wolf, D. et al. HIV-1 Nef-associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nature Med. 7, 1217–1224 (2001). References 109 and 110 describe how Nef protects infected cells against apoptosis.

    Article  CAS  PubMed  Google Scholar 

  111. Korsmeyer, S. J. et al. Death and survival signals determine active/inactive conformations of pro-apoptotic BAX, BAD and BID molecules. Cold Spring Harb. Symp. Quant. Biol. 64, 343–350 (1999).

    Article  CAS  PubMed  Google Scholar 

  112. Greenway, A. L. et al. Human immunodeficiency virus type 1 Nef binds to tumor suppressor p53 and protects cells against p53-mediated apoptosis. J. Virol. 76, 2692–2702 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Rosenberg, E. S. et al. Vigorous HIV-1-specific CD4+ T-cell responses associated with control of viremia. Science 278, 1447–1450 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  115. Polyak, S. et al. Impaired class II expression and antigen uptake in monocytic cells after HIV-1 infection. J. Immunol. 159, 2177–2188 (1997).

    CAS  PubMed  Google Scholar 

  116. Kanazawa, S., Okamoto, T. & Peterlin, B. M. Tat competes with CIITA for the binding to P-TEFb and blocks the expression of MHC class II genes in HIV infection. Immunity 12, 61–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  117. Rakoff-Nahoum, S. et al. Regulation of class II expression in monocytic cells after HIV-1 infection. J. Immunol. 167, 2331–2342 (2001).

    Article  CAS  PubMed  Google Scholar 

  118. Viscidi, R. P., Mayur, K., Lederman, H. M. & Frankel, A. D. Inhibition of antigen-induced lymphocyte proliferation by Tat protein from HIV-1. Science 246, 1606–1608 (1989).

    Article  CAS  PubMed  Google Scholar 

  119. Lori, F., Foli, A. & Lisziewicz, J. Structured treatment interruptions as a potential alternative therapeutic regimen for HIV-infected patients: a review of recent clinical data and future prospects. J. Antimicrob. Chemother. 50, 155–160 (2002).

    Article  CAS  PubMed  Google Scholar 

  120. Miller, V. Structured treatment interruptions in antiretroviral management of HIV-1. Curr. Opin. Infect. Dis. 14, 29–37 (2001).

    Article  PubMed  Google Scholar 

  121. Oxenius, A. et al. Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection. Proc. Natl Acad. Sci. USA 99, 13747–13752 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Chun, T. W. et al. Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy. Nature Med. 5, 651–655 (1999).

    Article  CAS  PubMed  Google Scholar 

  123. Fraser, C. et al. Reduction of the HIV-1-infected T-cell reservoir by immune activation treatment is dose-dependent and restricted by the potency of antiretroviral drugs. AIDS 14, 659–669 (2000).

    Article  CAS  PubMed  Google Scholar 

  124. Kulkosky, J. et al. Intensification and stimulation therapy for human immunodeficiency virus type 1 reservoirs in infected persons receiving virally suppressive highly active antiretroviral therapy. J. Infect. Dis. 186, 1403–1411 (2002).

    Article  CAS  PubMed  Google Scholar 

  125. Letvin, N. L., Barouch, D. H. & Montefiori, D. C. Prospects for vaccine protection against HIV-1 infection and AIDS. Annu. Rev. Immunol. 20, 73–99 (2002).

    Article  CAS  PubMed  Google Scholar 

  126. Migueles, S. A. et al. HLA-B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long-term nonprogressors. Proc. Natl Acad. Sci. USA 97, 2709–2714 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kelleher, A. D. et al. Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T-lymphocyte responses. J. Exp. Med. 193, 375–386 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Moore, C. B. et al. Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science 296, 1439–1443 (2002).

    Article  CAS  PubMed  Google Scholar 

  129. Amado, R. G. & Chen, I. S. Lentiviral vectors for gene therapy of HIV-induced disease. Curr. Top. Microbiol. Immunol. 261, 229–243 (2002).

    CAS  PubMed  Google Scholar 

  130. Jacque, J. M., Triques, K. & Stevenson, M. Modulation of HIV-1 replication by RNA interference. Nature 418, 435–438 (2002).

    Article  CAS  PubMed  Google Scholar 

  131. Lee, N. S. et al. Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells. Nature Biotechnol. 20, 500–505 (2002).

    Article  CAS  Google Scholar 

  132. Novina, C. D. et al. siRNA-directed inhibition of HIV-1 infection. Nature Med. 8, 681–686 (2002). References 130–132 describe the inhibition of HIV replication by RNA interference.

    Article  CAS  PubMed  Google Scholar 

  133. Salmon, P. & Trono, D. Lentiviral vectors for the gene therapy of lympho-hematological disorders. Curr. Top. Microbiol. Immunol. 261, 211–227 (2002).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank members of our laboratories for helpful discussions, and G. Thomas for communicating unpublished results. This work was supported by grants from the National Institutes of Health, the Nora Eccles Treadwell Foundation and the Universitywide AIDS Research Program (to B.M.P.), and the Swiss National Science Foundation and the National Centre for Competence in Research 'Frontiers in Genetics' (to D.T.).

Author information

Authors and Affiliations

Authors

Related links

Related links

DATABASES

Entrez

HIV-1

Nef

Rev

Tat

Vif

Vpr

Vpu

LocusLink

AP2

ARF6

ARNO

ASK1

β2-m

BAD

BAK

BAX

BCL-2

BCL-W

BCL-XL

BID

CCR5

CD4

CDK7

CDK9

CXCR4

CYCT1

CYCT2

CYCK

DC-SIGN

FAS

FASL

M6PR

p53

PACS1

RD

RNAPII

SF1

SPT4

SPT5

TAFII250

TAP

TFIIH

TNF

TRX

TSG101

VPS4

7SK RNA

Glossary

MICROGLIAL CELLS

Resident brain macrophages. Bone-marrow-derived cells that express CD4 and chemokine receptors

PRE-INTEGRATION COMPLEX

A large complex of viral complementary DNA, integrase (IN) protein, matrix (MA) protein, reverse transcriptase (RT), viral protein r (Vpr) and host proteins that is docked at the nuclear envelope. The viral genome then crosses the nucleopore, together with an as-yet-undefined set of these proteins, before integrating into host chromosomes.

TATA BOX

A highly conserved DNA sequence (consensus TATAA) that is found in the promoter of many (mainly rapidly transcribed) cellular and viral genes, 25–35 bases upstream of the RNA start site.

POSITIVE TRANSCRIPTION ELONGATION FACTOR B

(P-TEFb). This complex consists of the carboxy-terminal domain kinase CDK9 and the C-type cyclin CYCT1, CYCT2a, CYCT2b or CYCK. It is required for the elongation of transcription.

NEGATIVE TRANSCRIPTION ELONGATION FACTOR

(N-TEF). This complex consists most probably of 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB)-sensitivity-inducing factor (DSIF) and negative elongation factor (NELF); the subunit containing arginine–glutamate repeats (RD) binds TAR.

PRE-INITIATION COMPLEX

The transcription complex that is recruited to promoters through activators, consisting of RNA polymerase II and mediators that bind its unphosphorylated carboxy-terminal domain.

CRM1/RANGTP COMPLEX

A complex that transports proteins containing a nuclear-export signal from the nucleus to the cytoplasm. The cargo is released in the cytoplasm after the hydrolysis of GTP to GDP.

CLATHRIN-COATED PITS

Subdomains of the plasma or endosomal membranes that are involved in endocytosis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Peterlin, B., Trono, D. Hide, shield and strike back: how HIV-infected cells avoid immune eradication. Nat Rev Immunol 3, 97–107 (2003). https://doi.org/10.1038/nri998

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri998

This article is cited by

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