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

Nature Reviews Immunology

Volumn 3, Issue 2, 2003, Pages 97-107

  Peterlin, B Matija ^a   Trono, Didier ^b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF GENEVA   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIRETROVIRUS AGENT; CELL SURFACE RECEPTOR;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; CYTOTOXIC T LYMPHOCYTE; EFFECTOR CELL; GLYCOSYLATION; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HUMORAL IMMUNITY; IMMUNE RESPONSE; IMMUNOCOMPETENT CELL; LONG TERMINAL REPEAT; PRIORITY JOURNAL; REVIEW; TATA BOX; TRANSCRIPTION REGULATION; VIRUS LATENCY; VIRUS REPLICATION; APOPTOSIS; BIOLOGICAL MODEL; GENETICS; HUMAN IMMUNODEFICIENCY VIRUS; IMMUNOLOGY; PATHOGENICITY; PHYSIOLOGY; PROVIRUS; T LYMPHOCYTE; VIROLOGY; VIRUS GENOME;

APOPTOSIS; GENOME, VIRAL; HIV; HIV INFECTIONS; HUMANS; MODELS, IMMUNOLOGICAL; PROVIRUSES; T-LYMPHOCYTES; VIRUS REPLICATION;

EID: 0037313577     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri998     Document Type: Review

References (133)

1. Cohen, O. J. & Fauci, A. S. Current strategies in the treatment of HIV infection. Adv. Intern. Med. 46, 207-246 (2001).
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).
3. Pantaleo, G. et al. Role of lymphoid organs in the pethogenesis of human immunodeficiency virus (HIV) infection. Immunol. Rev. 140, 105-130 (1994).
4. Webster, R. G. 1918 Spanish influenza: the secrets remain elusive. Proc. Natl Acad. Sci. USA 96, 1164-1166 (1999).
5. Oldstone, M. B. Viral persistence: mechanisms and consequences. Curr. Opin. Microbiol. 1, 436-441 (1998).
6. Ploegh, H. L. Viral strategies of immune evasion. Science 280, 248-253 (1998).
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).
8. Tang, H., Kuhen, K. L. & Wong-Staal, F. Lentivirus replication and regulation. Annu. Rev. Genet. 33, 133-170 (1999).
9. Frankel, A. D. & Young, J. A. HIV-1: fifteen proteins and an RNA. Annu. Rev. Biochem. 67, 1-25 (1998).
10. Doms, R. W. & Trono, D. The plasma membrane as a combat zone in the HIV battlefield. Genes Dev. 14, 2677-2688 (2000).
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.
12. Kwon, D. S., Gregorio, G., Bitton, N., Hendrickson, W. A. & Litman, D. R. DC-SIGN-mediated internalization of HIV is required for trans-enhancement of T-cell infection. Immunity 16, 135-144 (2002).
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).
14. Buknnsky, 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).
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).
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).
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.
18. Schroder, A. et al. HIV-1 integretion in the human genome favors active genes and local hotspots. Cell 110, 521 (2002). HIV integration favours active genes in the host genome.
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).
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).
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).
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).
23. 0 lymphocytes. J. Virol. 73, 6526-6532 (1999).
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).
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).
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).
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).
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).
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).
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.
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.
32. Price, D. H. P-TEFb, a cyclin-dependent kinase controlling elongation by RNA polymerase II. Mol. Cell. Biol. 20, 2629-2634 (2000).
33. Chao, S. H. et al. Flavopiridol inhibits P-TEFb and blocks HIV-1 replication. J. Biol. Chem. 275, 28345-28348 (2000).
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.
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).
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).
37. Cullen, B. R. Retroviruses as model systems for the study of nuclear RNA export pathways. Virology 249, 203-210 (1998).
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).
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).
40. Garrus, J. E. et al. Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. Cell 107, 55-65 (2001).
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).
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).
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).
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).
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).
46. Ho, D. D. et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123-126 (1995).
47. Wei, X. et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373, 117-122 (1995).
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.
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).
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).
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).
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.
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).
54. Finzi, D. et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy Science 278, 1295-1300 (1997).
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.
56. + memory T cells by opposing cytokines. Science 288, 675-678 (2000).
57. Sprent, J. & Surh, C. D. T-cell memory. Annu. Rev. Immunol. 20, 551-579 (2002).
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).
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 dunng prolonged anti-retroviral therapy Nature Med. 6, 82-85 (2000).
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).
61. Brack-Werner, R. Astrocytes: HIV cellular reservoirs and important participants in neuropathogenesis. AIDS 13, 1-22 (1999).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
78. Schwartz, O., Marechal, V., Le Gall, S., Lemonnier, F. & Heard, J. M. Endocytosis of major histocampatibility complex class I molecules is induced by the HIV-1 Nef protein. Nature Med. 2, 338-342 (1996).
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.
80. Bijlmakers, M. J. & Ploegh, H. L. Putting together an MHC class I molecule. Curr. Opin. Immunol. 5, 21-26 (1993).
81. + T lymphocytes. Cell 77, 525-535 (1994).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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.
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).
99. Le Gall, S. et al. Nef interacts with the mu subunit of clathrin adaptor complexes and reveals a cryptic sorting signal in MHCI molecules. Immunity 8, 483-495 (1998).
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).
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).
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).
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).
104. + T cells. Immunity 15, 871-882 (2001).
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.
106. Champagne, P. et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410, 106-111 (2001).
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).
108. - T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4. Nature 395, 189-194 (1998).
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).
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.
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).
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).
113. - T-cell responses associated with control of viremia. Science 278, 1447-1450 (1997).
114. - T cells. Nature 417, 95-98 (2002).
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).
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).
117. Rakoff-Nahoum, S. et al. Regulation of class II expression in monocytic cells after HIV-1 infection. J. Immunol. 167, 2331-2342 (2001).
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).
119. Lori, F., Foli, A. & Liszlewicz, 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).
120. Miller, V. Structured treatment interruptions in antiretroviral management of HIV-1. Curr. Opin. Infect. Dis. 14, 29-37 (2001).
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).
122. + T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy. Nature Med. 5, 651-655 (1999).
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).
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).
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).
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).
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).
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).
129. Amado, R. G. & Chen, I. S. Lentiviral vectors for gene therapy of HIV-induced disease Curr. Top. Microbiol. Immunol. 281, 229-243 (2002).
130. Jacque, J. M., Triques, K. & Stevenson, M. Modulation of HIV-1 replication by RNA interference. Nature 418, 435-438 (2002).
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).
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.
133. Salmon, P. & Trono, D. Lentiviral vectors for the gene therapy of lympho-hematological disorders. Curr. Top. Microbiol. Immunol. 261, 211-227 (2002).