The Italian Concerted Action on HIV/AIDS Vaccine Development (ICAV) has been established under the National AIDS Programme coordinated by the National AIDS Centre and consists of a network of approximately 70 Italian centres. The activities of the ICAV programme are described in Table 12.
Through these and the other networks in which ISS participates, several vaccines and formulations by different participants are in the pipeline. These novel vaccine candidates also include second-generation Tat-based vaccines such as the Tat/ΔV2Env combination [AVIP, Mucosal vaccines for poverty-related diseases (MUVAPRED), very innovative AIDS vaccine (VIAV) and ISS/Novartis–Chiron agreement] and Tat alone or in combination with other HIV products delivered by micro/nanoparticles (ICAV) as well as herpesvirus vectors (ICAV) and replication-competent adenovirus vectors (Italy–USA, ISS/National Cancer Institute–National Institutes of Health) for parenteral and mucosal vaccination strategies.
The establishment of national and international networks, including private companies, public and academic institutions, is essential for vaccine development and should always include training programmes such as the AVIP International School (www.avip-eu.com), which is proving to be an optimal forum to train students, scientists and clinicians in the difficult aspects of HIV/AIDS vaccine development. Although creating these networks has been a very challenging task, particularly for management, the intellectual, scientific, and human interactions among the participants have generated true cooperative teams adding a synergistic value to research conduct.
In conclusion, the development of the Tat vaccine programme required a multidisciplinary approach, adequate economic resources, training and a great effort of managing and coordination. The programme has been fully funded and conducted by the ISS, which is the Italian health governmental agency. A great effort was, therefore, dedicated to build up a structure capable of translational research. The accomplishment of this task took 10 years and taught us important lessons (Table 13), at the same time resulting in key achievements. This structure is now ready to run the following clinical phases of the Tat vaccine, as well as new vaccine programmes. In addition, such organization offers the flexibility to update all the different areas of the programme rapidly in response to scientific needs and innovation, with no interference from private/profit interests or ‘fashioned’ scientific agendas, which have undermined targeting regulatory genes as well as conducting therapeutic vaccine trials that may offer new opportunities in HIV treatment. In particular, the parallel conduct of preventive and therapeutic trials with the Tat vaccine candidate has provided important insights into HIV pathogenesis and for the development of a preventive vaccine based on virus control and not on sterilizing immunity. Finally, the creation of networks for vaccine development is greatly helping in this task and provides a suitable forum for training programmes, which are greatly needed in the field.
The authors wish to thank all the personnel at the National AIDS Centre, ISS, and particularly: S. Moretti, M.R. Pavone-Cossutt, F. Nappi, A. Borsetti, M.T. Maggiorella, L. Sernicola, R. Belli, I. Macchia, P. Leone, O. Longo, F. Ferrantelli, S. Bellino, C. Sgadari, D. Bernasconi, E. Fanales-Belasio, L. Tavoschi, and all the personnel from the animal facilities and technical services; the AHL (Division of Epidemiology, MIPI, ISS): A. Luzi, P. Gallo, B. De Mei, A. Colucci, A. Santoro, A. D'Agostini, R. Valli, G. Rezza; Division of Biologic Products, MIPI, ISS: C. Pini; the Joint ISS/S. Gallicano Laboratory site: A. Tripiciano, A. Scoglio, B. Collacchi, M. Ruiz-Alvarez, V. Francavilla, G. Paniccia, A. Fazio, P. Cordiali-Fei, G. Prignano, A. Arancio, F. Stivali; the Institute of Biochemistry, University of Urbino: M.E. Laguardia; the clinical sites: A. Lazzarin, G. Tambussi, R. Visintini (S. Raffaele Hospital, Milan); P. Narciso, A. Antinori, G. D'Offizi, M. Giulianelli (L. Spallanzani Hospital, Rome); A. Di Carlo, G. Palamara, M. Giuliani (S. Gallicano Hospital); M. Carta (University of Rome ‘La Sapienza’); the Adverse Events Monitoring Committee: P. Popoli (Istituto Superiore di Sanità); M. Galli (L. Sacco Hospital, Milan); M. Picardo (San Gallicano Hospital, Rome); and C.F. Perno (University of Rome ‘Tor Vergata’); the Community Advisory Board: R. Iardino (NPS); S. Marcotullio (I-CAB); A. Vatrella (LILA); C. Valvo (GITA); G. Bevacqua (Positifs Onlus); S. Lombardo (M. Mieli); R. Gavioli and P. Marconi (University of Ferrara); S. Barnett (Novartis, Emeryville, USA); M. Robert-Guroff (NCI–NIH, Bethesda, USA); E. Vardas (University of the Witwatersrand, Soweto, South Africa); F.M. Regini and P. Sergiampietri for technical and secretarial support and A. Carinci and S. Ceccarelli for editorial assistance. A particular thanks to all trial volunteers.
1. Zolla-Pazner S. Identifying epitopes of HIV-1 that induce protective antibodies. Nat Rev Immunol 2004; 4:199–210.
2. Humbert M, Dietrich U. The role of neutralizing antibodies in HIV infection. AIDS Rev 2006; 8:51–59.
3. Srivastava IK, Ulmer JB, Barnett SW. Neutralizing antibody responses to HIV: role in protective immunity and challenges for vaccine design. Expert Rev Vaccines 2004; 3(4 Suppl.):S33–S52.
4. Burton DR, Desrosiers RC, Doms RW, Koff WC, Kwong PD, Moore JP, et al
. HIV vaccine design and the neutralizing antibody problem. Nat Immunol 2004; 5:233–236.
5. Burton DR, Desrosiers RC, Doms RW, Feinberg MB, Gallo RC, Hahn B, et al
. Public health. A sound rationale needed for phase III HIV-1 vaccine trials. Science 2004; 303:316.
6. McNeil JG, Johnston MI, Birx DL, Tramont EC. Policy rebuttal HIV vaccine trial justified. Science 2004; 303:961.
7. Trinvuthipong C. Thailand's prime-boost HIV vaccine phase III. Science 2004; 303:954–955.
8. Belshe R, Franchini G, Girard MP, Gotch F, Kaleebu P, Marthas ML, et al
. Support for the RV144 HIV vaccine trial. Science 2004; 305:177–180.
9. Slobod KS, Bonsignori M, Brown SA, Zhan X, Stambas J, Hurwitz JL. HIV vaccines: brief review and discussion of future directions. Expert Rev Vaccines 2005; 4:305–313.
10. Graham BS, Mascola JR. Lessons from failure–preparing for future HIV-1 vaccine efficacy trials. J Infect Dis 2005; 191:647–649.
11. Flynn NM, Forthal DN, Harro CD, Judson FN, Mayer KH, Para MF. Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J Infect Dis 2005; 191:654–665.
12. Hel Z, Nacsa J, Tryniszewska E, Tsai WP, Parks RW, Montefiori DC, et al
. Containment of simian immunodeficiency virus infection in vaccinated macaques: correlation with the magnitude of virus-specific pre- and postchallenge CD4+ and CD8+ T cell responses 2. J Immunol 2002; 169:4778–4787.
13. Okuda K, Bukawa H, Hamajima K, Kawamoto S, Sekigawa K, Yamada Y, et al
. Induction of potent humoral and cell-mediated immune responses following direct injection of DNA encoding the HIV type 1 env and rev gene products. AIDS Res Hum Retroviruses 1995; 11:933–943.
14. Kim JJ, Ayyavoo V, Bagarazzi ML, Chattergoon MA, Dang K, Wang B, et al
. In vivo engineering of a cellular immune response by coadministration of IL-12 expression vector with a DNA immunogen. J Immunol 1997; 158:816–826.
15. Negri DR, Baroncelli S, Catone S, Comini A, Michelini Z, Maggiorella MT, et al
. Protective efficacy of a multicomponent vector vaccine in cynomolgus monkeys after intrarectal simian immunodeficiency virus challenge. J Gen Virol 2004; 85:1191–1201.
16. Caputo A, Gavioli R, Altavilla G, Brocca-Cofano E, Boarini C, Betti M, et al
. Immunization with low doses of HIV-1 tat DNA delivered by novel cationic block copolymers induces CTL responses against Tat. Vaccine 2003; 21:1103–1111.
17. Caselli E, Betti M, Grossi MP, Balboni PG, Rossi C, Boarini C, et al
. DNA immunization with HIV-1 tat mutated in the trans activation domain induces humoral and cellular immune responses against wild-type Tat. J Immunol 1999; 162:5631–5638.
18. Cui Z, Patel J, Tuzova M, Ray P, Phillips R, Woodward JG, et al
. Strong T cell type-1 immune responses to HIV-1 Tat (1-72) protein-coated nanoparticles. Vaccine 2004; 22:2631–2640.
19. Marinaro M, Riccomi A, Rappuoli R, Pizza M, Fiorelli V, Tripiciano A, et al
. Mucosal delivery of the human immunodeficiency virus-1 Tat protein in mice elicits systemic neutralizing antibodies, cytotoxic T lymphocytes and mucosal IgA. Vaccine 2003; 21:3972–3981.
20. Morris CB, Thanawastien A, Sullivan DE, Clements JD. Identification of a peptide capable of inducing an HIV-1 Tat-specific CTL response. Vaccine 2001; 20:12–15.
21. Gringeri A, Santagostino E, Muca-Perja M, Mannucci PM, Zagury JF, Bizzini B, et al
. Safety and immunogenicity of HIV-1 Tat toxoid in immunocompromised HIV-1-infected patients. J Hum Virol 1998; 1:293–298.
22. Boykins RA, Ardans JA, Wahl LM, Lal RB, Yamada KM, Dhawan S. Immunization with a novel HIV-1-Tat multiple-peptide conjugate induces effective immune response in mice. Peptides 2000; 21:1839–1847.
23. Cosma A, Nagaraj R, Buhler S, Hinkula J, Busch DH, Sutter G, et al
. Therapeutic vaccination with MVA–HIV-1 nef elicits Nef-specific T-helper cell responses in chronically HIV-1 infected individuals. Vaccine 2003; 22:21–29.
24. Osterhaus AD, van Baalen CA, Gruters RA, Schutten M, Siebelink CH, Hulskotte EG, et al
. Vaccination with Rev and Tat against AIDS. Vaccine 1999; 17:2713–2714.
25. Hel Z, Tryniszewska E, Tsai WP, Johnson JM, Harrod R, Fullen J, et al
. Design and in vivo immunogenicity of a polyvalent vaccine based on SIVmac regulatory genes. DNA Cell Biol 2002; 21:619–626.
26. Hejdeman B, Bostrom AC, Matsuda R, Calarota S, Lenkei R, Fredriksson EL, et al
. DNA immunization with HIV early genes in HIV type 1-infected patients on highly active antiretroviral therapy. AIDS Res Hum Retroviruses 2004; 20:860–870.
27. Mooij P, Nieuwenhuis IG, Knoop CJ, Doms RW, Bogers WM, Ten Haaft PJ, et al
. Qualitative T-helper responses to multiple viral antigens correlate with vaccine-induced immunity to simian/human immunodeficiency virus infection. J Virol 2004; 78:3333–3342.
28. Hanke T, Samuel RV, Blanchard TJ, Neumann VC, Allen TM, Boyson JE, et al
. Effective induction of simian immunodeficiency virus-specific cytotoxic T lymphocytes in macaques by using a multiepitope gene and DNA prime-modified vaccinia virus Ankara boost vaccination regimen. J Virol 1999; 73:7524–7532.
29. Mwau M, Cebere I, Sutton J, Chikoti P, Winstone N, Wee EG, et al
. A human immunodeficiency virus 1 (HIV-1) clade A vaccine in clinical trials: stimulation of HIV-specific T-cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans. J Gen Virol 2004; 85:911–919.
30. Makitalo B, Lundholm P, Hinkula J, Nilsson C, Karlen K, Morner A, et al
. Enhanced cellular immunity and systemic control of SHIV infection by combined parenteral and mucosal administration of a DNA prime MVA boost vaccine regimen. J Gen Virol 2004; 85:2407–2419.
31. Nilsson C, Makitalo B, Berglund P, Bex F, Liljestrom P, Sutter G, et al
. Enhanced simian immunodeficiency virus-specific immune responses in macaques induced by priming with recombinant Semliki Forest virus and boosting with modified vaccinia virus Ankara. Vaccine 2001; 19:3526–3536.
32. Asakura Y, Hinkula J, Leandersson AC, Fukushima J, Okuda K, Wahren B. Induction of HIV-1 specific mucosal immune responses by DNA vaccination. Scand J Immunol 1997; 46:326–330.
33. Dominici S, Laguardia ME, Serafini G, Chiarantini L, Fortini C, Tripiciano A, et al
. Red blood cell-mediated delivery of recombinant HIV-1 Tat protein in mice induces anti-Tat neutralizing antibodies and CTL. Vaccine 2003; 21:2073–2081.
34. Opi S, Peloponese JM Jr, Esquieu D, Watkins J, Campbell G, De MJ, et al
. Full-length HIV-1 Tat protein necessary for a vaccine. Vaccine 2004; 22:3105–3111.
35. Kim JJ, Yang JS, Nottingham LK, Lee DJ, Lee M, Manson KH, et al
. Protection from immunodeficiency virus challenges in rhesus macaques by multicomponent DNA immunization. Virology 2001; 285:204–217.
36. Allen TM, Mortara L, Mothe BR, Liebl M, Jing P, Calore B, et al
. Tat-vaccinated macaques do not control simian immunodeficiency virus SIVmac239 replication. J Virol 2002; 76:4108–4112.
37. Calarota S, Bratt G, Nordlund S, Hinkula J, Leandersson AC, Sandstrom E, et al
. Cellular cytotoxic response induced by DNA vaccination in HIV-1-infected patients. Lancet 1998; 351:1320–1325.
38. Calarota SA, Leandersson AC, Bratt G, Hinkula J, Klinman DM, Weinhold KJ, et al
. Immune responses in asymptomatic HIV-1-infected patients after HIV-DNA immunization followed by highly active antiretroviral treatment. J Immunol 1999; 163:2330–2338.
39. Malkevitch N, Rohne D, Pinczewski J, Aldrich K, Kalyanaraman VS, Letvin NL, et al
. Evaluation of combination DNA/replication-competent Ad-SIV recombinant immunization regimens in rhesus macaques. AIDS Res Hum Retroviruses 2004; 20:235–244.
40. Ayyavoo V, Kudchodkar S, Ramanathan MP, Le P, Muthumani K, Megalai NM, et al
. Immunogenicity of a novel DNA vaccine cassette expressing multiple human immunodeficiency virus (HIV-1) accessory genes. AIDS 2000; 14:1–9.
41. Borsutzky S, Fiorelli V, Ebensen T, Tripiciano A, Rharbaoui F, Scoglio A, et al
. Efficient mucosal delivery of the HIV-1 Tat protein using the synthetic lipopeptide MALP-2 as adjuvant. Eur J Immunol 2003; 33:1548–1556.
42. Goldstein G, Manson K, Tribbick G, Smith R. Minimization of chronic plasma viremia in rhesus macaques immunized with synthetic HIV-1 Tat peptides and infected with a chimeric simian/human immunodeficiency virus (SHIV33). Vaccine 2000; 18:2789–2795.
43. Asakura Y, Hamajima K, Fukushima J, Mohri H, Okubo T, Okuda K. Induction of HIV-1 Nef-specific cytotoxic T lymphocytes by Nef-expressing DNA vaccine. Am J Hematol 1996; 53:116–117.
44. Muthumani K, Bagarazzi M, Conway D, Hwang DS, Ayyavoo V, Zhang D, et al
. Inclusion of Vpr accessory gene in a plasmid vaccine cocktail markedly reduces Nef vaccine effectiveness in vivo resulting in CD4 cell loss and increased viral loads in rhesus macaques. J Med Primatol 2002; 31:179–185.
45. Kjerrstrom A, Hinkula J, Engstrom G, Ovod V, Krohn K, Benthin R, et al
. Interactions of single and combined human immunodeficiency virus type 1 (HIV-1) DNA vaccines. Virology 2001; 284:46–61.
46. Hanke T, Schneider J, Gilbert SC, Hill AV, McMichael A. DNA multi-CTL epitope vaccines for HIV and Plasmodium falciparum
: immunogenicity in mice. Vaccine 1998; 16:426–435.
47. Hinkula J, Svanholm C, Schwartz S, Lundholm P, Brytting M, Engstrom G, et al
. Recognition of prominent viral epitopes induced by immunization with human immunodeficiency virus type 1 regulatory genes. J Virol 1997; 71:5528–5539.
48. Hinkula J, Lundholm P, Wahren B. Nucleic acid vaccination with HIV regulatory genes: a combination of HIV-1 genes in separate plasmids induces strong immune responses. Vaccine 1997; 15:874–878.
49. Hanke T, Barnfield C, Wee EG, Agren L, Samuel RV, Larke N, et al
. Construction and immunogenicity in a prime-boost regimen of a Semliki Forest virus-vectored experimental HIV clade A vaccine. J Gen Virol 2003; 84:361–368.
50. MacGregor RR, Ginsberg R, Ugen KE, Baine Y, Kang CU, Tu XM, et al
. T-cell responses induced in normal volunteers immunized with a DNA-based vaccine containing HIV-1 env and rev. AIDS 2002; 16:2137–2143.
51. Okuda K, Xin KO, Tsuji T, Bukawa H, Tanaka S, Koff WC, et al
. DNA vaccination followed by macromolecular multicomponent peptide vaccination against HIV-1 induces strong antigen-specific immunity. Vaccine 1997; 15:1049–1056.
52. Ishii N, Fukushima J, Kaneko T, Okada E, Tani K, Tanaka SI, et al
. Cationic liposomes are a strong adjuvant for a DNA vaccine of human immunodeficiency virus type 1. AIDS Res Hum Retroviruses 1997; 13:1421–1428.
53. Boyer JD, Ugen KE, Wang B, Agadjanyan M, Gilbert L, Bagarazzi ML, et al
. Protection of chimpanzees from high-dose heterologous HIV-1 challenge by DNA vaccination. Nat Med 1997; 3:526–532.
54. Gomez-Roman VR, Florese RH, Peng B, Montefiori DC, Kalyanaraman VS, Venzon D, et al
. An adenovirus-based HIV subtype B prime/boost vaccine regimen elicits antibodies mediating broad antibody-dependent cellular cytotoxicity against non-subtype B HIV strains.J Acquir Immune Defic Syndr
24 August 2006; E-pub ahead of print. in press.
55. Castaldello A, Brocca-Cofano E, Voltan R, Triulzi C, Altavilla G, Laus M, et al
. DNA prime and protein boost immunization with innovative polymeric cationic core-shell nanoparticles elicits broad immune responses and strongly enhance cellular responses of HIV-1 tat DNA vaccination. Vaccine 2006; 24:5655–5669.
56. Pal R, Venzon D, Santra S, Kalyanaraman VS, Montefiori DC, Hocker L, et al
. Systemic immunization with an ALVAC–HIV-1/protein boost vaccine strategy protects rhesus macaques from CD4+ T-cell loss and reduces both systemic and mucosal simian–human immunodeficiency virus SHIVKU2 RNA levels. J Virol 2006; 80:3732–3742.
57. Neumann J, Stitz J, Konig R, Seibold E, Norley S, Flory E, et al
. Retroviral vectors for vaccine development: induction of HIV-1-specific humoral and cellular immune responses in rhesus macaques using a novel MLV(HIV-1) pseudotype vector. J Biotechnol 2006; 124:615–625.
58. Borsutzky S, Ebensen T, Link C, Becker PD, Fiorelli V, Cafaro A, et al
. Efficient systemic and mucosal responses against the HIV-1 Tat protein by prime/boost vaccination using the lipopeptide MALP-2 as adjuvant. Vaccine 2006; 24:2049–2056.
59. Patel J, Galey D, Jones J, Ray P, Woodward JG, Nath A, et al
. HIV-1 Tat-coated nanoparticles result in enhanced humoral immune responses and neutralizing antibodies compared to alum adjuvant. Vaccine 2006; 24:3564–3573.
60. Amara RR, Smith JM, Staprans SI, Montefiori DC, Villinger F, Altman JD, et al
. Critical role for Env as well as Gag-Pol in control of a simian–human immunodeficiency virus 89.6P challenge by a DNA prime/recombinant modified vaccinia virus Ankara vaccine. J Virol 2002; 76:6138–6146.
61. Verrier B, Le GR, Taman-Onal Y, Terrat C, Guillon C, Durand PY, et al
. Evaluation in rhesus macaques of Tat and rev-targeted immunization as a preventive vaccine against mucosal challenge with SHIV-BX08. DNA Cell Biol 2002; 21:653–658.
62. Stittelaar KJ, Gruters RA, Schutten M, van Baalen CA, van AG, Cranage M, et al
. Comparison of the efficacy of early versus late viral proteins in vaccination against SIV. Vaccine 2002; 20:2921–2927.
63. Voss G, Manson K, Montefiori D, Watkins DI, Heeney J, Wyand M, et al
. Prevention of disease induced by a partially heterologous AIDS virus in rhesus monkeys by using an adjuvanted multicomponent protein vaccine. J Virol 2003; 77:1049–1058.
64. Patterson LJ, Malkevitch N, Zhao J, Peng B, Robert-Guroff M. Potent, persistent cellular immune responses elicited by sequential immunization of rhesus macaques with Ad5 host range mutant recombinants encoding SIV Rev and SIV Nef. DNA Cell Biol 2002; 21:627–635.
65. Amara RR, Villinger F, Altman JD, Lydy SL, O'Neil SP, Staprans SI, et al
. Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Vaccine 2002; 20:1949–1955.
66. Partidos CD, Moreau E, Chaloin O, Tunis M, Briand JP, Desgranges C, et al
. A synthetic HIV-1 Tat protein breaches the skin barrier and elicits Tat-neutralizing antibodies and cellular immunity. Eur J Immunol 2004; 34:3723–3731.
67. Dale CJ, De RR, Stratov I, Chea S, Montefiori DC, Thomson S, et al
. Efficacy of DNA and fowlpox virus priming/boosting vaccines for simian/human immunodeficiency virus. J Virol 2004; 78:13819–13828.
68. Goldstein G. HIV-1 Tat protein as a potential AIDS vaccine. Nat Med 1996; 2:960–964.
69. Gallo RC. Tat as one key to HIV-induced immune pathogenesis and Tat (correction of Pat) toxoid as an important component of a vaccine. Proc Natl Acad Sci U S A 1999; 96:8324–8326.
70. Ensoli B, Buonaguro L, Barillari G, Fiorelli V, Gendelman R, Morgan RA, et al
. Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. J Virol 1993; 67:277–287.
71. Arya SK, Guo C, Josephs SF, Wong-Staal F. Trans-activator gene of human T-lymphotropic virus type III (HTLV-III). Science 1985; 229:69–73.
72. Fisher AG, Feinberg MB, Josephs SF, Harper ME, Marselle LM, Reyes G, et al
. The trans-activator gene of HTLV-III is essential for virus replication. Nature 1986; 320:367–371.
73. Peruzzi F. The multiple functions of HIV-1 Tat: proliferation versus apoptosis. Front Biosci 2006; 11:708–717.
74. Huigen MC, Kamp W, Nottet HS. Multiple effects of HIV-1 trans-activator protein on the pathogenesis of HIV-1 infection. Eur J Clin Invest 2004; 34:57–66.
75. Wu Y, Marsh JW. Selective transcription and modulation of resting T cell activity by preintegrated HIV DNA. Science 2001; 293:1503–1506.
76. Chen D, Wang M, Zhou S, Zhou Q. HIV-1 Tat targets microtubules to induce apoptosis, a process promoted by the pro-apoptotic Bcl-2 relative Bim. EMBO J 2002; 21:6801–6810.
77. Campbell GR, Watkins JD, Esquieu D, Pasquier E, Loret EP, Spector SA. The C terminus of HIV-1 Tat modulates the extent of CD178-mediated apoptosis of T cells. J Biol Chem 2005; 280:38376–38382.
78. Bartz SR, Emerman M. Human immunodeficiency virus type 1 Tat induces apoptosis and increases sensitivity to apoptotic signals by up-regulating FLICE/caspase-8. J Virol 1999; 73:1956–1963.
79. Gibellini D, Re MC, Ponti C, Vitone F, Bon I, Fabbri G, et al
. HIV-1 Tat protein concomitantly down-regulates apical caspase-10 and up-regulates c-FLIP in lymphoid T cells: a potential molecular mechanism to escape TRAIL cytotoxicity. J Cell Physiol 2005; 203:547–556.
80. Yang Y, Tikhonov I, Ruckwardt TJ, Djavani M, Zapata JC, Pauza CD, et al
. Monocytes treated with human immunodeficiency virus Tat kill uninfected CD4(+) cells by a tumor necrosis factor-related apoptosis-induced ligand-mediated mechanism. J Virol 2003; 77:6700–6708.
81. Westendorp MO, Frank R, Ochsenbauer C, Stricker K, Dhein J, Walczak H, et al
. Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 1995; 375:497–500.
82. Ott M, Emiliani S, Van LC, Herbein G, Lovett J, Chirmule N, et al
. Immune hyperactivation of HIV-1-infected T cells mediated by Tat and the CD28 pathway. Science 1997; 275:1481–1485.
83. Li CJ, Ueda Y, Shi B, Borodyansky L, Huang L, Li YZ, et al
. Tat protein induces self-perpetuating permissivity for productive HIV-1 infection. Proc Natl Acad Sci U S A 1997; 94:8116–8120.
84. Li CJ, Friedman DJ, Wang C, Metelev V, Pardee AB. Induction of apoptosis in uninfected lymphocytes by HIV-1 Tat protein. Science 1995; 268:429–431.
85. McCloskey TW, Ott M, Tribble E, Khan SA, Teichberg S, Paul MO, et al
. Dual role of HIV Tat in regulation of apoptosis in T cells. J Immunol 1997; 158:1014–1019.
86. Chang HC, Samaniego F, Nair BC, Buonaguro L, Ensoli B. HIV-1 Tat protein exits from cells via a leaderless secretory pathway and binds to extracellular matrix-associated heparan sulfate proteoglycans through its basic region. AIDS 1997; 11:1421–1431.
87. Ensoli B, Barillari G, Salahuddin SZ, Gallo RC, Wong-Staal F. Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients. Nature 1990; 345:84–86.
88. Ensoli B, Gendelman R, Markham P, Fiorelli V, Colombini S, Raffeld M, et al
. Synergy between basic fibroblast growth factor and HIV-1 Tat protein in induction of Kaposi's sarcoma. Nature 1994; 371:674–680.
89. Marchio S, Alfano M, Primo L, Gramaglia D, Butini L, Gennero L, et al
. Cell surface-associated Tat modulates HIV-1 infection and spreading through a specific interaction with gp120 viral envelope protein. Blood 2005; 105:2802–2811.
90. Chang HK, Gallo RC, Ensoli B. Regulation of cellular gene expression and function by the human immunodeficiency virus type 1 Tat protein. J Biomed Sci 1995; 2:189–202.
91. Frankel AD, Pabo CO. Cellular uptake of the tat protein from human immunodeficiency virus. Cell 1988; 55:1189–1193.
92. Shutt DC, Soll DR. HIV-induced T-cell syncytia release a two component T-helper cell chemoattractant composed of Nef and Tat. J Cell Sci 1999; 112:3931–3941.
93. Koedel U, Kohleisen B, Sporer B, Lahrtz F, Ovod V, Fontana A, et al
. HIV type 1 Nef protein is a viral factor for leukocyte recruitment into the central nervous system. J Immunol 1999; 163:1237–1245.
94. Ferrantelli F, Cafaro A, Ensoli B. Nonstructural HIV proteins as targets for prophylactic or therapeutic vaccines. Curr Opin Biotechnol 2004; 15:543–556.
95. Caputo A, Gavioli R, Ensoli B. Recent advances in the development of HIV-1 Tat-based vaccines. Curr HIV Res 2004; 2:357–376.
96. Reiss P, Lange JM, de Ronde A, de Wolf F, Dekker J, Debouck C, et al
. Speed of progression to AIDS and degree of antibody response to accessory gene products of HIV-1. J Med Virol 1990; 30:163–168.
97. Rodman TC, To SE, Hashish H, Manchester K. Epitopes for natural antibodies of human immunodeficiency virus (HIV)-negative (normal) and HIV-positive sera are coincident with two key functional sequences of HIV Tat protein. Proc Natl Acad Sci U S A 1993; 90:7719–7723.
98. Zagury JF, Sill A, Blattner W, Lachgar A, Le BH, Richardson M, et al
. Antibodies to the HIV-1 Tat protein correlated with nonprogression to AIDS: a rationale for the use of Tat toxoid as an HIV-1 vaccine. J Hum Virol 1998; 1:282–292.
99. Re MC, Furlini G, Vignoli M, Ramazzotti E, Roderigo G, De Rosa V, et al
. Effect of antibody to HIV-1 Tat protein on viral replication in vitro and progression of HIV-1 disease in vivo
. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 10:408–416.
100. Re MC, Vignoli M, Furlini G, Gibellini D, Colangeli V, Vitone F, et al
. Antibodies against full-length Tat protein and some low-molecular-weight Tat-peptides correlate with low or undetectable viral load in HIV-1 seropositive patients. J Clin Virol 2001; 21:81–89.
101. Richardson MW, Mirchandani J, Duong J, Grimaldo S, Kocieda V, Hendel H, et al
. Antibodies to Tat and Vpr in the GRIV cohort: differential association with maintenance of long-term non-progression status in HIV-1 infection. Biomed Pharmacother 2003; 57:4–14.
102. Demirhan I, Chandra A, Mueller F, Mueller H, Biberfeld P, Hasselmayer O, et al
. Antibody spectrum against the viral transactivator protein in patients with human immunodeficiency virus type 1 infection and Kaposi's sarcoma. J Hum Virol 2000; 3:137–143.
103. Krone WJ, Debouck C, Epstein LG, Heutink P, Meloen R, Goudsmit J. Natural antibodies to HIV-tat epitopes and expression of HIV-1 genes in vivo
. J Med Virol 1988; 26:261–270.
104. Butto S, Fiorelli V, Tripiciano A, Ruiz-Alvarez MJ, Scoglio A, Ensoli F, et al
. Sequence conservation and antibody cross-recognition of clade B human immunodeficiency virus (HIV) type 1 Tat protein in HIV-1-infected Italians, Ugandans, and South Africans. J Infect Dis 2003; 188:1171–1180.
105. Rezza G, Fiorelli V, Dorrucci M, Ciccozzi M, Tripiciano A, Scoglio A, et al
. The presence of anti-Tat antibodies is predictive of long-term nonprogression to AIDS or severe immunodeficiency: findings in a cohort of HIV-1 seroconverters. J Infect Dis 2005; 191:1321–1324.
106. Addo MM, Altfeld M, Rosenberg ES, Eldridge RL, Philips MN, Habeeb K, 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 U S A 2001; 98:1781–1786.
107. Novitsky V, Rybak N, McLane MF, Gilbert P, Chigwedere P, Klein I, et al
. Identification of human immunodeficiency virus type 1 subtype C Gag-, Tat-, Rev-, and Nef-specific elispot-based cytotoxic T-lymphocyte responses for AIDS vaccine design. J Virol 2001; 75:9210–9228.
108. Cao J, McNevin J, Holte S, Fink L, Corey L, McElrath MJ. Comprehensive analysis of human immunodeficiency virus type 1 (HIV-1)-specific gamma interferon-secreting CD8+ T cells in primary HIV-1 infection. J Virol 2003; 77:6867–6878.
109. Novitsky V, Cao H, Rybak N, Gilbert P, McLane MF, Gaolekwe S, et al
. Magnitude and frequency of cytotoxic T-lymphocyte responses: identification of immunodominant regions of human immunodeficiency virus type 1 subtype C. J Virol 2002; 76:10155–10168.
110. van Baalen CA, Schutten M, Huisman RC, Boers PH, Gruters RA, Osterhaus AD. Kinetics of antiviral activity by human immunodeficiency virus type 1-specific cytotoxic T lymphocytes (CTL) and rapid selection of CTL escape virus in vitro. J Virol 1998; 72:6851–6857.
111. Jones NA, Wei X, Flower DR, Wong M, Michor F, Saag MS, et al
. Determinants of human immunodeficiency virus type 1 escape from the primary CD8+ cytotoxic T lymphocyte response. J Exp Med 2004; 200:1243–1256.
112. Cao J, McNevin J, Malhotra U, McElrath MJ. Evolution of CD8+ T cell immunity and viral escape following acute HIV-1 infection. J Immunol 2003; 171:3837–3846.
113. Allen TM, O'Connor DH, Jing P, Dzuris JL, Mothe BR, Vogel TU, et al
. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 2000; 407:386–390.
114. O'Connor DH, Allen TM, Vogel TU, Jing P, DeSouza IP, Dodds E, et al
. Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection. Nat Med 2002; 8:493–499.
115. Tikhonov I, Ruckwardt TJ, Hatfield GS, Pauza CD. Tat-neutralizing antibodies in vaccinated macaques. J Virol 2003; 77:3157–3166.
116. Ramakrishna L, Anand KK, Mohankumar KM, Ranga U. Codon optimization of the tat antigen of human immunodeficiency virus type 1 generates strong immune responses in mice following genetic immunization. J Virol 2004; 78:9174–9189.
117. Opi S, Peloponese JM Jr, Esquieu D, Campbell G, De MJ, Walburger A, et al
. Tat HIV-1 primary and tertiary structures critical to immune response against non-homologous variants. J Biol Chem 2002; 277:35915–35919.
118. Kuiken C, Foley B, Hahn B, Korber B, McCutchan F, Marx JW, et al
. Human retroviruses and AIDS: a compilation and analysis of nucleic acid and amino acid sequences
. Los Alamos, New Mexico: Los Alamos National Laboratory.
119. Fanales-Belasio E, Moretti S, Nappi F, Barillari G, Micheletti F, Cafaro A, et al
. Native HIV-1 Tat protein targets monocyte-derived dendritic cells and enhances their maturation, function, and antigen-specific T cell responses. J Immunol 2002; 168:197–206.
120. Gavioli R, Gallerani E, Fortini C, Fabris M, Bottoni A, Canella A, et al
. HIV-1 tat protein modulates the generation of cytotoxic T cell epitopes by modifying proteasome composition and enzymatic activity. J Immunol 2004; 173:3838–3843.
121. Remoli AL, Marsili G, Perrotti E, Gallerani E, Ilari R, Nappi F, et al
. Intracellular HIV-1 Tat protein represses constitutive LMP2 transcription increasing proteasome activity by interfering with the binding of IRF-1 to STAT1. Biochem J 2006; 396:371–380.
122. Barillari G, Gendelman R, Gallo RC, Ensoli B. The Tat protein of human immunodeficiency virus type 1, a growth factor for AIDS Kaposi sarcoma and cytokine-activated vascular cells, induces adhesion of the same cell types by using integrin receptors recognizing the RGD amino acid sequence. Proc Natl Acad Sci U S A 1993; 90:7941–7945.
123. Cafaro A, Titti F, Fracasso C, Maggiorella MT, Baroncelli S, Caputo A, et al
. Vaccination with DNA containing tat coding sequences and unmethylated CpG motifs protects cynomolgus monkeys upon infection with simian/human immunodeficiency virus (SHIV89.6P). Vaccine 2001; 19:2862–2877.
124. Cafaro A, Caputo A, Fracasso C, Maggiorella MT, Goletti D, Baroncelli S, et al
. Control of SHIV-89.6P-infection of cynomolgus monkeys by HIV-1 Tat protein vaccine. Nat Med 1999; 5:643–650.
125. Caputo A, Betti M, Altavilla G, Bonaccorsi A, Boarini C, Marchisio M, et al
. Micellar-type complexes of tailor-made synthetic block copolymers containing the HIV-1 tat DNA for vaccine application. Vaccine 2002; 20:2303–2317.
126. Betti M, Voltan R, Marchisio M, Mantovani I, Boarini C, Nappi F, et al
. Characterization of HIV-1 Tat proteins mutated in the transactivation domain for prophylactic and therapeutic application. Vaccine 2001; 19:3408–3419.
127. Samaniego F, Markham PD, Gallo RC, Ensoli B. Inflammatory cytokines induce AIDS–Kaposi's sarcoma-derived spindle cells to produce and release basic fibroblast growth factor and enhance Kaposi's sarcoma-like lesion formation in nude mice. J Immunol 1995; 154:3582–3592.
128. Maggiorella MT, Baroncelli S, Michelini Z, Fanales-Belasio E, Moretti S, Sernicola L, et al
. Long-term protection against SHIV89.6P replication in HIV-1 Tat vaccinated cynomolgus monkeys. Vaccine 2004; 22:3258–3269.
129. Ensoli B, Cafaro A. HIV-1 Tat vaccines. Virus Res 2002; 82:91–101.
130. Various authors. Forum in immunology: rational vaccination strategies against AIDS.Microbes Infect