HIV-1 Tat immunization restores immune homeostasis and attacks the HAART-resistant blood HIV DNA: Results of a randomized phase II exploratory clinical trial

Retrovirology

Volumn 12, Issue 1, 2015, Pages

  Ensoli, Fabrizio ^a   Cafaro, Aurelio ^b   Casabianca, Anna ^c   Tripiciano, Antonella ^a,b   Bellino, Stefania ^b   Longo, Olimpia ^b   Francavilla, Vittorio ^a,b   Picconi, Orietta ^b   Sgadari, Cecilia ^b   Moretti, Sonia ^b   Cossut, Maria Pavone R ^b   Arancio, Angela ^a,b   Orlandi, Chiara ^c   Sernicola, Leonardo ^b   Maggiorella, Maria T ^b   Paniccia, Giovanni ^a,b   Mussini, Cristina ^d   Lazzarin, Adriano ^e   Sighinolfi, Laura ^f   Palamara, Guido ^a   Gori, Andrea ^g   Angarano, Gioacchino ^h   Di Pietro, Massimo ⁱ   Galli, Massimo ^j   Mercurio, Vito S ^k   Castelli, Francesco ^l   Di Perri, Giovanni ^m   Monini, Paolo ^b   Magnani, Mauro ^c   Garaci, Enrico ^b,n   Ensoli, Barbara ^b   more..

^a SAN GALLICANO DERMATOLOGICAL INSTITUTE   (Italy)

^b ISTITUTO SUPERIORE DI SANITÀ   (Italy)

^c UNIVERSITY OF URBINO   (Italy)

^d UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

^e SAN RAFFAELE HOSPITAL   (Italy)

^f UNIVERSITY HOSPITAL OF FERRARA   (Italy)

^g SAN GERARDO HOSPITAL   (Italy)

^h UNIVERSITY OF BARI   (Italy)

ⁱ SANTA MARIA ANNUNZIATA HOSPITAL   (Italy)

^j UNIVERSITY OF MILAN   (Italy)

^k SANTA MARIA GORETTI HOSPITAL   (Italy)

^l Institute of Infectious and Tropical Diseases   (Italy)

^m AMEDEO DI SAVOIA HOSPITAL   (Italy)

ⁿ UNIVERSITY OF ROME TOR VERGATA   (Italy)

more..

Author keywords

Antibodies; CD38+HLA DR+ CD8+ T cells; HAART; HIV 1; Neutralization; Proviral DNA; Tat protein; Vaccine

Indexed keywords

HLA DR ANTIGEN; IMMUNOGLOBULIN G; IMMUNOGLOBULIN M; TRANSACTIVATOR PROTEIN; VIRUS DNA; VIRUS ENVELOPE PROTEIN;

ADULT; ARTICLE; ATAXIC APHASIA; B LYMPHOCYTE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CONTROLLED STUDY; DENDRITIC CELL; DISEASE DURATION; DRUG SAFETY; DRUG TOLERABILITY; DYSARTHRIA; FEMALE; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HOMEOSTASIS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNE RESPONSE; IMMUNIZATION; ITALY; MAJOR CLINICAL STUDY; MALE; MULTICENTER STUDY; NATURAL KILLER CELL; OBSERVATIONAL STUDY; PARESTHESIA; PATHOGENESIS; PHASE 2 CLINICAL TRIAL; PHENOTYPE; RANDOMIZED CONTROLLED TRIAL; RETROSTERNAL PAIN; T LYMPHOCYTE; VIREMIA; WEAKNESS;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 84928563445     PISSN: None     EISSN: 17424690     Source Type: Journal    
DOI: 10.1186/s12977-015-0151-y     Document Type: Article

References (84)

1. Klatt NR, Chomont N, Douek DC, Deeks SG. Immune activation and HIV persistence: implications for curative approaches to HIV infection. Immunol Rev. 2013;254:326-42.
2. Tsiara CG, Nikolopoulos GK, Bagos PG, Goujard C, Katzenstein TL, Minga AK, et al. Impact of HIV type 1 DNA levels on spontaneous disease progression: a meta-analysis. AIDS Res Hum Retroviruses. 2012;28:366-73.
3. Deeks SG, Phillips AN. HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ. 2009;338:a3172.
4. Appay V, Sauce D. Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol. 2008;214:231-41.
5. Alexaki A, Liu Y, Wigdahl B. Cellular reservoirs of HIV-1 and their role in viral persistence. Curr HIV Res. 2008;6:388-400.
6. Sigal A, Kim JT, Balazs AB, Dekel E, Mayo A, Milo R, et al. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature. 2011;477:95-8.
7. Kostrikis LG, Touloumi G, Karanicolas R, Pantazis N, Anastassopoulou C, Karafoulidou A, et al. Quantitation of human immunodeficiency virus type 1 DNA forms with the second template switch in peripheral blood cells predicts disease progression independently of plasma RNA load. J Virol. 2002;76:10099-108.
8. Nicastri E, Palmisano L, Sarmati L, D'ettorre G, Parisi S, Andreotti M, et al. HIV-1 residual viremia and proviral DNA in patients with suppressed plasma viral load (<400 HIV-RNA cp/mL) during differential antiretroviral regimens. Curr HIV Res. 2008;6:261-6.
9. Katlama C, Deeks SG, Autran B, Martinez-Picado J, van Lunzen J, Rouzioux C, et al. Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs. Lancet. 2013;381:2109-17.
10. Drechsler H, Powderly WG. Switching effective antiretroviral therapy: a review. Clin Infect Dis. 2002;35:1219-30.
11. McKinnon JE, Mellors JW, Swindells S. Simplification strategies to reduce antiretroviral drug exposure: progress and prospects. Antivir Ther. 2009;14:1-12.
12. Volberding PA, Deeks SG. Antiretroviral therapy and management of HIV infection. Lancet. 2010;376:49-62.
13. Weinberger LS, Burnett JC, Toettcher JE, Arkin AP, Schaffer DV. Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 Tat fluctuations drive phenotypic diversity. Cell. 2005;122:169-82.
14. 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;345:84-6.
15. 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;67:277-87.
16. 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;371:674-80.
17. 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;11:1421-31.
18. Rayne F, Debaisieux S, Yezid H, Lin YL, Mettling C, Konate K, et al. Phosphatidylinositol-(4,5)-bisphosphate enables efficient secretion of HIV-1 Tat by infected T-cells. EMBO J. 2010;29:1348-62.
19. Ott M, Emiliani S, Van Lint C, 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;275:1481-5.
20. Wu Y, Marsh JW. Selective transcription and modulation of resting T cell activity by preintegrated HIV DNA. Science. 2001;293:1503-6.
21. Mediouni S, Darque A, Baillat G, Ravaux I, Dhiver C, Tissot-Dupont H, et al. Antiretroviral therapy does not block the secretion of the human immunodeficiency virus Tat protein. Infect Disord Drug Targets. 2012;12:81-6.
22. Ensoli B, Bellino S, Tripiciano A, Longo O, Francavilla V, Marcotullio S, et al. Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART. PLoS ONE. 2010;5:e13540.
23. Johnson TP, Patel K, Johnson KR, Maric D, Calabresi PA, Hasbun R, et al. Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein. Proc Natl Acad Sci USA. 2013;110:13588-93.
24. 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.
25. 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;173:3838-43.
26. Ensoli B, Fiorelli V, Ensoli F, Lazzarin A, Visintini R, Narciso P, et al. The therapeutic phase I trial of the recombinant native HIV-1 Tat protein. AIDS. 2008;22:2207-9.
27. Ensoli B, Fiorelli V, Ensoli F, Lazzarin A, Visintini R, Narciso P, et al. The preventive phase I trial with the HIV-1 Tat-based vaccine. Vaccine. 2009;28:371-8.
28. Longo O, Tripiciano A, Fiorelli V, Bellino S, Scoglio A, Collacchi B, et al. Phase I therapeutic trial of the HIV-1 Tat protein and long term follow-up. Vaccine. 2009;27:3306-12.
29. Huang L, Bosch I, Hofmann W, Sodroski J, Pardee AB. Tat protein induces human immunodeficiency virus type 1 (HIV-1) coreceptors and promotes infection with both macrophage-tropic and T-lymphotropic HIV-1 strains. J Virol. 1998;72:8952-60.
30. 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 USA. 1997;94:8116-20.
31. Nappi F, Chiozzini C, Bordignon V, Borsetti A, Bellino S, Cippitelli M, et al. Immobilized HIV-1 Tat protein promotes gene transfer via a transactivation-independent mechanism which requires binding of Tat to viral particles. J Gene Med. 2009;11:955-65.
32. Monini P, Cafaro A, Srivastava IK, Moretti S, Sharma VA, Andreini C, et al. HIV-1 Tat Promotes Integrin-Mediated HIV Transmission to Dendritic Cells by Binding Env Spikes and Competes Neutralization by Anti-HIV Antibodies. PLoS ONE. 2012;7:e48781.
33. Chertova E, Chertov O, Coren LV, Roser JD, Trubey CM, Bess Jr JW, et al. Proteomic and biochemical analysis of purified human immunodeficiency virus type 1 produced from infected monocyte-derived macrophages. J Virol. 2006;80:9039-52.
34. 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;5:643-50.
35. Cafaro A, Bellino S, Titti F, Maggiorella MT, Sernicola L, Wiseman RW, et al. Impact of viral dose and major histocompatibility complex class IB haplotype on viral outcome in Tat-vaccinated mauritian cynomolgus monkeys upon challenge with SHIV89.6P. J Virol. 2010;84:8953-8.
36. Bachler BC, Humbert M, Palikuqi B, Siddappa NB, Lakhashe SK, Rasmussen RA, et al. Novel biopanning strategy to identify epitopes associated with vaccine protection. J Virol. 2013;87:4403-16.
37. Reiss P, de Wolf F, Kuiken CL, de Ronde A, Dekker J, Boucher CA, et al. Contribution of antibody response to recombinant HIV-1 gene-encoded products nef, rev, tat, and protease in predicting development of AIDS in HIV-1-infected individuals. J Acquir Immune Defic Syndr. 1991;4:165-72.
38. 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;10:408-16.
39. 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.
40. 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;191:1321-4.
41. Bellino S, Tripiciano A, Picconi O, Francavilla V, Longo O, Sgadari C, et al. The presence of anti-Tat antibodies in HIV-infected individuals is associated with containment of CD4+ T-cell decay and viral load, and with delay of disease progression: results of a 3-year cohort study. Retrovirology. 2014;11:49.
42. Fanales-Belasio E, Moretti S, Fiorelli V, Tripiciano A, Pavone Cossut MR, Scoglio A, et al. HIV-1 Tat addresses dendritic cells to induce a predominant Th1-type adaptive immune response that appears prevalent in the asymptomatic stage of infection. J Immunol. 2009;182:2888-97.
43. Gavioli R, Cellini S, Castaldello A, Voltan R, Gallerani E, Gagliardoni F, et al. The Tat protein broadens T cell responses directed to the HIV-1 antigens Gag and Env: implications for the design of new vaccination strategies against AIDS. Vaccine. 2008;26:727-37.
44. Sforza F, Nicoli F, Gallerani E, Finessi V, Reali E, Cafaro A, et al. HIV-1 Tat affects the programming and functionality of human CD8+ T cells by modulating the expression of T-box transcription factors. AIDS. 2014;28:1729-38.
45. Nicoli F, Finessi V, Sicurella M, Rizzotto L, Gallerani E, Destro F, et al. The HIV-1 Tat protein induces the activation of CD8+ T cells and affects in vivo the magnitude and kinetics of antiviral responses. PLoS ONE. 2013;8:e77746.
46. Migueles SA, Weeks KA, Nou E, Berkley A, Rood JE, Osborne CM, et al. Defective human immunodeficiency virus-specific CD8+ T-cell polyfunctionality, proliferation, and cytotoxicity are not restored by antiretroviral therapy. J Virol. 2009;83:11876-89.
47. Sáez-Cirión A, Sinet M, Shin SY, Urrutia A, Versmisse P, Lacabaratz C, et al. Heterogeneity in HIV suppression by CD8 T cells from HIV controllers: association with Gag-specific CD8 T cell responses. J Immunol. 2009;182:7828-37.
48. Shan L, Deng K, Shroff NS, Durand CM, Rabi SA, Yang HC, et al. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity. 2012;36:491-501.
49. Chiozzini C, Collacchi B, Nappi F, Bauer T, Arenaccio C, Tripiciano A, et al. Surface-bound Tat inhibits antigen-specific CD8+ T-cell activation in an integrin-dependent manner. AIDS. 2014;28:2189-200.
50. European Medicines Agency. Note for Guidance on Choice of Control Group in Clinical Trials (CPMP/ICH/364/96). January 2001.
51. Kelley CF, Kitchen CM, Hunt PW, Rodriguez B, Hecht FM, Kitahata M, et al. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis. 2009;48:787-94.
52. Robbins GK, Spritzler JG, Chan ES, Asmuth DM, Gandhi RT, Rodriguez BA, et al. Incomplete reconstitution of T cell subsets on combination antiretroviral therapy in the AIDS Clinical Trials Group protocol 384. Clin Infect Dis. 2009;48:350-61.
53. Rallón N, Sempere-Ortells JM, Soriano V, Benito JM. Central memory CD4 T cells are associated with incomplete restoration of the CD4 T cell pool after treatment-induced long-term undetectable HIV viraemia. J Antimicrob Chemoter. 2013;68:2616-25.
54. Casazza JP, Betts MR, Picker LJ, Koup RA. Decay kinetics of human immunodeficiency virus-specific CD8+ T cells in peripheral blood after initiation of highly active antiretroviral therapy. J Virol. 2001;75:6508-16.
55. Serrano-Villar Serrano-Villar S, Gutiérrez C, Vallejo A, Hernández-Novoa B, Díaz L, Abad Fernández M, et al. The CD4/CD8 ratio in HIV-infected subjects is independently associated with T-cell activation despite long-term viral suppression. J Infect. 2013;66:57-66.
56. Serrano-Villar S, Sainz T, Lee SA, Hunt PW, Sinclair E, Shacklett BL, et al. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality. PLoS Pathogens. 2014;10:e1004078.
57. Brunetta E, Hudspeth KL, Mavilio D. Pathologic natural killer cell subset redistribution in HIV-1 infection: new insights in pathophysiology and clinical outcomes. J Leukoc Biol. 2010;88:1119-30.
58. Pensieroso S, Galli L, Nozza S, Ruffin N, Castagna A, Tambussi G, et al. B-cell subset alterations and correlated factors in HIV-1 infection. AIDS. 2013;27:1209-17.
59. Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick JB, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med. 2003;9:727-8.
60. Costiniuk CT, Jenabian MA. HIV Reservoir Dynamics in the Face of Highly Active Antiretroviral Therapy. AIDS Patient Care STDs. 2015;29:55-68.
61. Medina-Ramírez M, Sánchez-Merino V, Sánchez-Palomino S, Merino-Mansilla A, Ferreira CB, Pérez I, et al. Broadly cross-neutralizing antibodies in HIV-1 patients with undetectable viremia. J Virol. 2011;85:5804-13.
62. Sáez-Cirión A, Lacabaratz C, Lambotte O, Versmisse P, Urrutia A, Boufassa F, et al. HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc Natl Acad Sci USA. 2007;104:6776-81.
63. Archin NM, Sung JM, Garrido C, Soriano-Sarabia N, Margolis DM. Eradicating HIV-1 infection: seeking to clear a persistent pathogen. Nat Rev Microbiol. 2014;12:750-64.
64. McKinstry KK, Strutt TM, Swain SL. The potential of CD4 T-cell memory. Immunology. 2010;130:1-9.
65. Cui W, Kaech SM. Generation of effector CD8+ T cells and their conversion to memory T cells. Immunol Rev. 2010;236:151-66.
66. Hoxie JA, June CH. Novel cell and gene therapies for HIV. Cold Spring Harb Perspect Med. 2012; 2(10).
67. García F, León A, Gatell JM, Plana M, Gallart T. Therapeutic vaccines against HIV infection. Hum Vaccin Immunother. 2012;8:569-81.
68. Ensoli B, Cafaro A, Monini P, Marcotullio S, Ensoli F. Challenges in HIV Vaccine Research for Treatment and Prevention. Frontiers Immunol. 2014;5:417.
69. Walker B, McMichael A. The T-cell response to HIV. Cold Spring Harb Perspect Med. 2012;2:a007054.
70. Carrington M, Alter G. Innate immune control of HIV. Cold Spring Harb Perspect Med. 2012;2:a007070.
71. Castells M. Rapid desensitization for hypersensitivity reactions to medications. Immunol Allergy Clin North Am. 2009;29:585-606.
72. Keet CA, Wood RA. Emerging therapies for food allergy. J Clin Invest. 2014;124:1880-6.
73. Kenney RT, Frech SA, Muenz LR, Villar CP, Glenn GM. Dose sparing with intradermal injection of influenza vaccine. N Engl J Med. 2004;351:2295-301.
74. Leroux-Roels I, Borkowski A, Vanwolleghem T, Dramé M, Clement F, Hons E, et al. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet. 2007;370:580-9.
75. Pope M, Haase AT. Transmission, acute HIV-1 infection and the quest for strategies to prevent infection. Nat Med. 2003;9:847-52.
76. Haase A. Targeting early infection to prevent HIV-1 mucosal transmission. Nature. 2010;464:217-23.
77. Coleman CM, Wu L. HIV interactions with monocytes and dendritic cells: viral latency and reservoirs. Retrovirology. 2009;6:51.
78. Saksena NK, Wang B, Zhou L, Soedjono M, Ho YS, Conceicao V. HIV reservoirs in vivo and new strategies for possible eradication of HIV from the reservoir sites. HIV/AIDS (Auckl). 2010;2:103-22.
79. Iglesias-Ussel MD, Romerio F. HIV reservoirs: the new frontier. AIDS Rev. 2011;13:13-29.
80. Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999;5:512-7.
81. Buttò 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;188:1171-80.
82. Gregory TR. Animal Genome Size Database http://www.genomesize.com 2013.
83. Casabianca A, Orlandi C, Canovari B, Scotti M, Acetoso M, Valentini M, et al. A real time PCR platform for the simultaneous quantification of total and extrachromosomal HIV DNA forms in blood of HIV-1 infected patients. PLoS ONE. 2014;9:e111919.
84. Bannert N, Kurth R. The evolutionary dynamics of Human Endogenous Retroviral families. Annu Rev Genomics Hum Genet. 2006;7:149-73.