Observational Study for the Evaluation of the Role of HIV-1 Tat Protein and Anti-Tat Immune Response In HIV Reservoir

NCT04263207 | Suspended

• 1 other identifier: ISS OBS T-005
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

A longitudinal observational study in HIV-infected subjects receiving cART addressed to explore the effect of the Tat protein and anti-Tat immunity on the formation and maintenance of HIV-1 virus reservoir.

Conditions

HIV/AIDS

Keywords

HIV/AIDS; Immune responses; Tat; HIV reservoire; Biomarkers

Outcome Measures

Primary Outcomes (3)

• HIV proviral DNA levels

  Changes of total HIV-1 proviral DNA copies/1.000.000 CD4+ T-cells

  Baseline and through study completion, an average of 3 years

• HIV plasma viremia

  Changes of HIV plasma viral load (copies/mL)

  Baseline and through study completion, an average of 3 years

• CD4+ and CD8+ T-cell levels

  Changes of CD4+ and CD8+ T-cell counts (cells/microL)

  Baseline and through study completion, an average of 3 years

Secondary Outcomes (4)

• lymphocytes subset apoptosis

  Baseline and through study completion, an average of 3 years

• Induction of replication of competent latent HIV-1 from resting CD4+ T-cell

  Baseline and through study completion, an average of 3 years

• Inflammation/immune activation biomarkers

  Baseline and through study completion, an average of 3 years

• Anti-Tat Ab isotypes

  Baseline and through study completion, an average of 3 years

Study Arms (2)

anti-Tat Ab positive subjects

Other: No intervention

anti-Tat Ab negative subjects

Other: No intervention

Interventions

No intervention OTHER

No intervention

anti-Tat Ab negative subjects; anti-Tat Ab positive subjects

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

HIV-1 infected adult subjects of either gender, ≥18 years old, under cART, with CD4+ T-cell count ≥250 cells/µL.

You may qualify if:

• Age ≥18 years
• Diagnosis of HIV-1 infection
• To be under cART treatment
• CD4+ T-cell count ≥250 cells/microliters
• Testing for anti-Tat Ab performed during pre-screening
• Signed informed consent

You may not qualify if:

• \. Current therapy with immunomodulators or immunosuppressive drugs or chemotherapy for neoplastic disorders.

Sponsors & Collaborators

• Barbara Ensoli, MD, PhD: lead

Study Sites (1)

Infectious Dermatology STI Unit San Gallicano Dermatologic Institute , IRCCS

Rome, 00144, Italy

Location

Related Publications (33)

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• Ensoli F, Cafaro A, Casabianca A, Tripiciano A, Bellino S, Longo O, Francavilla V, Picconi O, Sgadari C, Moretti S, Cossut MR, Arancio A, Orlandi C, Sernicola L, Maggiorella MT, Paniccia G, Mussini C, Lazzarin A, Sighinolfi L, Palamara G, Gori A, Angarano G, Di Pietro M, Galli M, Mercurio VS, Castelli F, Di Perri G, Monini P, Magnani M, Garaci E, Ensoli B. 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. 2015 Apr 29;12:33. doi: 10.1186/s12977-015-0151-y.

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• Deng K, Pertea M, Rongvaux A, Wang L, Durand CM, Ghiaur G, Lai J, McHugh HL, Hao H, Zhang H, Margolick JB, Gurer C, Murphy AJ, Valenzuela DM, Yancopoulos GD, Deeks SG, Strowig T, Kumar P, Siliciano JD, Salzberg SL, Flavell RA, Shan L, Siliciano RF. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature. 2015 Jan 15;517(7534):381-5. doi: 10.1038/nature14053. Epub 2015 Jan 7.

  PMID: 25561180 BACKGROUND

• Hosmane NN, Kwon KJ, Bruner KM, Capoferri AA, Beg S, Rosenbloom DI, Keele BF, Ho YC, Siliciano JD, Siliciano RF. Proliferation of latently infected CD4+ T cells carrying replication-competent HIV-1: Potential role in latent reservoir dynamics. J Exp Med. 2017 Apr 3;214(4):959-972. doi: 10.1084/jem.20170193. Epub 2017 Mar 24.

  PMID: 28341641 BACKGROUND

• 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. 2001 Apr 2;20(7):1726-38. doi: 10.1093/emboj/20.7.1726.

  PMID: 11285236 BACKGROUND

• C Quaresma AJ, Bugai A, Barboric M. Cracking the control of RNA polymerase II elongation by 7SK snRNP and P-TEFb. Nucleic Acids Res. 2016 Sep 19;44(16):7527-39. doi: 10.1093/nar/gkw585. Epub 2016 Jul 1.

  PMID: 27369380 BACKGROUND

• 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 Jul 29;122(2):169-82. doi: 10.1016/j.cell.2005.06.006.

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• Razooky BS, Pai A, Aull K, Rouzine IM, Weinberger LS. A hardwired HIV latency program. Cell. 2015 Feb 26;160(5):990-1001. doi: 10.1016/j.cell.2015.02.009.

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• Cafaro A, Sgadari C, Picconi O, Tripiciano A, Moretti S, Francavilla V, Pavone Cossut MR, Butto S, Cozzone G, Ensoli F, Monini P, Ensoli B. "cART intensification by the HIV-1 Tat B clade vaccine: progress to phase III efficacy studies". Expert Rev Vaccines. 2018 Feb;17(2):115-126. doi: 10.1080/14760584.2018.1418666. Epub 2017 Dec 22.

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• Frankel AD, Pabo CO. Cellular uptake of the tat protein from human immunodeficiency virus. Cell. 1988 Dec 23;55(6):1189-93. doi: 10.1016/0092-8674(88)90263-2.

  PMID: 2849510 BACKGROUND

• Ensoli B, Buonaguro L, Barillari G, Fiorelli V, Gendelman R, Morgan RA, Wingfield P, Gallo RC. Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. J Virol. 1993 Jan;67(1):277-87. doi: 10.1128/JVI.67.1.277-287.1993.

  PMID: 8416373 BACKGROUND

• Mousseau G, Kessing CF, Fromentin R, Trautmann L, Chomont N, Valente ST. The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency. mBio. 2015 Jul 7;6(4):e00465. doi: 10.1128/mBio.00465-15.

  PMID: 26152583 BACKGROUND

• Kessing CF, Nixon CC, Li C, Tsai P, Takata H, Mousseau G, Ho PT, Honeycutt JB, Fallahi M, Trautmann L, Garcia JV, Valente ST. In Vivo Suppression of HIV Rebound by Didehydro-Cortistatin A, a "Block-and-Lock" Strategy for HIV-1 Treatment. Cell Rep. 2017 Oct 17;21(3):600-611. doi: 10.1016/j.celrep.2017.09.080.

  PMID: 29045830 BACKGROUND

• Johnson TP, Patel K, Johnson KR, Maric D, Calabresi PA, Hasbun R, Nath A. Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein. Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13588-93. doi: 10.1073/pnas.1308673110. Epub 2013 Jul 29.

  PMID: 23898208 BACKGROUND

• Lopez-Huertas MR, Mateos E, Sanchez Del Cojo M, Gomez-Esquer F, Diaz-Gil G, Rodriguez-Mora S, Lopez JA, Calvo E, Lopez-Campos G, Alcami J, Coiras M. The presence of HIV-1 Tat protein second exon delays fas protein-mediated apoptosis in CD4+ T lymphocytes: a potential mechanism for persistent viral production. J Biol Chem. 2013 Mar 15;288(11):7626-7644. doi: 10.1074/jbc.M112.408294. Epub 2013 Jan 30.

  PMID: 23364796 BACKGROUND

• Zauli G, Gibellini D, Caputo A, Bassini A, Negrini M, Monne M, Mazzoni M, Capitani S. The human immunodeficiency virus type-1 Tat protein upregulates Bcl-2 gene expression in Jurkat T-cell lines and primary peripheral blood mononuclear cells. Blood. 1995 Nov 15;86(10):3823-34.

  PMID: 7579350 BACKGROUND

• Chiozzini C, Collacchi B, Nappi F, Bauer T, Arenaccio C, Tripiciano A, Longo O, Ensoli F, Cafaro A, Ensoli B, Federico M. Surface-bound Tat inhibits antigen-specific CD8+ T-cell activation in an integrin-dependent manner. AIDS. 2014 Sep 24;28(15):2189-200. doi: 10.1097/QAD.0000000000000389.

  PMID: 25313583 BACKGROUND

• Rezza G, Fiorelli V, Dorrucci M, Ciccozzi M, Tripiciano A, Scoglio A, Collacchi B, Ruiz-Alvarez M, Giannetto C, Caputo A, Tomasoni L, Castelli F, Sciandra M, Sinicco A, Ensoli F, Butto S, Ensoli B. 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 Apr 15;191(8):1321-4. doi: 10.1086/428909. Epub 2005 Mar 14.

  PMID: 15776379 BACKGROUND

• Bellino S, Tripiciano A, Picconi O, Francavilla V, Longo O, Sgadari C, Paniccia G, Arancio A, Angarano G, Ladisa N, Lazzarin A, Tambussi G, Nozza S, Torti C, Foca E, Palamara G, Latini A, Sighinolfi L, Mazzotta F, Di Pietro M, Di Perri G, Bonora S, Mercurio VS, Mussini C, Gori A, Galli M, Monini P, Cafaro A, Ensoli F, Ensoli B. 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 Jun 24;11:49. doi: 10.1186/1742-4690-11-49.

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• Ensoli B, Bellino S, Tripiciano A, Longo O, Francavilla V, Marcotullio S, Cafaro A, Picconi O, Paniccia G, Scoglio A, Arancio A, Ariola C, Ruiz Alvarez MJ, Campagna M, Scaramuzzi D, Iori C, Esposito R, Mussini C, Ghinelli F, Sighinolfi L, Palamara G, Latini A, Angarano G, Ladisa N, Soscia F, Mercurio VS, Lazzarin A, Tambussi G, Visintini R, Mazzotta F, Di Pietro M, Galli M, Rusconi S, Carosi G, Torti C, Di Perri G, Bonora S, Ensoli F, Garaci E. 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 Nov 11;5(11):e13540. doi: 10.1371/journal.pone.0013540.

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• Ensoli B, Nchabeleng M, Ensoli F, Tripiciano A, Bellino S, Picconi O, Sgadari C, Longo O, Tavoschi L, Joffe D, Cafaro A, Francavilla V, Moretti S, Pavone Cossut MR, Collacchi B, Arancio A, Paniccia G, Casabianca A, Magnani M, Butto S, Levendal E, Ndimande JV, Asia B, Pillay Y, Garaci E, Monini P; SMU-MeCRU study group. HIV-Tat immunization induces cross-clade neutralizing antibodies and CD4(+) T cell increases in antiretroviral-treated South African volunteers: a randomized phase II clinical trial. Retrovirology. 2016 Jun 9;13(1):34. doi: 10.1186/s12977-016-0261-1.

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• Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T, Smith K, Lisziewicz J, Lori F, Flexner C, Quinn TC, Chaisson RE, Rosenberg E, Walker B, Gange S, Gallant J, Siliciano RF. 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 May;5(5):512-7. doi: 10.1038/8394.

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• Sanyal A, Mailliard RB, Rinaldo CR, Ratner D, Ding M, Chen Y, Zerbato JM, Giacobbi NS, Venkatachari NJ, Patterson BK, Chargin A, Sluis-Cremer N, Gupta P. Novel assay reveals a large, inducible, replication-competent HIV-1 reservoir in resting CD4+ T cells. Nat Med. 2017 Jul;23(7):885-889. doi: 10.1038/nm.4347. Epub 2017 May 29.

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• Monini P, Cafaro A, Srivastava IK, Moretti S, Sharma VA, Andreini C, Chiozzini C, Ferrantelli F, Cossut MR, Tripiciano A, Nappi F, Longo O, Bellino S, Picconi O, Fanales-Belasio E, Borsetti A, Toschi E, Schiavoni I, Bacigalupo I, Kan E, Sernicola L, Maggiorella MT, Montin K, Porcu M, Leone P, Leone P, Collacchi B, Palladino C, Ridolfi B, Falchi M, Macchia I, Ulmer JB, Butto S, Sgadari C, Magnani M, Federico MP, Titti F, Banci L, Dallocchio F, Rappuoli R, Ensoli F, Barnett SW, Garaci E, Ensoli B. 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(11):e48781. doi: 10.1371/journal.pone.0048781. Epub 2012 Nov 13.

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• Sgadari C, Barillari G, Palladino C, Bellino S, Taddeo B, Toschi E, Ensoli B. Fibroblast Growth Factor-2 and the HIV-1 Tat Protein Synergize in Promoting Bcl-2 Expression and Preventing Endothelial Cell Apoptosis: Implications for the Pathogenesis of AIDS-Associated Kaposi's Sarcoma. Int J Vasc Med. 2011;2011:452729. doi: 10.1155/2011/452729. Epub 2011 Oct 9.

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• Sgadari C, Monini P, Tripiciano A, Picconi O, Casabianca A, Orlandi C, Moretti S, Francavilla V, Arancio A, Paniccia G, Campagna M, Bellino S, Meschiari M, Nozza S, Sighinolfi L, Latini A, Muscatello A, Saracino A, Di Pietro M, Galli M, Cafaro A, Magnani M, Ensoli F, Ensoli B. Continued Decay of HIV Proviral DNA Upon Vaccination With HIV-1 Tat of Subjects on Long-Term ART: An 8-Year Follow-Up Study. Front Immunol. 2019 Feb 13;10:233. doi: 10.3389/fimmu.2019.00233. eCollection 2019.

  PMID: 30815001 BACKGROUND

• Cafaro A, Tripiciano A, Picconi O, Sgadari C, Moretti S, Butto S, Monini P, Ensoli B. Anti-Tat Immunity in HIV-1 Infection: Effects of Naturally Occurring and Vaccine-Induced Antibodies Against Tat on the Course of the Disease. Vaccines (Basel). 2019 Aug 26;7(3):99. doi: 10.3390/vaccines7030099.

  PMID: 31454973 BACKGROUND

• Moretti S, Cafaro A, Tripiciano A, Picconi O, Butto S, Ensoli F, Sgadari C, Monini P, Ensoli B. HIV therapeutic vaccines aimed at intensifying combination antiretroviral therapy. Expert Rev Vaccines. 2020 Jan;19(1):71-84. doi: 10.1080/14760584.2020.1712199. Epub 2020 Jan 19.

  PMID: 31957513 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Periferal blood mononuclear cells and plasma

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director, National HIV/AIDS Research Center (CNAIDS)

Study Record Dates

• First Submitted: February 5, 2020
• First Posted: February 10, 2020
• Study Start: February 4, 2020
• Primary Completion: December 1, 2024
• Study Completion: June 1, 2025
• Last Updated: March 5, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)