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

HIV/AIDS Clinical Trial

— ISS OBS T-005  

Official title:

Observational Study for the Evaluation of the Role of HIV-1 Tat Protein and Anti-Tat Immune Response in Peripheral Blood HIV Reservoir Dynamics

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT04263207
• Other study ID #: ISS OBS T-005
• Status: Suspended
• Start date: February 4, 2020
• Est. completion date: June 2025

Study information

• Verified date: March 2024
• Source: Istituto Superiore di Sanità
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Description:

The study is designed as a longitudinal observational study addressed to identify the effects of Tat protein and humoral/cellular anti-Tat immune responses (induced in the natural infection or by Tat vaccination) in HIV-1 reservoir dynamics in blood of HIV infected patients receiving cART. HIV DNA data will be used for analyzing the decay dynamics.

The primary objective of the study is to determine the rate of decay of total HIV DNA in blood of anti-Tat antibody (Ab) positive versus anti-Tat Ab negative HIV patients receiving cART.

The secondary objectives of the study are to relate the HIV DNA decay data to:

1. the persistence of anti-Tat humoral responses;

2. biomarkers of HIV reservoir stability potentially affected by the Tat protein or anti-Tat immune responses, including: i) apoptotic/survival index of CD4+ T cells; ii) reactivation dynamics of latent HIV in resting CD4+ T cells upon exposure to Tat protein and/or activation stimuli; iii) cellular and humoral biomarkers relevant to inflammation and immune dysregulation.

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 100
• Est. completion date: June 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age =18 years

2. Diagnosis of HIV-1 infection

3. To be under cART treatment

4. CD4+ T-cell count =250 cells/microliters

5. Testing for anti-Tat Ab performed during pre-screening

6. Signed informed consent

Exclusion Criteria:

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

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• HIV/AIDS

Intervention

Other:
• No intervention
No intervention

Locations

Country	Name	City	State
Italy	Infectious Dermatology STI Unit San Gallicano Dermatologic Institute , IRCCS	Rome

Sponsors (1)

Lead Sponsor	Collaborator
Barbara Ensoli, MD, PhD

Country where clinical trial is conducted

Italy, 

References & Publications (33)

Avettand-Fenoel V, Hocqueloux L, Ghosn J, Cheret A, Frange P, Melard A, Viard JP, Rouzioux C. Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications. Clin Microbiol Rev. 2016 Oct;29(4):859-80. doi: 10.1128/CMR.00015-16. — View Citation

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. — View Citation

Blankson JN, Finzi D, Pierson TC, Sabundayo BP, Chadwick K, Margolick JB, Quinn TC, Siliciano RF. Biphasic decay of latently infected CD4+ T cells in acute human immunodeficiency virus type 1 infection. J Infect Dis. 2000 Dec;182(6):1636-42. doi: 10.1086/317615. Epub 2000 Nov 8. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Lorenzo-Redondo R, Fryer HR, Bedford T, Kim EY, Archer J, Pond SLK, Chung YS, Penugonda S, Chipman J, Fletcher CV, Schacker TW, Malim MH, Rambaut A, Haase AT, McLean AR, Wolinsky SM. Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature. 2016 Feb 4;530(7588):51-56. doi: 10.1038/nature16933. Epub 2016 Jan 27. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Murray AJ, Kwon KJ, Farber DL, Siliciano RF. The Latent Reservoir for HIV-1: How Immunologic Memory and Clonal Expansion Contribute to HIV-1 Persistence. J Immunol. 2016 Jul 15;197(2):407-17. doi: 10.4049/jimmunol.1600343. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Sigal A, Kim JT, Balazs AB, Dekel E, Mayo A, Milo R, Baltimore D. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature. 2011 Aug 17;477(7362):95-8. doi: 10.1038/nature10347. — View Citation

Siliciano JM, Siliciano RF. The Remarkable Stability of the Latent Reservoir for HIV-1 in Resting Memory CD4+ T Cells. J Infect Dis. 2015 Nov 1;212(9):1345-7. doi: 10.1093/infdis/jiv219. Epub 2015 Apr 15. No abstract available. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 33 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	HIV plasma viremia	Changes of HIV plasma viral load (copies/mL)	Baseline and through study completion, an average of 3 years
Primary	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	lymphocytes subset apoptosis	Apoptotic index of isolated lymphocytes subsets	Baseline and through study completion, an average of 3 years
Secondary	Induction of replication of competent latent HIV-1 from resting CD4+ T-cell	Quantification of replication competent latent HIV-1 from isolated resting CD4+ T cells [TZM-bl cell based assay (TZA)]	Baseline and through study completion, an average of 3 years
Secondary	Inflammation/immune activation biomarkers	Plasma levels of inflammation and immune activation biomarkers	Baseline and through study completion, an average of 3 years
Secondary	Anti-Tat Ab isotypes	Anti-Tat humoral response in terms of anti-Tat IgM, IgG and IgA Ab	Baseline and through study completion, an average of 3 years