Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Infectious Diseases
Published in: BMC Infectious Diseases 1/2016

Open Access 01-12-2016 | Research article

HIV-1 Tat protein vaccination in mice infected with Mycobacterium tuberculosis is safe, immunogenic and reduces bacterial lung pathology

Authors: Aurelio Cafaro, Giovanni Piccaro, Giuseppe Altavilla, Vincenzo Gigantino, Giuseppe Matarese, Erika Olivieri, Flavia Ferrantelli, Barbara Ensoli, Carla Palma

Published in: BMC Infectious Diseases | Issue 1/2016

Login to get access

Abstract

Background

The therapeutic HIV-1 Tat protein vaccine is in advanced clinical development. Tuberculosis, the main AIDS co-infection, is highly endemic in areas where AIDS prevention through vaccination is needed. However, safety and immunogenicity of Tat vaccination in the course of Mycobacterium tuberculosis (Mtb) infection is still unknown and it prevents the possibility to administer the vaccine to Mtb-infected individuals. We addressed the interplay and effects of Tat vaccination on Mtb infection in immunocompetent mice.

Methods

C57BL/6 mice were vaccinated or not with Bacillus Calmette-Guerin (BCG), the current tuberculosis vaccine, and after 5 weeks were infected with Mtb by intravenous route. The Tat protein was injected intradermally at 1, 2 and 4 weeks after Mtb challenge. Eight weeks after Mtb infection, all mice were sacrificed, and both the degree of pathology and immune responses to Mtb and Tat were evaluated. As additional control, some mice were either vaccinated or not with BCG, were not challenged with Mtb, but received the Tat protein. Statistical significances were evaluated by one-way or two-way ANOVA and Tukey’s multiple comparisons post-test.

Results

In the lungs of Mtb-infected mice, Tat-vaccine did not favour Mtb replication and indeed reduced both area of cellular infiltration and protein levels of Interferon-γ, Chemokine (C-C motif) ligand-4 and Interleukin-1β, pathological events triggered by Mtb-infection. Moreover, the protection against Mtb infection conferred by BCG remained good after Tat protein treatment. In spleen cells of Mtb-infected mice, Tat vaccination enhanced Mtb-specific Interferon-γ and Interleukin-17 responses, which may have a protective role. Of note, Mtb infection reduced, but did not suppress, the development of anti-Tat antibodies, required for Tat vaccine efficacy and the titer of anti-Tat IgG was potentiated by BCG vaccination in Mtb-free mice. In general, Tat treatment was well tolerated in both Mtb-infected and Mtb-free mice.

Conclusions

Tat protein vaccine, administered in Mtb-infected mice with a protocol resembling that used in the clinical trials, was safe, immunogenic, limited the lung Mtb-associated immunopathology and did not abrogate the protective efficacy of BCG. These data provide preliminary evidence for a safe use of Tat vaccine in people vaccinated with BCG and/or suffering from tuberculosis.
Literature
1.
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;320:367–71.CrossRefPubMed
2.
Chang HK, Gendelman R, Lisziewicz J, Gallo RC, Ensoli B. Block of HIV-1 infection by a combination of antisense tat RNA and TAR decoys: a strategy for control of HIV-1. Gene Ther. 1994;1:208–16.PubMed
3.
Wu Y, Marsh JW. Selective transcription and modulation of resting T cell activity by preintegrated HIV DNA. Science. 2001;293:1503–6.CrossRefPubMed
4.
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.CrossRefPubMed
5.
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.CrossRefPubMed
6.
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.CrossRefPubMed
7.
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.CrossRefPubMed
8.
Cafaro A, Tripiciano A, Sgadari C, Bellino S, Picconi O, Longo O, et al. Development of a novel AIDS vaccine: the HIV-1 transactivator of transcription protein vaccine. Expert Opin Biol Ther 2015;1–17. doi:10.​1517/​14712598.​2015.​1021328.
9.
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.CrossRefPubMed
10.
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.CrossRefPubMed
11.
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 mauritian cynomolgus monkeys vaccinated with Tat upon challenge with simian/human immunodeficiency virus SHIV89.6P. J Virol. 2010;84:8953–8.CrossRefPubMedPubMedCentral
12.
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.CrossRefPubMed
13.
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.CrossRefPubMed
14.
15.
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.CrossRefPubMed
16.
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.CrossRefPubMedPubMedCentral
17.
Sáez-Cirión A, Sinet M, Shin SY, Urrutia A, Lacabaratz C, Versmisse P, 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.CrossRefPubMed
18.
Ensoli F, Cafaro A, Casabianca A, Tripiciano A, Bellino S, Longo O, et al. HIV-1 Tat immunization restores immune homeostasis and attacks the HAART-resistant blood HIV DNA: results of a randomized phase II exploratory clinical trial. Retrovirol. 2015;12:33. doi:10.​1186/​s12977-015-0151-y.CrossRef
19.
Middelkoop K, Bekker LG, Mathema B, Shashkina E, Kurepina N, Whitelaw A, et al. Molecular epidemiology of Mycobacterium tuberculosis in South African community with high HIV prevalence. J Infect Dis. 2009;200:1207–11.CrossRefPubMedPubMedCentral
20.
Fanales-Belasio E, Moretti S, Nappi F, Barillari G, Micheletti F, Cafaro A, Ensoli B. 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.CrossRefPubMed
21.
Palma C, Iona E, Giannoni F, Pardini M, Brunori L, Orefici G, et al. The Ag85B protein of Mycobacterium tuberculosis may turn a protective immune response induced by Ag85B-DNA vaccine into a potent but non-protective Th1 immune response in mice. Cell Microbiol. 2007;9:1455–65.CrossRef
22.
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.CrossRef
23.
Juffermans NP, Florquin S, Camoglio L, Verbon A, Kolk AH, Speelman P, et al. Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis. J Infect Dis. 2000;182:902–8.CrossRefPubMed
24.
Mishra BB, Rathinam VA, Martens GW, Martinot AJ, Kornfeld H, Fitzgerald KA, Sassetti CM. Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1β. Nat Immunol. 2013;14:52–60.CrossRefPubMed
25.
Mayer-Barber KD, Barber DL, Shenderov K, White SD, Wilson MS, Cheever A, et al. Caspase-1 independent IL-1beta production is critical for host resistance to Mycobacterium tuberculosis and does not require TLR signaling in vivo. J Immunol. 2010;184:3326–30.CrossRefPubMedPubMedCentral
26.
Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med. 1993;178:2249–54.CrossRefPubMed
27.
Dorman SE, Picard C, Lammas D, Heyne K, van Dissel JT, Baretto R, et al. Clinical features of dominant and recessive interferon gamma receptor 1 deficiencies. Lancet. 2004;364:2113–21.CrossRefPubMed
28.
Khader SA, Bell K, Pearl JE, Fountain JJ, Rangel-Moreno J, Cilley GE, et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol. 2007;8:369–77.CrossRefPubMed
29.
van Dissel JT, Soonawala D, Joosten SA, Prins C, Arend SM, Bang P, Tingskov PN, et al. Ag85B-ESAT-6 adjuvanted with IC31® promotes strong and long-lived Mycobacterium tuberculosis specific T cell responses in volunteers with previous BCG vaccination or tuberculosis infection. Vaccine. 2011;29:2100–9.CrossRefPubMed
30.
Weinrich Olsen A, van Pinxteren LA, Meng Okkels L, Birk Rasmussen P, Andersen P. Protection of mice with a tuberculosis subunit vaccine based on a fusion protein of antigen 85B and esat-6. Infect Immun. 2001;69:2773–8.CrossRefPubMed
31.
Palma C, Iona E, Giannoni F, Pardini M, Brunori L, Fattorini L, et al. The LTK63 adjuvant improves protection conferred by Ag85B DNA-protein prime-boosting vaccination against Mycobacterium tuberculosis infection by dampening IFN-γ response. Vaccine. 2008;26:4237–43.CrossRefPubMed
32.
33.
34.
Honda JR, Shang S, Shanley CA, Caraway ML, Henao-Tamayo M, Chan ED, et al. Immune responses of HIV-1 tat transgenic mice to Mycobacterium tuberculosis W-Beijng SA161. Open AIDS J. 2011;5:86–95.CrossRefPubMedPubMedCentral
35.
36.
37.
Eum SY, Kong JH, Hong MS, Lee YJ, Kim JH, Hwang SH, et al. Neutrophils are the predominant infected phagocytic cells in the airways of patients with active pulmonary TB. Chest. 2010;137:122–8.CrossRefPubMed
38.
Ribeiro-Rodrigues R, Resende T, Johnson JL, Ribeiro F, Palaci M, Sá RT, et al. Sputum cytokine levels in patients with pulmonary tuberculosis as early markers of mycobacterial clearance. Clin Diagn Lab Immunol. 2002;9:818–23.PubMedPubMedCentral
39.
40.
41.
Fanales-Belasio E, Moretti S, Fiorelli V, Tripiciano A, Pavone Cossut MR, 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.CrossRefPubMed
42.
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.CrossRefPubMed
43.
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.CrossRefPubMed
45.
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 USA. 2013;110:13588–93.CrossRefPubMedPubMedCentral
46.
Palma C, Schiavoni G, Abalsamo L, Mattei F, Piccaro G, Sanchez M, et al. Mycobacterium tuberculosis PstS1 amplifies IFN-γ and induces IL-17/IL-22 responses by unrelated memory CD4+ T cells via dendritic cell activation. Eur J Immunol. 2013;43:2386–97.CrossRefPubMed
47.
Jayaraman P, Sada-Ovalle I, Nishimura T, Anderson AC, Kuchroo VK, Remold HG, Behar SM. IL-1β promotes antimicrobial immunity in macrophages by regulating TNFR signaling and caspase-3 activation. J Immunol. 2013;190:4196–204.CrossRefPubMedPubMedCentral
48.
Brandau S, Suttmann H. Thirty years of BCG immunotherapy for non-muscle invasive bladder cancer: a success story with room for improvement. Biomed Pharmacother. 2007;61:299–305.CrossRefPubMed
49.
Hall MC, Chang SS, Dalbagni G, Pruthi RS, Seigne JD, Skinner EC, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol. 2007;178:2314–30.CrossRefPubMed
50.
Liu X, Dowell AC, Patel P, Viney RP, Foster MC, Porfiri E, et al. Cytokines as effectors and predictors of responses in the treatment of bladder cancer by bacillus Calmette-Guérin. Future Oncol. 2014;10:1443–56.CrossRefPubMed
51.
Böhle A, Gerdes J, Ulmer AJ, Hofstetter AG, Flad HD. Effects of local bacillus Calmette-Guérin therapy in patients with bladder carcinoma on immunocompetent cells of the bladder wall. J Urol. 1990;144:53–8.PubMed
52.
53.
Pryor K, Goddard J, Goldstein D, Russell P, Golovsky D, Penny R. Bacillus Calmette-Guérin enhances monocyte- and lymphocyte-mediated bladder tumour cell killing. Br J Cancer. 1995;71:801–7.CrossRefPubMedPubMedCentral
54.
Algood HM, Flynn JL. CCR5-deficient mice control Mycobacterium tuberculosis infection despite increased pulmonary lymphocytic infiltration. J Immunol. 2004;173:3287–96.CrossRefPubMed
55.
De Groote MA, Gilliland JC, Wells CL, Brooks EJ, Woolhiser LK, Gruppo V, et al. Comparative studies evaluating mouse models used for efficacy testing of experimental drugs against Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2011;55:1237–47.CrossRefPubMed
56.
Copenhaver RH, Sepulveda E, Armitige LY, Actor JK, Wanger A, Norris SJ, et al. A mutant of Mycobacterium tuberculosis H37Rv that lacks expression of antigen 85A is attenuated in mice but retains vaccinogenic potential. Infect Immun. 2004;72:7084–95.CrossRefPubMedPubMedCentral
Metadata
Title
HIV-1 Tat protein vaccination in mice infected with Mycobacterium tuberculosis is safe, immunogenic and reduces bacterial lung pathology
Authors
Aurelio Cafaro
Giovanni Piccaro
Giuseppe Altavilla
Vincenzo Gigantino
Giuseppe Matarese
Erika Olivieri
Flavia Ferrantelli
Barbara Ensoli
Carla Palma
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Infectious Diseases / Issue 1/2016
Electronic ISSN: 1471-2334
DOI
https://doi.org/10.1186/s12879-016-1724-7

Other articles of this Issue 1/2016

BMC Infectious Diseases 1/2016 Go to the issue

Research article

Clinical and molecular analyses of norovirus-associated sporadic acute gastroenteritis: the emergence of GII.17 over GII.4, Huzhou, China, 2015

Research article

Performance of an electronic health record-based phenotype algorithm to identify community associated methicillin-resistant Staphylococcus aureus cases and controls for genetic association studies

Research article

Molecular epidemiology and characteristic of virulence gene of community-acquired and hospital-acquired methicillin-resistant Staphylococcus aureus isolates in Sun Yat-sen Memorial hospital, Guangzhou, Southern China

Study protocol

Personalized prescription feedback to reduce antibiotic overuse in primary care: rationale and design of a nationwide pragmatic randomized trial

Research article

Epidemiology and outcome of Clostridium difficile infections in patients hospitalized in Internal Medicine: findings from the nationwide FADOI-PRACTICE study

Study protocol

HealthMap: a cluster randomised trial of interactive health plans and self-management support to prevent coronary heart disease in people with HIV
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits