52 results on '"V. Fiorelli"'
Search Results
2. Role of immune-derived diffusible mediators in AIDS-associated neurological disorders
- Author
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F, Ensoli, V, Fiorelli, M, De Cristofaro, D S, Muratori, A, Novi, A, Isgrò, and F, Aiuti
- Subjects
Diffusion ,Neurons ,Acquired Immunodeficiency Syndrome ,Neurotoxins ,HIV-1 ,Brain ,Humans ,Nervous System Diseases ,Neuroglia - Abstract
Neurologic abnormalities are common in HIV-1 infected patients and often represent the dominant clinical manifestation of pediatric AIDS. Although the neurological dysfunction has been directly related to CNS invasion by HIV-1, the pathogenesis of neurologic disorders remains unclear. This review will first discuss the spectrum of potential interactions between HIV-1 and neural (neuronal and glial) cells, in the face of experimental data. Next, we will focus on the role of immune-derived cytokines and other soluble compounds which have been proposed to act as neurotoxic mediators and appear to play a role in the pathogenesis of AIDS-associated neurodegeneration.
- Published
- 2000
3. gamma-Interferon production in peripheral blood mononuclear cells and tumor infiltrating lymphocytes from Kaposi's sarcoma patients: correlation with the presence of human herpesvirus-8 in peripheral blood mononuclear cells and lesional macrophages
- Author
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M C, Sirianni, L, Vincenzi, V, Fiorelli, S, Topino, E, Scala, S, Uccini, A, Angeloni, A, Faggioni, D, Cerimele, F, Cottoni, F, Aiuti, and B, Ensoli
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Male ,Macrophages ,CD8-Positive T-Lymphocytes ,Immunohistochemistry ,Interferon-gamma ,Lymphocytes, Tumor-Infiltrating ,Herpesvirus 8, Human ,Leukocytes, Mononuclear ,Humans ,Female ,Interleukin-4 ,Sarcoma, Kaposi ,Cells, Cultured - Abstract
Evidence indicates that, at least in the early stage, Kaposi's sarcoma (KS) is a cytokine-mediated disease and that it is consistently associated with a novel herpesvirus termed human herpesvirus-8 (HHV-8). To gain insights into the mechanisms by which cytokines and HHV-8 may cooperate in disease pathogenesis, we examined the phenotype, the Th1 (gamma-interferon [gamma IFN]) and Th2 (interleukin-4 [IL-4] cytokine profile and the presence of HHV-8 in peripheral blood mononuclear cells (PBMC), tumor-infiltrating lymphocytes (TIL), and spindle cell cultures derived from skin lesions of patients affected by classical KS (C-KS) and acquired immunodeficiency syndrome (AIDS)-associated KS (AIDS-KS). TIL and spindle cell cultures were examined at day 0 or after culture in conditioned media from activated T cells (TCM) that contain the same cytokines increased in KS tissues. No differences were found in the immunophenotype of PBMC from C-KS patients versus controls, except for AIDS-KS patients who showed a T-CD8+ expansion. However, a preferential infiltration of T-CD8+ cells was found in all KS lesions examined, which was maintained after culture of TIL in TCM. gamma IFN production was found in both PBMC and cultures derived from all KS examined; some IL-4 positive supernatants were found only in three AIDS-KS cases. Uninvolved skin did not show appreciable lymphocyte infiltration or cytokine production. The culture conditions of the lesional skin allowed also the appearance of adherent, spindle-like cells bearing markers of tissue macrophages. Finally, most or all of the PBMC, lesions, and macrophagic cell cultures from the skin lesions were found to be positive for HHV-8 infection by nested polymerase chain reaction (PCR). These findings indicate that patients with KS express a Th1 phenotype with a prevalent gamma IFN production, likely accounted for by the local T-CD8+ infiltration. By analogy with other viral infections (i.e., Epstein-Barr virus), this suggests that in loco recruitment of lymphoid cells and the subsequent gamma IFN production may be in response to or elicited by HHV-8 that was found in both PBMC and macrophagic cell cultures from the lesions of the same patients.
- Published
- 1998
4. gamma-Interferon produced by CD8+ T cells infiltrating Kaposi's sarcoma induces spindle cells with angiogenic phenotype and synergy with human immunodeficiency virus-1 Tat protein: an immune response to human herpesvirus-8 infection?
- Author
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V, Fiorelli, R, Gendelman, M C, Sirianni, H K, Chang, S, Colombini, P D, Markham, P, Monini, J, Sonnabend, A, Pintus, R C, Gallo, and B, Ensoli
- Subjects
Neovascularization, Pathologic ,Macrophages ,Mice, Nude ,Drug Synergism ,HLA-DR Antigens ,Herpesviridae Infections ,CD8-Positive T-Lymphocytes ,Monocytes ,Interferon-gamma ,Mice ,Phenotype ,Gene Products, tat ,Herpesvirus 8, Human ,HIV-1 ,Animals ,Humans ,tat Gene Products, Human Immunodeficiency Virus ,Endothelium, Vascular ,Sarcoma, Kaposi - Abstract
Kaposi's sarcoma (KS) is an angioproliferative disease associated with infection by the human herpesvirus-8 (HHV-8). HHV-8 possesses genes including homologs of interleukin-8 (IL-8) receptor, Bcl-2, and cyclin D, which can potentially transform the host cell. However, the expression of these genes in KS tissues is very low or undetectable and HHV-8 does not seem to transform human cells in vitro. In addition, KS may not be a true cancer at least in the early stage. This indicated that besides its transforming potential, HHV-8 may act in KS pathogenesis also through indirect mechanisms. Evidence suggests that KS may start as an inflammatory-angiogenic lesion mediated by cytokines. However, little is known on the nature of the inflammatory cell infiltration present in KS, on the type of cytokines produced and on their role in KS, and whether this correlates with the presence of HHV-8. Here we show that both acquired immunodeficiency syndrome (AIDS)-KS and classical KS (C-KS) lesions are infiltrated by CD8+ T cells and CD14+/CD68+ monocytes-macrophages producing high levels of gamma-interferon (gamma IFN) which, in turn, promotes the formation of KS spindle cells with angiogenic phenotype. gamma IFN, in fact, induces endothelial cells to acquire the same features of KS cells, including the spindle morphology and the pattern of cell marker expression. In addition, endothelial cells activated by gamma IFN induce angiogenic lesions in nude mice closely resembling early KS. These KS-like lesions are accompanied by production of basic fibroblast growth factor, an angiogenic factor highly expressed in primary lesions that mediates angiogenesis and spindle cell growth. The formation of KS-like lesions is upregulated by the human immunodeficiency virus Tat protein demonstrating its role as a progression factor in AIDS-KS. Finally, gamma IFN and HLA-DR expression correlate with the presence of HHV-8 in lesional and uninvolved tissues from the same patients. As HHV-8 infects both mononuclear cells infiltrating KS lesions and KS spindle cells, these results suggest that HHV-8 may elicit or participate in a local immune response characterized by infiltration of CD8+ T cells and intense production of gamma IFN which, in turn, plays a key role in KS development.
- Published
- 1998
5. New developments: a look to the future
- Author
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B, Ensoli, R C, Gallo, and V, Fiorelli
- Subjects
Gene Expression Regulation, Neoplastic ,Acquired Immunodeficiency Syndrome ,Risk Factors ,Gene Products, tat ,Cytokines ,Humans ,tat Gene Products, Human Immunodeficiency Virus ,Sarcoma, Kaposi - Abstract
Inflammatory cytokines plus the human immunodeficiency virus Tat protein apparently trigger the development of early Kaposi's sarcoma. Activated spindle cells provide a self-perpetuating, autocrine-supported mechanism for further development of hyperplastic lesions. In more advanced stages, a true neoplastic process may develop.
- Published
- 1996
6. Th-1 cytokine profile in PBMC and tumor infiltrating lymphocytes (TIL) of HHV-8+ Kaposi's sarcoma (KS) patients
- Author
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Aurelio Cafaro, Barbara Ensoli, C. Sirianni, P. Leonc, Stefano Buttò, R Gendelman, V. Fiorelli, Robert C. Gallo, Michael Stürzl, Paolo Monini, and Sandra Colombini
- Subjects
Immune system ,Tumor-infiltrating lymphocytes ,business.industry ,Virology ,Cytokine profile ,Immunology ,medicine ,Immunology and Allergy ,medicine.disease ,business ,Peripheral blood mononuclear cell ,Kaposi's sarcoma - Published
- 1997
7. HIV-1 Tat protein enhances angiogenesis and Kaposi's sarcoma (KS) development triggered by inflammatory cytokines (IC) or bFGF by engaging theαvβ3 integrin
- Author
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R Gendelman, Sandra Colombini, Barbara Ensoli, Cecilia Sgadari, V. Fiorelli, Giovanni Barillari, C. Bohan Morris, Robert C. Gallo, and Philip Markham
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biology ,business.industry ,Angiogenesis ,Immunology ,Integrin ,Hiv 1 tat ,medicine.disease ,Proinflammatory cytokine ,Virology ,Cancer research ,biology.protein ,Immunology and Allergy ,Medicine ,business ,Kaposi's sarcoma - Published
- 1997
8. HTLV-I antibodies and lymphoproliferative disease of granular lymphocytes
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G. De Rossi, Renato Zambello, K. Shriver, Franco Pandolfi, D.M. Strong, G. Semenzato, Teodoro Chisesi, Elisa Scarselli, and V. Fiorelli
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Adult ,Deltaretrovirus Infections ,business.industry ,Deltaretrovirus Antibodies ,General Medicine ,Middle Aged ,Antibodies, Viral ,Virology ,Deltaretrovirus ,Lymphoproliferative Disorders ,HTLV I Antibody ,Medicine ,Humans ,Lymphocytes ,Lymphoproliferative disease ,business ,Aged - Published
- 1987
9. Tra analfabetismo e politica: scuola e democrazia tra Otto e Novecento
- Author
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MUSELLA, LUIGI, V. FIORELLI, and Musella, Luigi
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scuola ,politica ,società rurale - Abstract
La scuola come forma di coinvolgimento dei ceti rurali al processo di formazione nazionale.
- Published
- 2012
10. Una biblioteca (poco) provinciale: i libri degli Acquaviva d'Atri
- Author
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SODANO, Giulio, E. NOVI CHAVARRIA, V. FIORELLI, and Sodano, Giulio
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Età moderna ,Feudalità ,Biblioteche provate - Published
- 2011
11. Feudalità ecclesiastica nel Regno di Napoli: giurisdizione feudale e rendita fondiaria dell'Abbazia di Montecassino nel XVIII secolo
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Angelo Di Falco, E. Novi Chavarria, V. Fiorelli, and DI FALCO, Angelo
- Published
- 2011
12. Circulating stem cell vary with NYHA stage in heart failure patients.
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Fortini C, Toffoletto B, Fucili A, Puppato E, Olivares A, Beltrami AP, Fiorelli V, Bergamin N, Cesselli D, Morelli C, Francolini G, Ferrari R, and Beltrami CA
- Subjects
- Aged, Analysis of Variance, Becaplermin, Chemokine CXCL12 blood, Endothelial Cells metabolism, Enzyme-Linked Immunosorbent Assay, Female, Fibroblast Growth Factor 2 blood, Heart Failure classification, Heart Failure pathology, Hematopoietic Stem Cells metabolism, Hepatocyte Growth Factor blood, Humans, Male, Mesenchymal Stem Cells metabolism, Middle Aged, Platelet-Derived Growth Factor metabolism, Proto-Oncogene Proteins c-sis, Receptors, CXCR4 blood, Severity of Illness Index, Thy-1 Antigens blood, Tumor Necrosis Factor-alpha blood, Vascular Endothelial Growth Factor A blood, Antigens, CD blood, Cytokines blood, Heart Failure blood, Stem Cells metabolism
- Abstract
We have investigated the blood levels of sub-classes of stem cells (SCs) [mesenchymal stem cells (MSCs), haematopoietic stem cells (HSCs), endothelial progenitor cells/circulating endothelial cells (EPCs/CECs) and tissue-committed stem cells (TCSCs)] in heart failure (HF) patients at different stage of pathology and correlated it with plasmatic levels of proangiogenic cytokines. Peripheral blood level of SCs were analysed in 97 HF patients (24 in NYHA class I, 41 in class II, 17 in class III and 15 in class IV) and in 23 healthy controls. Plasmatic levels of PDGF-BB, bFGF, HGF, vascular endothelial growth factor (VEGF), SDF-1α, TNF-α and NTproBNP were also measured. Compared with healthy individuals, MSC, and in particular the sub-classes CD45(-) CD34(-) CD90(+) , CD45(-) CD34(-) CD105(+) and CD45(-) CD34(-) CXCR4(+) were significantly enhanced in NYHA class IV patients (16.8-, 6.4- and 2.7-fold, respectively). Level of CD45(-) CD34(-) CD90(+) CXCR4(+) cells progressively increased from class II to class IV (fold increases compared with controls: 8.5, 12 and 21.5, respectively). A significant involvement of CXCR4(+) subpopulation of HSC (CD45(+) CD34(+) CD90(+) CXCR4(+) , 1.4 versus 13.3 cells/μl in controls and NYHA class III patients, respectively) and TCSC (CD45(-) CD34(+) CXCR4(+) , 1.5 cells/ μl in controls versus 12.4 and 28.6 cells/μl in NYHA classes II and IV, respectively) were also observed. All tested cytokines were enhanced in HF patients. In particular, for PDGF-BB and SDF-1α we studied specific ligand/receptors pairs. Interestingly, the first one positively correlated with TCSCs expressing PDGFR (r = 0.52, P = 0.001), whereas the second one correlated with TCSCs (r = 0.34, P = 0.005) and with MSCs CD90(+) expressing CXCR4 (r = 0.39, P = 0.001). HF is characterized by the increase in the circulating levels of different MSC, HSC, EPC and TCSC subsets. Both the entity and kinetic of this process varied in distinct cell subsets. Specifically, differently from HSCs and EPCs/CECs, MSCs and TCSCs significantly increased with the progression of the disease, suggesting a possible distinct role of these cells in the pathophysiology of HF., (© 2011 The Authors Journal compilation © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)
- Published
- 2011
- Full Text
- View/download PDF
13. The preventive phase I trial with the HIV-1 Tat-based vaccine.
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Ensoli B, Fiorelli V, Ensoli F, Lazzarin A, Visintini R, Narciso P, Di Carlo A, Tripiciano A, Longo O, Bellino S, Francavilla V, Paniccia G, Arancio A, Scoglio A, Collacchi B, Ruiz Alvarez MJ, Tambussi G, Tassan Din C, Palamara G, Latini A, Antinori A, D'Offizi G, Giuliani M, Giulianelli M, Carta M, Monini P, Magnani M, and Garaci E
- Subjects
- AIDS Vaccines adverse effects, AIDS Vaccines therapeutic use, Adult, Epitope Mapping, Female, Humans, Immunity, Cellular immunology, Interferon-gamma metabolism, Interleukin-4 metabolism, Male, Middle Aged, T-Lymphocytes immunology, HIV Infections immunology, HIV Infections prevention & control, HIV-1 immunology
- Abstract
The native HIV-1 Tat protein was chosen as vaccine candidate for phase I clinical trials based on its role in the natural infection and AIDS pathogenesis, on the association of Tat-specific immune response with the asymptomatic stage as well as on its sequence conservation among HIV clades. A randomized, double blind, placebo-controlled phase I study (ISS P-001) was conducted in healthy adult volunteers without identifiable risk of HIV infection. Tat was administered 5 times monthly, subcute in alum or intradermic alone at 7.5 microg, 15 microg or 30 microg, respectively (ClinicalTrials.gov identifier: NCT00529698). Vaccination with Tat resulted to be safe and well tolerated (primary endpoint) both locally and systemically. In addition, Tat induced both Th1 and Th2 type specific immune responses in all subjects (secondary endpoint) with a wide spectrum of functional antibodies that are rarely seen in natural infection, providing key information for further clinical development of the Tat vaccine candidate.
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- 2009
- Full Text
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14. Parallel conduction of the phase I preventive and therapeutic trials based on the Tat vaccine candidate.
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Bellino S, Francavilla V, Longo O, Tripiciano A, Paniccia G, Arancio A, Fiorelli V, Scoglio A, Collacchi B, Campagna M, Lazzarin A, Tambussi G, Din CT, Visintini R, Narciso P, Antinori A, D'Offizi G, Giulianelli M, Carta M, Di Carlo A, Palamara G, Giuliani M, Laguardia ME, Monini P, Magnani M, Ensoli F, and Ensoli B
- Subjects
- AIDS Vaccines adverse effects, Adult, Double-Blind Method, Humans, Placebos, Randomized Controlled Trials as Topic, Research Design, AIDS Vaccines immunology, Clinical Trials, Phase I as Topic, HIV-1, tat Gene Products, Human Immunodeficiency Virus immunology
- Abstract
The native HIV-1 Tat protein was chosen as vaccine candidate for phase I clinical trials in both uninfected (ClinicalTrials.gov identifier: NCT00529698) and infected volunteers (ClinicalTrials.gov identifier: NCT00505401). The rationale was based on the role of Tat in the natural infection and AIDS pathogenesis, on the association of Tat-specific immune responses with the asymptomatic stage and slow-progression rate as well as on its sequence conservation among HIV clades (http://www.hiv1tat-vaccines.info/). The parallel conduction in the same clinical centers of randomized, double blind, placebo-controlled phase I studies both in healthy, immunologically competent adults and in HIV-infected, clinically asymptomatic, individuals represents a unique occasion to compare the vaccine-induced immune response in both the preventive and therapeutic setting. In both studies, the same lot of the native Tat protein was administered 5 times, every four weeks, subcute (SC) with alum adjuvant or intradermic (ID), in the absence of adjuvant, at 7.5 microg, 15 microg or 30 microg doses, respectively. The primary and secondary endpoints of these studies were the safety and immunogenicity of the vaccine candidate, respectively. The study lasted 52 weeks and monitoring was conducted for on additional 3 years. The results of both studies indicated that the Tat vaccine is safe and well tolerated both locally and systemically and it is highly immunogenic at all the dosages and by both routes of administration. Vaccination with Tat induced a balanced immune response in uninfected and infected individuals. In particular, therapeutic immunization induced functional antibodies and partially reverted the marked Th1 polarization of anti-Tat immunity seen in natural infection, and elicited a more balanced Th1/Th2 immune response. Further, the number of CD4 T cells correlated positively with anti-Tat antibody titers. Based on these results, a phase II study is ongoing in infected drug-treated individuals (http://www.hiv1tat-vaccines.info/).
- Published
- 2009
- Full Text
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15. Phase I therapeutic trial of the HIV-1 Tat protein and long term follow-up.
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Longo O, Tripiciano A, Fiorelli V, Bellino S, Scoglio A, Collacchi B, Alvarez MJ, Francavilla V, Arancio A, Paniccia G, Lazzarin A, Tambussi G, Din CT, Visintini R, Narciso P, Antinori A, D'Offizi G, Giulianelli M, Carta M, Di Carlo A, Palamara G, Giuliani M, Laguardia ME, Monini P, Magnani M, Ensoli F, and Ensoli B
- Subjects
- AIDS Vaccines adverse effects, AIDS Vaccines therapeutic use, B-Lymphocytes immunology, CD4 Lymphocyte Count, Double-Blind Method, Follow-Up Studies, HIV Antibodies blood, Humans, Interferon-gamma biosynthesis, Interleukin-4 biosynthesis, Viral Load, HIV Infections therapy
- Abstract
A randomized, double blind, placebo-controlled phase I vaccine trial based on the native Tat protein was conducted in HIV-infected asymptomatic individuals. The vaccine was administered five times subcute with alum or intradermally without adjuvant at 7.5microg, 15microg or 30microg doses, respectively. The Tat vaccine was well tolerated both locally and systemically and induced and/or maintained Tat-specific T helper (Th)-1 T-cell responses and Th-2 responses in all subjects with a wide spectrum of functional anti-Tat antibodies, rarely seen in HIV-infected subjects. The data indicate the achievement of both the primary (safety) and secondary (immunogenicity) endpoints of the study.
- Published
- 2009
- Full Text
- View/download PDF
16. HIV-1 Tat addresses dendritic cells to induce a predominant Th1-type adaptive immune response that appears prevalent in the asymptomatic stage of infection.
- Author
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Fanales-Belasio E, Moretti S, Fiorelli V, Tripiciano A, Pavone Cossut MR, Scoglio A, Collacchi B, Nappi F, Macchia I, Bellino S, Francavilla V, Caputo A, Barillari G, Magnani M, Laguardia ME, Cafaro A, Titti F, Monini P, Ensoli F, and Ensoli B
- Subjects
- AIDS Vaccines administration & dosage, AIDS Vaccines immunology, Adult, Aged, Animals, Cells, Cultured, Chemokines, CC biosynthesis, Cytokines biosynthesis, Dendritic Cells metabolism, Female, HIV Antibodies biosynthesis, HIV Infections prevention & control, HeLa Cells, Humans, Immunity, Innate, Macaca fascicularis, Male, Middle Aged, Monocytes immunology, Monocytes virology, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Cytotoxic virology, Th1 Cells metabolism, tat Gene Products, Human Immunodeficiency Virus administration & dosage, tat Gene Products, Human Immunodeficiency Virus immunology, Dendritic Cells immunology, Dendritic Cells virology, HIV Infections immunology, HIV Infections pathology, HIV-1 immunology, Th1 Cells immunology, Th1 Cells virology, tat Gene Products, Human Immunodeficiency Virus physiology
- Abstract
Tat is an early regulatory protein that plays a major role in human HIV-1 replication and AIDS pathogenesis, and therefore, it represents a key target for the host immune response. In natural infection, however, Abs against Tat are produced only by a small fraction (approximately 20%) of asymptomatic individuals and are rarely seen in progressors, suggesting that Tat may possess properties diverting the adaptive immunity from generating humoral responses. Here we show that a Th1-type T cell response against Tat is predominant over a Th2-type B cell response in natural HIV-1 infection. This is likely due to the capability of Tat to selectively target and very efficiently enter CD1a-expressing monocyte-derived dendritic cells (MDDC), which represent a primary target for the recognition and response to virus Ag. Upon cellular uptake, Tat induces MDDC maturation and Th1-associated cytokines and beta-chemokines production and polarizes the immune response in vitro to the Th1 pattern through the transcriptional activation of TNF-alpha gene expression. This requires the full conservation of Tat transactivation activity since neither MDDC maturation nor TNF-alpha production are found with either an oxidized Tat, which does not enter MDDC, or with a Tat protein mutated in the cysteine-rich region (cys22 Tat), which enters MDDC as the wild-type Tat but is transactivation silent. Consistently with these data, inoculation of monkeys with the native wild-type Tat induced a predominant Th1 response, whereas cys22 Tat generated mostly Th2 responses, therefore providing evidence that Tat induces a predominant Th1 polarized adaptive immune response in the host.
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- 2009
- Full Text
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17. The therapeutic phase I trial of the recombinant native HIV-1 Tat protein.
- Author
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Ensoli B, Fiorelli V, Ensoli F, Lazzarin A, Visintini R, Narciso P, Di Carlo A, Monini P, Magnani M, and Garaci E
- Subjects
- AIDS Vaccines immunology, CD4 Lymphocyte Count, Double-Blind Method, HIV Antibodies biosynthesis, HIV Infections virology, Humans, Recombinant Proteins adverse effects, Recombinant Proteins immunology, Viral Load, tat Gene Products, Human Immunodeficiency Virus immunology, AIDS Vaccines adverse effects, HIV Infections immunology, HIV-1 immunology, tat Gene Products, Human Immunodeficiency Virus adverse effects
- Abstract
The native HIV-1 Tat protein was chosen as a vaccine candidate based on its key role in the virus life cycle and on the correlation of Tat-specific immune responses with the asymptomatic stage and lower disease progression rates, but also due to its sequence conservation amongst the various HIV clades as well as the adjuvant effects on dendritic cells. Safety, immunogenicity and efficacy data in monkeys support the development of this vaccine concept.
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- 2008
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18. Candidate HIV-1 Tat vaccine development: from basic science to clinical trials.
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Ensoli B, Fiorelli V, Ensoli F, Cafaro A, Titti F, Buttò S, Monini P, Magnani M, Caputo A, and Garaci E
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- AIDS Vaccines immunology, Animals, Clinical Trials as Topic, Gene Products, tat genetics, Gene Products, tat immunology, Genes, tat immunology, HIV Infections drug therapy, HIV Infections prevention & control, HIV-1 immunology, Haplorhini, Humans, International Cooperation, Mice, Protein Biosynthesis genetics, Protein Biosynthesis immunology, tat Gene Products, Human Immunodeficiency Virus, AIDS Vaccines genetics, Genes, tat genetics, HIV-1 genetics
- Published
- 2006
- Full Text
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19. Efficient systemic and mucosal responses against the HIV-1 Tat protein by prime/boost vaccination using the lipopeptide MALP-2 as adjuvant.
- Author
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Borsutzky S, Ebensen T, Link C, Becker PD, Fiorelli V, Cafaro A, Ensoli B, and Guzmán CA
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- AIDS Vaccines immunology, Adjuvants, Immunologic, Animals, Cell Culture Techniques, Gene Products, tat administration & dosage, Gene Products, tat immunology, HIV Antibodies blood, HIV-1 immunology, Lipopeptides, Mice, Mice, Inbred BALB C, Oligopeptides administration & dosage, Vaccination, Vaccines, Synthetic immunology, tat Gene Products, Human Immunodeficiency Virus, AIDS Vaccines administration & dosage, HIV Antibodies biosynthesis, HIV-1 chemistry, Immunity, Mucosal immunology, Oligopeptides immunology
- Abstract
A major goal of HIV-1 vaccine development is the induction of mucosal immune responses able to stop or reduce viral infection directly at the portal of entry. We established a heterologous prime/boost vaccination protocol based on intradermal priming with the HIV-1 Tat protein and intranasal boosting with the Tat protein co-administered with the mucosal adjuvant MALP-2. Strong Tat-specific humoral responses were elicited in vaccinated mice at both systemic and mucosal levels. The cellular responses were characterized by a Th1 dominant helper pattern. The heterologous prime/boost regimen was also able to induce Tat-specific CTL, which were absent in animals receiving the homologous prime boost scheme. Thus, the heterologous prime/boost protocol was the only regimen able to evoke both CTL and sIgA responses. This suggests that a similar approach can be exploited to develop multi-component vaccines against HIV-1 infections able to induce both systemic and mucosal immune responses.
- Published
- 2006
- Full Text
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20. Vaccines based on the native HIV Tat protein and on the combination of Tat and the structural HIV protein variant DeltaV2 Env.
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Ensoli B, Cafaro A, Caputo A, Fiorelli V, Ensoli F, Gavioli R, Ferrantelli F, Cara A, Titti F, and Magnani M
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- AIDS Vaccines adverse effects, AIDS Vaccines genetics, Adjuvants, Immunologic, Animals, Clinical Trials, Phase I as Topic, Gene Products, env genetics, Gene Products, tat genetics, HIV Antibodies blood, Humans, Macaca fascicularis, Male, Mice, Models, Animal, Neutralization Tests, Vaccines, Combined adverse effects, Vaccines, Combined genetics, Vaccines, Combined immunology, Vaccines, Subunit adverse effects, Vaccines, Subunit genetics, Vaccines, Subunit immunology, Vaccines, Synthetic adverse effects, Vaccines, Synthetic genetics, Vaccines, Synthetic immunology, env Gene Products, Human Immunodeficiency Virus, tat Gene Products, Human Immunodeficiency Virus, AIDS Vaccines immunology, Gene Products, env immunology, Gene Products, tat immunology, HIV-1 immunology
- Abstract
The promising results obtained with the HIV-1 Tat-based vaccines in mice, monkeys and humans, a better understanding of Tat immunomodulatory functions, as well as evidence that vaccination with trimeric V2 loop-deleted HIV-1 Env induces cross-clade neutralizing antibodies led to the rational design of a novel vaccine based on the combination of Tat and V2-deleted Env.
- Published
- 2005
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21. 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.
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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, Buttò S, and Ensoli B
- Subjects
- Acquired Immunodeficiency Syndrome immunology, Adolescent, Adult, Aged, Antibody Specificity, Cohort Studies, Disease Progression, Disease Susceptibility, Female, Humans, Male, Middle Aged, Survival Analysis, Time Factors, tat Gene Products, Human Immunodeficiency Virus, Gene Products, tat immunology, HIV Antibodies immunology, HIV Long-Term Survivors, HIV Seropositivity immunology
- Abstract
The human immunodeficiency virus (HIV) type 1 Tat protein plays a key role in the life cycle of the virus and in pathogenesis and is highly conserved among HIV subtypes. On the basis of this and of safety, immunogenicity, and efficacy findings in monkeys, Tat is being tested as a vaccine in phase 1 trials. Here, we evaluated the incidence and risk of progression to advanced HIV disease by anti-Tat serostatus in a cohort of 252 HIV-1 seroconverters. The risk of progression was lower in the anti-Tat-positive subjects than in the anti-Tat-negative subjects. Progression was faster in the persistently anti-Tat-negative subjects than in the transiently anti-Tat-positive subjects, and no progression was observed in the persistently anti-Tat-positive subjects.
- Published
- 2005
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22. Long-term protection against SHIV89.6P replication in HIV-1 Tat vaccinated cynomolgus monkeys.
- Author
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Maggiorella MT, Baroncelli S, Michelini Z, Fanales-Belasio E, Moretti S, Sernicola L, Cara A, Negri DR, Buttò S, Fiorelli V, Tripiciano A, Scoglio A, Caputo A, Borsetti A, Ridolfi B, Bona R, ten Haaft P, Macchia I, Leone P, Pavone-Cossut MR, Nappi F, Ciccozzi M, Heeney J, Titti F, Cafaro A, and Ensoli B
- Subjects
- Animals, B-Lymphocytes immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, DNA, Viral biosynthesis, DNA, Viral immunology, Gene Products, env analysis, Gene Products, env biosynthesis, Gene Products, gag analysis, Gene Products, gag biosynthesis, Humans, Interferon-gamma analysis, Interferon-gamma biosynthesis, Lymph Nodes pathology, Macaca fascicularis, Male, RNA, Viral biosynthesis, Recombinant Proteins biosynthesis, Recombinant Proteins immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome pathology, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus immunology, Vaccination, Viral Load, tat Gene Products, Human Immunodeficiency Virus, AIDS Vaccines therapeutic use, Gene Products, tat immunology, HIV-1 immunology, Simian Acquired Immunodeficiency Syndrome prevention & control, Simian Immunodeficiency Virus physiology, Virus Replication drug effects
- Abstract
Vaccination with a biologically active Tat protein or tat DNA contained infection with the highly pathogenic SHIV89.6P virus, preventing CD4 T-cell decline and disease onset. Here we show that protection was prolonged, since neither CD4 T-cell decline nor active virus replication was observed in all vaccinated animals that controlled virus replication up to week 104 after the challenge. In contrast, virus persisted and replicated in peripheral blood mononuclear cells and lymph nodes of infected animals, two of which died. Tat-specific antibody, CD4 and CD8 T-cell responses were high and stable only in the animals controlling the infection. In contrast, Gag-specific antibody production and CD4 and CD8 T-cell responses were consistently and persistently positive only in the monkeys that did not control primary virus replication. These results indicate that vaccination with Tat protein or DNA induced long-term memory Tat-specific immune responses and controlled primary infection at its early stages allowing a long-term containment of virus replication and spread in blood and tissues.
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- 2004
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23. 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.
- Author
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Buttò S, Fiorelli V, Tripiciano A, Ruiz-Alvarez MJ, Scoglio A, Ensoli F, Ciccozzi M, Collacchi B, Sabbatucci M, Cafaro A, Guzmán CA, Borsetti A, Caputo A, Vardas E, Colvin M, Lukwiya M, Rezza G, and Ensoli B
- Subjects
- AIDS Vaccines, Adolescent, Adult, Amino Acid Sequence, Cross Reactions, Cross-Sectional Studies, Epitope Mapping, Female, Gene Products, tat chemistry, HIV Infections immunology, HIV Infections virology, HIV-1 genetics, HIV-1 immunology, Humans, Italy, Male, Middle Aged, Molecular Sequence Data, Phylogeny, Sequence Analysis, DNA, South Africa, Uganda, tat Gene Products, Human Immunodeficiency Virus, Conserved Sequence, Gene Products, tat genetics, Gene Products, tat immunology, HIV Antibodies blood, HIV-1 classification
- Abstract
We determined immune cross-recognition and the degree of Tat conservation in patients infected by local human immunodeficiency virus (HIV) type 1 strains. The data indicated a similar prevalence of total and epitope-specific anti-Tat IgG in 578 serum samples from HIV-infected Italian (n=302), Ugandan (n=139), and South African (n=137) subjects, using the same B clade Tat protein that is being used in vaccine trials. In particular, anti-Tat antibodies were detected in 13.2%, 10.8%, and 13.9% of HIV-1-infected individuals from Italy, Uganda, and South Africa, respectively. Sequence analysis results indicated a high similarity of Tat from the different circulating viruses with BH-10 Tat, particularly in the 1-58 amino acid region, which contains most of the immunogenic epitopes. These data indicate an effective cross-recognition of a B-clade laboratory strain-derived Tat protein vaccine by individuals infected with different local viruses, owing to the high similarity of Tat epitopes.
- Published
- 2003
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24. Mucosal delivery of the human immunodeficiency virus-1 Tat protein in mice elicits systemic neutralizing antibodies, cytotoxic T lymphocytes and mucosal IgA.
- Author
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Marinaro M, Riccomi A, Rappuoli R, Pizza M, Fiorelli V, Tripiciano A, Cafaro A, Ensoli B, and De Magistris MT
- Subjects
- Adjuvants, Immunologic pharmacology, Administration, Intranasal, Amino Acid Sequence, Animals, Bacterial Toxins pharmacology, Cell Division physiology, Cytokines biosynthesis, Enterotoxins pharmacology, Enzyme-Linked Immunosorbent Assay, Epitope Mapping, Female, Gene Products, tat administration & dosage, Humans, Immunoglobulin G biosynthesis, Immunoglobulin G blood, Intestines immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Molecular Sequence Data, Neutralization Tests, T-Lymphocytes, Cytotoxic immunology, Vagina immunology, Escherichia coli Proteins, Gene Products, tat immunology, HIV Antibodies biosynthesis, Immunity, Mucosal immunology, Immunoglobulin A biosynthesis, Immunoglobulin A immunology, T-Lymphocytes, Cytotoxic physiology
- Abstract
Human immunodeficiency virus (HIV)-1 Tat protein induces protection in non-human primates upon systemic vaccination. In view of the design of mucosal vaccines against HIV-1 we studied the immune response to native Tat (aa 1-86) in mice following intranasal delivery of the protein with two mucosal adjuvants, Escherichia coli heat-labile enterotoxin (LT) and LT-R72, a non-toxic mutant of LT. Immunization with Tat and the two adjuvants induced in BALB/c but not in C57BL/6 mice high and persistent levels of serum IgG and secretory IgA in vaginal and intestinal fluids. Mice sera neutralized Tat and recognized two epitopes mapping in the regions 1-20 and 46-60. Furthermore, their splenocytes proliferated and secreted IFN-gamma and IL-6 in response to Tat. Finally, CTLs were also elicited and they recognized an epitope localized within aa 11-40 of Tat.
- Published
- 2003
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- View/download PDF
25. Efficient mucosal delivery of the HIV-1 Tat protein using the synthetic lipopeptide MALP-2 as adjuvant.
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Borsutzky S, Fiorelli V, Ebensen T, Tripiciano A, Rharbaoui F, Scoglio A, Link C, Nappi F, Morr M, Buttó S, Cafaro A, Mühlradt PF, Ensoli B, and Guzmán CA
- Subjects
- AIDS Vaccines immunology, Administration, Intranasal, Amino Acid Sequence, Animals, B-Lymphocytes immunology, Bronchoalveolar Lavage Fluid immunology, Epitopes immunology, Female, Freund's Adjuvant, Gene Products, tat administration & dosage, HIV Antibodies blood, Immunoglobulin A biosynthesis, Immunoglobulin A blood, Immunoglobulin G biosynthesis, Immunoglobulin G blood, Injections, Intraperitoneal, Interferon-gamma biosynthesis, Lipopeptides, Lung immunology, Lymphokines biosynthesis, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Nasal Mucosa immunology, Oligopeptides administration & dosage, Spleen cytology, Spleen immunology, Th1 Cells immunology, Th2 Cells immunology, Vagina immunology, tat Gene Products, Human Immunodeficiency Virus, AIDS Vaccines administration & dosage, Adjuvants, Immunologic, Gene Products, tat immunology, HIV Antibodies biosynthesis, HIV-1 immunology, Immunity, Mucosal immunology, Oligopeptides immunology
- Abstract
A major requirement for HIV/AIDS research is the development of a mucosal vaccine that stimulates humoral and cell-mediated immune responses at systemic and mucosal levels, thereby blocking virus replication at the entry port. Thus, a vaccine prototype based on biologically active HIV-1 Tat protein as antigen and the synthetic lipopeptide, macrophage-activating lipopeptide-2 (MALP-2), asa mucosal adjuvant was developed. Intranasal administration to mice stimulated systemic and mucosal anti-Tat antibody responses, and Tat-specific T cell responses, that were more efficient than those observed after i.p. immunization with Tat plus incomplete Freund's adjuvant. Major linear B cell epitopes mapped within aa 1-20 and 46-60, whereas T cell epitopes were identified within aa 36-50 and 56-70. These epitopes have also been described in vaccinated primates and in HIV-1-infected individuals with better prognosis. Analysis of the anti-Tat IgG isotypes in serum, and the cytokine profile of spleen cells indicated that a dominant Th1 helper response was stimulated by Tat plus MALP-2, as opposed to the Th2 response observed with Tat plus incomplete Freund's adjuvant. Tat-specific IFN-gamma-producing cells were significantly increased only in response to Tat plus MALP-2. These data suggest that Malp-2 may represent an optimal mucosal adjuvant for candidate HIV vaccines based on Tat alone or in combination with other HIV antigens.
- Published
- 2003
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26. Red blood cell-mediated delivery of recombinant HIV-1 Tat protein in mice induces anti-Tat neutralizing antibodies and CTL.
- Author
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Dominici S, Laguardia ME, Serafini G, Chiarantini L, Fortini C, Tripiciano A, Brocca-Cofano E, Scoglio A, Caputo A, Fiorelli V, Gavioli R, Cafaro A, Ensoli B, and Magnani M
- Subjects
- AIDS Vaccines administration & dosage, Animals, Antibodies, Viral blood, Antibody Formation, Biotinylation, Gene Products, tat immunology, Immunization Schedule, Mice, Recombinant Proteins immunology, Transplantation, Autologous, tat Gene Products, Human Immunodeficiency Virus, AIDS Vaccines immunology, Erythrocyte Transfusion, Gene Products, tat genetics, HIV-1 immunology, T-Lymphocytes, Cytotoxic immunology
- Abstract
The immunotherapeutic potential of biologically active HIV-1 Tat protein coupled to autologous red blood cells (RBCs) was evaluated in a mouse model. HIV-1 Tat expressed in Escherichia coli and purified to homogeneity was found to be active in viral trans activation and efficiently internalised by monocyte-derived dendritic cells (MDDCs). The product of HIV-Tat biotinylation and coupling to RBCs by means of a biotin-avidin-biotin bridge, (RBC-Tat), showed no trans activation activity and was still efficiently internalized by MDDCs as compared to uncoupled Tat.Balb/c mice were then immunized with 10 microg of soluble Tat in complete Freund's adjuvant or with 40 ng of Tat coupled on RBCs surface and boosted at week 3, 6 and 25 with 5 microg soluble Tat in incomplete Freund's adjuvant or with 20 ng of RBC-coupled Tat, respectively. Anti-Tat antibody response was similar in both groups; however, 2/6 animals immunized with soluble Tat and 6/6 animals immunized with RBC-Tat developed anti-Tat neutralizing antibodies. In addition, at week 28 cytolytic anti-Tat CTLs were detected in all animals although they were slightly higher in mice immunized with RBC-Tat. These results indicate that RBC-mediated delivery of HIV-1 Tat, in amounts 250 times lower than soluble Tat, is safe and induces specific CTL responses and neutralizing antibodies.
- Published
- 2003
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27. HIV-1 Tat-based vaccines: from basic science to clinical trials.
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Fanales-Belasio E, Cafaro A, Cara A, Negri DR, Fiorelli V, Butto S, Moretti S, Maggiorella MT, Baroncelli S, Michelini Z, Tripiciano A, Sernicola L, Scoglio A, Borsetti A, Ridolfi B, Bona R, Ten Haaft P, Macchia I, Leone P, Pavone-Cossut MR, Nappi F, Vardas E, Magnani M, Laguardia E, Caputo A, Titti F, and Ensoli B
- Subjects
- AIDS Vaccines administration & dosage, Animals, CD4-Positive T-Lymphocytes immunology, Clinical Trials as Topic, Gene Products, tat metabolism, HIV-1 metabolism, Macaca fascicularis, South Africa, Th1 Cells immunology, Uganda, tat Gene Products, Human Immunodeficiency Virus, AIDS Vaccines immunology, Gene Products, tat immunology, HIV-1 immunology
- Abstract
Vaccination against human immunodeficiency virus (HIV)-1 infection requires candidate antigen(s) (Ag) capable of inducing an effective, broad, and long-lasting immune response against HIV-1 despite mutation events leading to differences in virus clades. The HIV-1 Tat protein is more conserved than envelope proteins, is essential in the virus life cycle and is expressed very early upon virus entry. In addition, both humoral and cellular responses to Tat have been reported to correlate with a delayed progression to disease in both humans and monkeys. This suggested that Tat is an optimal target for vaccine development aimed at controlling virus replication and blocking disease onset. Here are reviewed the results of our studies including the effects of the Tat protein on monocyte-derived dendritic cells (MDDCs) that are key antigen-presenting cells (APCs), and the results from vaccination trials with both the Tat protein or tat DNA in monkeys. We provide evidence that the HIV-1 Tat protein is very efficiently taken up by MDDCs and promotes T helper (Th)-1 type immune responses against itself as well as other Ag. In addition, a Tat-based vaccine elicits an immune response capable of controlling primary infection of monkeys with the pathogenic SHIV89.6P at its early stages allowing the containment of virus spread. Based on these results and on data of Tat conservation and immune cross-recognition in field isolates from different clades, phase I clinical trials are being initiated in Italy for both preventive and therapeutic vaccination.
- Published
- 2002
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28. Lymphomononuclear cells from multiple sclerosis patients spontaneously produce high levels of oncostatin M, tumor necrosis factors alpha and beta, and interferon gamma.
- Author
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Ensoli F, Fiorelli V, Lugaresi A, Farina D, De Cristofaro M, Collacchi B, Muratori DS, Scala E, Di Gioacchino M, Paganelli R, and Aiuti F
- Subjects
- Adolescent, Adult, Cells, Cultured, Cytokines blood, Female, Humans, Interferon-gamma analysis, Interferon-gamma blood, Leukocytes, Mononuclear cytology, Leukocytes, Mononuclear immunology, Lymphotoxin-alpha analysis, Lymphotoxin-alpha blood, Male, Oncostatin M, Peptides blood, Tumor Necrosis Factor-alpha analysis, Tumor Necrosis Factor-alpha metabolism, Cytokines analysis, Leukocytes, Mononuclear metabolism, Multiple Sclerosis immunology, Peptides analysis
- Abstract
Proinflammatory cytokines are deemed to play a pivotal role in the pathogenesis of multiple sderosis (MS). They provide signals for T-cell activation and inflammatory cell recruitment in the brain and might directly alter neuroglial and neuronal cell survival and function. We found that peripheral blood mononuclear cells (PBMCs) from MS patents spontaneously produce high levels of TNFalpha, TNFbeta, IFNgamma, and oncostatin M (oncM), a proinflammatory cytokine actng on cells of neural, vascular, hematopoietic, and lymphoid origin. Spontaneous production of these cytokines was significantly higher (p < 0.01) in PBMC short-term culture supernatants from MS patients than in blood donors (HC). On average, lectin-induced production of these cytokines by PBMC was higher in MS patents than in HC significantly so only for TNFalpha (p = 0.013). Determination of TNFalpha, TNFbeta IFNgamma, and oncM in corresponding sera showed that on average, oncM levels were higher in MS patients than in HC, though the results were not statistically significant whereas levels of TNFalpha, TNFbeta and IFNgamma were below the assay threshold in most patients. The finding that MS PBMCs are primed in vivo to produce and release high levels of proinflammatory cytokines suggests the presence of a basal activation of the immune system which, in turn, may play a role in the complex circuitry of molecular and cellular interactions responsible for neurologic damage in MS.
- Published
- 2002
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29. Endogenous cytokine production protects T cells from spontaneous apoptosis during highly active antiretroviral therapy.
- Author
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Ensoli F, Fiorelli V, De Cristofaro M, Collacchi B, Santini Muratori D, Alario C, Sacco G, Iebba F, and Aiuti F
- Subjects
- Antibodies, Monoclonal immunology, Cohort Studies, Enzyme-Linked Immunosorbent Assay, HIV Infections drug therapy, Humans, In Situ Nick-End Labeling, Interferon-gamma immunology, Interleukin-2 immunology, Interleukin-4 immunology, Neutralization Tests, Viral Load, Antiretroviral Therapy, Highly Active, Apoptosis immunology, HIV Infections immunology, Interferon-gamma biosynthesis, Interleukin-2 biosynthesis, Interleukin-4 biosynthesis, T-Lymphocytes metabolism
- Abstract
Background: The availability of therapeutic regimens that effectively interfere with HIV-1 replication provides novel opportunities to investigate mechanisms of T-cell depletion as well as repopulation in infected individuals., Methods: Nineteen HIV-1-infected individuals were investigated during one-year follow-up of highly active retroviral therapy (HAART). The frequencies of apoptotic T cells, as determined by propidium iodide, staining, TUNEL assay and analysis of annexin V, were assessed either in the absence or in the presence of anti-interleukin (IL)2 and anti-IL-4 neutralizing Ab. Spontaneous and lectin-induced cytokine production were assessed by ELISA., Results: Increments of both naive and memory CD4 and CD8 T cells during HAART are accompanied by a decrease of T-cell apoptosis that, after 12 months of HAART, reaches normal levels. This is associated with increments of both spontaneous and activation-induced production of IL-2 and IL-4 by peripheral blood mononuclear cells (PBMCs), though only the latter was found defective at enrolment. During HAART, blocking of either IL-2 or IL-4 production by PBMCs using neutralizing Ab restores levels of T-cell apoptosis consistent with those determined at enrolment. These data suggest that both IL-2 and IL-4 produced by PBMCs during HAART provide anti-apoptotic signals that can contribute to an increased survival of T cells and may thus play a part in long-term immune reconstitution., Conclusions: An effective viral suppression and, possibly, effects of PI on molecular targets other than viral components, can support a progressive normalization of T-cell survival that, at least in part, depends upon the restoration of proper soluble signals. These results provide evidence of a supporting role of endogenous cytokine production in peripheral T-cell repopulation during an effective and prolonged viral suppression. This may be relevant for the definition of immune-intervention targets aimed at immune reconstitution in HIV-1-infected patients.
- Published
- 2002
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30. Distribution of the natural killer-related receptor for HLA-C during highly active antiretroviral therapy for human immunodeficiency virus infection.
- Author
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Sirianni MC, Ensoli F, Alario C, Fiorelli V, Sacco G, Topino S, Iebba F, Mezzaroma I, and Aiuti F
- Subjects
- Adult, Antiretroviral Therapy, Highly Active, Cell Count, Female, Humans, Male, Middle Aged, Prospective Studies, Receptors, Immunologic genetics, Receptors, KIR, Receptors, KIR2DL1, Receptors, KIR2DL3, T-Lymphocytes metabolism, HIV Infections drug therapy, HIV Infections metabolism, HLA-C Antigens metabolism, Killer Cells, Natural metabolism, Receptors, Immunologic metabolism
- Abstract
Receptors interacting with Major Histocompatibility Complex class I molecules have been initially found on the surface of human natural killer (NK) cells, where they deliver inhibitory signals to the lysis, being thus defined killer inhibitory receptors (KIR). Subsequently, they were detected also on the surface of T-CD8(+) lymphocytes and are particularly expanded during human immunodeficiency virus (HIV) infection, where they downregulate HIV-specific cytolysis. The expression of KIR recognizing human leukocyte antigen-C alleles was assessed in HIV-infected patients, undergoing highly active antiretroviral therapy (HAART). To this end, the combined expression of CD16/CD56, of CD3 and CD8 as well as of KIR (CD158a and CD158b) surface molecules was analyzed on peripheral blood mononuclear cells by monoclonal antibodies, and flow cytometry. An increase of CD3(+)CD8(+)CD158b(+) cells was found after 6 months of HAART. This finding may have implications for the regulation of T-cell mediated cytolysis during HAART.
- Published
- 2001
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31. Decreased T cell apoptosis and T cell recovery during highly active antiretroviral therapy (HAART).
- Author
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Ensoli F, Fiorelli V, Alario C, De Cristofaro M, Santini Muratori D, Novi A, Cunsolo MG, Mazzetta F, Giovannetti A, Mollicone B, Pinter E, and Aiuti F
- Subjects
- Adult, Apoptosis drug effects, Apoptosis genetics, Cohort Studies, Female, Flow Cytometry, Humans, In Situ Nick-End Labeling, Male, Middle Aged, Phenotype, Prospective Studies, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets drug effects, Viral Load, Antiretroviral Therapy, Highly Active, T-Lymphocytes cytology
- Abstract
T cell apoptosis represents a common mechanism of T cell depletion in HIV-1-infected individuals reflecting maturational and functional T cell abnormalities either directly or indirectly induced by the virus. In the present study, the effects of highly active antiretroviral therapy (HAART) on the spontaneous apoptosis of distinct T cell subsets were investigated during a 6-month follow-up in a cohort of HIV-1-infected individuals with CD4(+) cell counts between 100 and 500 cells/microliter and plasma HIV-1 RNA levels >/=10, 000 copies/ml. We determined that the rapid and sustained increase of both naive (CD45RA(+)CD62L(+)) and memory (CD45R0(+) and CD45RA(+)/CD62L(-)) CD4(+) and, to as lesser extent, CD8(+) T cells in peripheral blood was associated with a significant decrease of apoptotic CD4(+) and CD8(+) as well as CD3(+)CD4(-)CD8(-) T cells. Among CD4(+) lymphocytes, at enrollment, the highest frequency of apoptotic cells was observed within the memory compartment, as defined by CD45R0 expression. During HAART, however, the frequency of CD4(+)CD45R0(+) apoptotic T cells progressively decreased in association with a significant downregulation of surface activation markers that indicated decreased levels of systemic immune stimulation. These results indicate that effective viral suppression can contribute to progressive normalization of maturational and functional T cell abnormalities responsible for the high levels of T cell apoptosis in HIV-1-infected individuals. This, in turn, may contribute to a reduced rate of T cell loss and immune reconstitution during HAART., (Copyright 2000 Academic Press.)
- Published
- 2000
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32. Role of immune-derived diffusible mediators in AIDS-associated neurological disorders.
- Author
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Ensoli F, Fiorelli V, De Cristofaro M, Muratori DS, Novi A, Isgrò A, and Aiuti F
- Subjects
- Acquired Immunodeficiency Syndrome complications, Diffusion, Humans, Nervous System Diseases complications, Neuroglia immunology, Neurons immunology, Acquired Immunodeficiency Syndrome immunology, Brain immunology, HIV-1 immunology, Nervous System Diseases immunology, Neurotoxins biosynthesis
- Abstract
Neurologic abnormalities are common in HIV-1 infected patients and often represent the dominant clinical manifestation of pediatric AIDS. Although the neurological dysfunction has been directly related to CNS invasion by HIV-1, the pathogenesis of neurologic disorders remains unclear. This review will first discuss the spectrum of potential interactions between HIV-1 and neural (neuronal and glial) cells, in the face of experimental data. Next, we will focus on the role of immune-derived cytokines and other soluble compounds which have been proposed to act as neurotoxic mediators and appear to play a role in the pathogenesis of AIDS-associated neurodegeneration.
- Published
- 2000
33. CCR5 and CXCR4 chemokine receptor expression and beta-chemokine production during early T cell repopulation induced by highly active anti-retroviral therapy.
- Author
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Giovannetti A, Ensoli F, Mazzetta F, De Cristofaro M, Pierdominici M, Muratori DS, Fiorelli V, and Aiuti F
- Subjects
- Adult, Anti-HIV Agents therapeutic use, Antigens, CD immunology, Antigens, CD metabolism, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Chemokine CCL3, Chemokine CCL4, Chemokine CCL5 biosynthesis, Drug Therapy, Combination, Female, Flow Cytometry, HIV Infections drug therapy, HIV Infections immunology, Humans, Lectins pharmacology, Macrophage Inflammatory Proteins biosynthesis, Male, Middle Aged, T-Lymphocytes drug effects, T-Lymphocytes immunology, Time Factors, Viral Load, Chemokines, CC biosynthesis, HIV Infections metabolism, Receptors, CCR5 biosynthesis, Receptors, CXCR4 biosynthesis, T-Lymphocytes metabolism
- Abstract
Expression of chemokine receptors and beta-chemokine production by peripheral blood mononuclear cells (PBMC) were determined in HIV-1-infected individuals before and after highly active anti-retroviral therapy (HAART) and their relationship to viral load, T cell phenotype and the expression of immunological activation markers was examined. We found that the expression of CCR5 is up-regulated in HIV-1-infected individuals while CXCR4 appears down-regulated on both CD4 and CD8 T cells compared with normal controls. These alterations are associated with the high levels of viral load. In addition, a relationship was observed between the degree of immune activation and chemokine receptor expression on T cells. However, after 3 months of combined anti-retroviral regimen, expression of CXCR4 significantly increased while CCR5 decreased when compared with pretherapy determinations. This was seen in strict association with a dramatic decrease of viral load and an increase of both CD45RA+/CD62L+ (naive) and CD45RA-/CD62L+ or CD45RA+/CD62L- (memory) T cells accompanied by a significant decrease of the expression of immune activation markers such as HLA-DR and CD38. At enrolment, both spontaneous and lectin-induced RANTES, macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta production by PBMC were higher in HIV-1-infected individuals compared with normal controls, although differences for MIP-1beta were not statistically significant. However, RANTES and MIP-1alpha production decreased during HAART at levels closer to that determined with normal controls, while MIP-1beta production was less consistently modified. These data indicate that the expression of chemokine receptors CCR5 and CXCR4 and the production of beta-chemokines are altered in HIV-infected individuals, and suggest that their early modifications during HAART reflect both the peripheral redistribution of naive/memory T cell compartments and the decrease in levels of T cell activation. Such modifications in the expression of host determinants of viral tropism and the production of anti-viral molecules may play a role in the emergence of virus variants when a failure of HAART occurs.
- Published
- 1999
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34. The Tat protein of human immunodeficiency virus type-1 promotes vascular cell growth and locomotion by engaging the alpha5beta1 and alphavbeta3 integrins and by mobilizing sequestered basic fibroblast growth factor.
- Author
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Barillari G, Sgadari C, Fiorelli V, Samaniego F, Colombini S, Manzari V, Modesti A, Nair BC, Cafaro A, Stürzl M, and Ensoli B
- Subjects
- Binding, Competitive, Cell Adhesion physiology, Cell Division, Cell Movement, Cytokines pharmacology, Extracellular Matrix Proteins physiology, Gene Products, tat chemistry, Genes, tat, HIV-1 genetics, Heparan Sulfate Proteoglycans metabolism, Humans, Macromolecular Substances, Molecular Mimicry, Oligopeptides physiology, Peptide Fragments pharmacology, Protein Conformation, Recombinant Proteins pharmacology, Sarcoma, Kaposi pathology, Skin Neoplasms pathology, Solubility, tat Gene Products, Human Immunodeficiency Virus, Endothelium, Vascular cytology, Fibroblast Growth Factor 2 metabolism, Gene Products, tat physiology, HIV-1 physiology, Neovascularization, Pathologic virology, Receptors, Fibronectin physiology, Receptors, Vitronectin physiology
- Abstract
The Tat protein of human immunodeficiency virus type-1 (HIV-1) has been shown to be released during acute infection of T cells by HIV-1 and to promote angiogenesis and Kaposi's sarcoma (KS) development in infected individuals. In this study, we investigated the molecular mechanisms responsible for the angiogenic effects of Tat. The results shown herein indicate that two different Tat domains cooperate to induce these effects by different pathways. The arginine-glycine-aspartic acid (RGD) sequence present at the carboxyterminal of Tat mediates vascular cell migration and invasion by binding to the alpha5beta1 and alphavbeta3 integrins. This interaction also provides endothelial cells with the adhesion signal they require to grow in response to mitogens. At the same time, the Tat basic sequence retrieves into a soluble form extracellular basic fibroblast growth factor (bFGF) bound to heparan sulfate proteoglycans by competing for heparin-binding sites. This soluble bFGF mediates Tat-induced vascular cell growth. These effects resemble those of extracellular matrix proteins, suggesting that Tat enhances angiogenesis and promotes KS progression by a molecular mimicry of these molecules.
- Published
- 1999
35. Inflammatory cytokines and HIV-1-associated neurodegeneration: oncostatin-M produced by mononuclear cells from HIV-1-infected individuals induces apoptosis of primary neurons.
- Author
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Ensoli F, Fiorelli V, DeCristofaro M, Santini Muratori D, Novi A, Vannelli B, Thiele CJ, Luzi G, and Aiuti F
- Subjects
- Apoptosis, Biological Assay, DNA Fragmentation, Drug Interactions, HIV Infections pathology, Humans, In Situ Nick-End Labeling, Leukocytes, Mononuclear immunology, Neurons, Afferent pathology, Oncostatin M, Time Factors, Transforming Growth Factor beta pharmacology, Cytokines metabolism, HIV Infections immunology, HIV-1 immunology, Inflammation Mediators metabolism, Neurons, Afferent drug effects, Neurotoxins metabolism, Peptides metabolism
- Abstract
Neurologic abnormalities are common in HIV-1-infected patients and often represent the dominant clinical manifestation of pediatric AIDS. The neurological dysfunction has been directly related to CNS invasion by HIV-1 that is principally, if not exclusively, supported by blood-derived monocytes/macrophages and lymphocytes. By using primary long term cultures of human fetal sensory neurons as well as sympathetic precursors-like neuronal cells, we determined that blood-derived mononuclear cells from HIV-1-infected individuals spontaneously release soluble mediators that can potently inhibit the growth and survival of developing neurons as well as the viability of postmitotic neuronal cells by inducing apoptotic cell death. Analysis of the cytokines produced by lymphomonocytic cells, HIV-1 infected or activated, indicated that oncostatin M (oncM) is a major mediator of these effects. Since low TGF-beta1 concentrations were capable of enhancing oncM-mediated neuronal alterations, our data indicate that by acting in concert with other cytokines, oncM may induce neuronal demise in both the developing and the mature brain. Thus, this cytokine may contribute to the setting of the neuronal cell damage observed in HIV-1-infected individuals.
- Published
- 1999
36. IFN-gamma induces endothelial cells to proliferate and to invade the extracellular matrix in response to the HIV-1 Tat protein: implications for AIDS-Kaposi's sarcoma pathogenesis.
- Author
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Fiorelli V, Barillari G, Toschi E, Sgadari C, Monini P, Stürzl M, and Ensoli B
- Subjects
- Acquired Immunodeficiency Syndrome virology, Cell Division immunology, Cells, Cultured, Endothelium, Vascular virology, Extracellular Matrix virology, Gene Products, tat metabolism, Growth Substances physiology, HIV-1 physiology, Humans, Receptors, Fibronectin biosynthesis, Receptors, Fibronectin physiology, Receptors, Virus biosynthesis, Receptors, Virus physiology, Receptors, Vitronectin biosynthesis, Receptors, Vitronectin physiology, Sarcoma, Kaposi pathology, Sarcoma, Kaposi virology, Umbilical Veins, Up-Regulation immunology, tat Gene Products, Human Immunodeficiency Virus, Acquired Immunodeficiency Syndrome pathology, Cell Movement immunology, Endothelium, Vascular pathology, Extracellular Matrix pathology, Gene Products, tat physiology, Interferon-gamma physiology, Sarcoma, Kaposi etiology
- Abstract
Previous studies indicated that the Tat protein of HIV functions as a progression factor in Kaposi's sarcoma (KS), an angioproliferative disease common and aggressive in HIV-1-infected individuals (AIDS-KS). In particular, Tat that is released by infected cells stimulates the growth and invasion of spindle cells of endothelial origin derived from KS lesions (KS cells). Other work suggested that inflammatory cytokines may act as initiating factors in KS since they induce normal endothelial cells to acquire the same phenotype and functional features of KS cells, including the responsiveness to Tat. In this study, we show that among the inflammatory cytokines increased in AIDS-KS lesions, IFN-gamma alone is sufficient to induce endothelial cells to proliferate and to invade the extracellular matrix in response to Tat. This is because IFN-gamma up-regulates the expression and activity of the receptors for Tat identified as the integrins alpha5beta1 and alpha(v)beta3. These results suggest that, by triggering Tat effects, IFN-gamma plays a major role in AIDS-KS pathogenesis.
- Published
- 1999
37. Immune-derived cytokines in the nervous system: epigenetic instructive signals or neuropathogenic mediators?
- Author
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Ensoli F, Fiorelli V, Muratori DS, De Cristofaro M, Vincenzi L, Topino S, Novi A, Luzi G, and Sirianni MC
- Subjects
- Animals, Central Nervous System pathology, Cytokines physiology, Humans, Neurodegenerative Diseases etiology, Neurodegenerative Diseases pathology, Central Nervous System immunology, Cytokines immunology, Neurodegenerative Diseases immunology, Signal Transduction immunology
- Abstract
The investigation of the effects of inflammatory cytokines (IC) on the growth and differentiation of neural cells has provided new insights on the role of such soluble mediators in nervous system development and/or plastic remodeling as well as in the pathogenesis of inflammatory neurodegenerative disorders, which are characterized by chronic IC dysregulation in the central nervous system (CNS). Thus, the study of the interaction between CNS and immune-derived soluble signals in physiological or pathological conditions is of increasing interest. This review first discusses experimental evidence supporting the instructive/permissive role of immune-derived cytokines on CNS development and plasticity. Next, we focus on human neurological disease states such as multiple sclerosis and the neurodegeneration associated to the acquired immune deficiency syndrome in which different inflammatory cytokines have been proposed as potential neuropathogenic mediators.
- Published
- 1999
38. Basic fibroblast growth factor supports human olfactory neurogenesis by autocrine/paracrine mechanisms.
- Author
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Ensoli F, Fiorelli V, Vannelli B, Barni T, De Cristofaro M, Ensoli B, and Thiele CJ
- Subjects
- Cell Differentiation drug effects, Cell Division drug effects, Cells, Cultured, DNA biosynthesis, Fetus, Fibroblast Growth Factor 2 pharmacology, Growth Substances physiology, Humans, Nasal Mucosa cytology, Nasal Mucosa drug effects, Nerve Growth Factors pharmacology, Neurons drug effects, Platelet-Derived Growth Factor pharmacology, Recombinant Proteins pharmacology, Transforming Growth Factor beta pharmacology, Fibroblast Growth Factor 2 biosynthesis, Fibroblast Growth Factor 2 genetics, Growth Substances pharmacology, Nasal Mucosa innervation, Neurons cytology, Neurons metabolism, Oligonucleotides, Antisense pharmacology
- Abstract
Throughout life, olfactory sensory neurons are renewed from a population of dividing stem cells. Little is known about the molecular mechanisms that regulate the activation, self-renewal and differentiation of olfactory neuronal precursors; however, evidence indicates that soluble mediators may play a central role in olfactory neurogenesis. To identify molecules that regulate olfactory self-renewal and differentiation, we have recently established, cloned and propagated in vitro primary long-term cell cultures from the human fetal olfactory neuroepithelium. Here we show that primary human olfactory neuroblasts synthesize and release biologically active basic fibroblast growth factor which, in turn, supports neuroblast growth by autocrine/paracrine mechanisms. The growth-promoting activity of basic fibroblast growth factor is dose dependent and is accompanied by morphological changes of the cells and by an increase in the expression of neuronal-related genes. These observations indicate that endogenous basic fibroblast growth factor participates in controlling olfactory self-renewal and suggest that this cytokine represents a key regulatory element of olfactory neurogenesis.
- Published
- 1998
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39. gamma-Interferon produced by CD8+ T cells infiltrating Kaposi's sarcoma induces spindle cells with angiogenic phenotype and synergy with human immunodeficiency virus-1 Tat protein: an immune response to human herpesvirus-8 infection?
- Author
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Fiorelli V, Gendelman R, Sirianni MC, Chang HK, Colombini S, Markham PD, Monini P, Sonnabend J, Pintus A, Gallo RC, and Ensoli B
- Subjects
- Animals, CD8-Positive T-Lymphocytes pathology, Drug Synergism, Endothelium, Vascular pathology, HIV-1, HLA-DR Antigens analysis, Herpesviridae Infections immunology, Humans, Interferon-gamma pharmacology, Macrophages pathology, Mice, Mice, Nude, Monocytes pathology, Phenotype, Sarcoma, Kaposi immunology, Sarcoma, Kaposi pathology, tat Gene Products, Human Immunodeficiency Virus, CD8-Positive T-Lymphocytes immunology, Gene Products, tat pharmacology, Herpesvirus 8, Human immunology, Interferon-gamma biosynthesis, Neovascularization, Pathologic pathology, Sarcoma, Kaposi virology
- Abstract
Kaposi's sarcoma (KS) is an angioproliferative disease associated with infection by the human herpesvirus-8 (HHV-8). HHV-8 possesses genes including homologs of interleukin-8 (IL-8) receptor, Bcl-2, and cyclin D, which can potentially transform the host cell. However, the expression of these genes in KS tissues is very low or undetectable and HHV-8 does not seem to transform human cells in vitro. In addition, KS may not be a true cancer at least in the early stage. This indicated that besides its transforming potential, HHV-8 may act in KS pathogenesis also through indirect mechanisms. Evidence suggests that KS may start as an inflammatory-angiogenic lesion mediated by cytokines. However, little is known on the nature of the inflammatory cell infiltration present in KS, on the type of cytokines produced and on their role in KS, and whether this correlates with the presence of HHV-8. Here we show that both acquired immunodeficiency syndrome (AIDS)-KS and classical KS (C-KS) lesions are infiltrated by CD8+ T cells and CD14+/CD68+ monocytes-macrophages producing high levels of gamma-interferon (gamma IFN) which, in turn, promotes the formation of KS spindle cells with angiogenic phenotype. gamma IFN, in fact, induces endothelial cells to acquire the same features of KS cells, including the spindle morphology and the pattern of cell marker expression. In addition, endothelial cells activated by gamma IFN induce angiogenic lesions in nude mice closely resembling early KS. These KS-like lesions are accompanied by production of basic fibroblast growth factor, an angiogenic factor highly expressed in primary lesions that mediates angiogenesis and spindle cell growth. The formation of KS-like lesions is upregulated by the human immunodeficiency virus Tat protein demonstrating its role as a progression factor in AIDS-KS. Finally, gamma IFN and HLA-DR expression correlate with the presence of HHV-8 in lesional and uninvolved tissues from the same patients. As HHV-8 infects both mononuclear cells infiltrating KS lesions and KS spindle cells, these results suggest that HHV-8 may elicit or participate in a local immune response characterized by infiltration of CD8+ T cells and intense production of gamma IFN which, in turn, plays a key role in KS development.
- Published
- 1998
40. gamma-Interferon production in peripheral blood mononuclear cells and tumor infiltrating lymphocytes from Kaposi's sarcoma patients: correlation with the presence of human herpesvirus-8 in peripheral blood mononuclear cells and lesional macrophages.
- Author
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Sirianni MC, Vincenzi L, Fiorelli V, Topino S, Scala E, Uccini S, Angeloni A, Faggioni A, Cerimele D, Cottoni F, Aiuti F, and Ensoli B
- Subjects
- Adult, CD4-Positive T-Lymphocytes pathology, CD8-Positive T-Lymphocytes pathology, Cells, Cultured, Female, Humans, Immunohistochemistry, Interferon-gamma analysis, Interleukin-4 analysis, Lymphocytes, Tumor-Infiltrating virology, Macrophages virology, Male, Sarcoma, Kaposi metabolism, Sarcoma, Kaposi pathology, Herpesvirus 8, Human isolation & purification, Interferon-gamma biosynthesis, Leukocytes, Mononuclear metabolism, Leukocytes, Mononuclear virology, Lymphocytes, Tumor-Infiltrating metabolism, Sarcoma, Kaposi virology
- Abstract
Evidence indicates that, at least in the early stage, Kaposi's sarcoma (KS) is a cytokine-mediated disease and that it is consistently associated with a novel herpesvirus termed human herpesvirus-8 (HHV-8). To gain insights into the mechanisms by which cytokines and HHV-8 may cooperate in disease pathogenesis, we examined the phenotype, the Th1 (gamma-interferon [gamma IFN]) and Th2 (interleukin-4 [IL-4] cytokine profile and the presence of HHV-8 in peripheral blood mononuclear cells (PBMC), tumor-infiltrating lymphocytes (TIL), and spindle cell cultures derived from skin lesions of patients affected by classical KS (C-KS) and acquired immunodeficiency syndrome (AIDS)-associated KS (AIDS-KS). TIL and spindle cell cultures were examined at day 0 or after culture in conditioned media from activated T cells (TCM) that contain the same cytokines increased in KS tissues. No differences were found in the immunophenotype of PBMC from C-KS patients versus controls, except for AIDS-KS patients who showed a T-CD8+ expansion. However, a preferential infiltration of T-CD8+ cells was found in all KS lesions examined, which was maintained after culture of TIL in TCM. gamma IFN production was found in both PBMC and cultures derived from all KS examined; some IL-4 positive supernatants were found only in three AIDS-KS cases. Uninvolved skin did not show appreciable lymphocyte infiltration or cytokine production. The culture conditions of the lesional skin allowed also the appearance of adherent, spindle-like cells bearing markers of tissue macrophages. Finally, most or all of the PBMC, lesions, and macrophagic cell cultures from the skin lesions were found to be positive for HHV-8 infection by nested polymerase chain reaction (PCR). These findings indicate that patients with KS express a Th1 phenotype with a prevalent gamma IFN production, likely accounted for by the local T-CD8+ infiltration. By analogy with other viral infections (i.e., Epstein-Barr virus), this suggests that in loco recruitment of lymphoid cells and the subsequent gamma IFN production may be in response to or elicited by HHV-8 that was found in both PBMC and macrophagic cell cultures from the lesions of the same patients.
- Published
- 1998
41. HIV-1 infection and the developing nervous system: lineage-specific regulation of viral gene expression and replication in distinct neuronal precursors.
- Author
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Ensoli F, Wang H, Fiorelli V, Zeichner SL, De Cristofaro MR, Luzi G, and Thiele CJ
- Subjects
- Cell Line, Cell Lineage, Central Nervous System growth & development, Gene Expression Regulation, Viral, HIV Infections genetics, HIV Long Terminal Repeat, HIV-1 genetics, Humans, Virus Replication, Central Nervous System virology, HIV Infections virology, HIV-1 physiology
- Abstract
Neurologic abnormalities are common in HIV-1 infected patients and often represent the dominant clinical manifestation of pediatric AIDS. Although the neurological dysfunction has been directly related to CNS invasion by HIV-1, the pathogenesis of neurologic disorders remains unclear. Microglia and macrophages are major HIV-1 targets in the brain, whereas HIV-1 infected neurons or glial cells have been rarely reported. This suggests that indirect mechanisms may account for the severe neuronal damage observed in these patients. Nevertheless, immature, mitotically active neuronal and glial cells, which are present during fetal development, are susceptible to HIV-1 infection and replication in vitro, suggesting that HIV-1 infection during organ development may present unique features. To better characterize virus-host cells interactions in the developing CNS, we have examined the susceptibility of embryologically and biochemically distinct neuronal cell lines to HIV-1 infection. Here we show that mitotically active, immature neurons of distinct lineages, have different susceptibilities to HIV-1 infection and replication and different abilities to support viral gene expression. Mutational analysis of HIV-1 LTR reveals that a region of the viral promoter between nucleotide -255 to -166 is responsible for most quantitative and qualitative differences in viral transactivation among different neuroblasts. This suggests that specific regions of the viral promoter and cellular factors, either lineage- or differentiation-dependent, which bind to those regions, may contribute to control the levels of virus replication and possibly restrict the viral tropism in the developing brain. This may contribute to the establishment of a virus reservoir in the immature CNS and participate by either direct or indirect mechanisms to the severity of the AIDS-related pediatric neurological dysfunction.
- Published
- 1997
- Full Text
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42. New developments: a look to the future.
- Author
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Ensoli B, Gallo RC, and Fiorelli V
- Subjects
- Acquired Immunodeficiency Syndrome complications, Cytokines metabolism, Gene Expression Regulation, Neoplastic, Gene Products, tat metabolism, Humans, Risk Factors, Sarcoma, Kaposi metabolism, tat Gene Products, Human Immunodeficiency Virus, Sarcoma, Kaposi etiology
- Abstract
Inflammatory cytokines plus the human immunodeficiency virus Tat protein apparently trigger the development of early Kaposi's sarcoma. Activated spindle cells provide a self-perpetuating, autocrine-supported mechanism for further development of hyperplastic lesions. In more advanced stages, a true neoplastic process may develop.
- Published
- 1996
43. HIV-1 infection of primary human neuroblasts.
- Author
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Ensoli F, Cafaro A, Fiorelli V, Vannelli B, Ensoli B, and Thiele CJ
- Subjects
- Acquired Immunodeficiency Syndrome pathology, Acquired Immunodeficiency Syndrome virology, Antigens, CD biosynthesis, CD4 Antigens biosynthesis, Cell Line, Clone Cells, Embryo, Mammalian, Epithelial Cells, Epithelium virology, Fetus, Gene Expression, HIV-1 pathogenicity, Humans, Infant, Infant, Newborn, Kinetics, Neuroectodermal Tumors, Neurons cytology, Olfactory Mucosa embryology, Olfactory Mucosa innervation, RNA, Messenger biosynthesis, Time Factors, Tumor Cells, Cultured, HIV-1 physiology, Neurons virology, Virus Replication
- Abstract
Central nervous system (CNS) disorders are frequent in HIV-1-infected individuals, particularly in newborns and children, and are accompanied by histological alterations resulting in neuronal loss. Although several tumor-derived neuroectodermal cell lines can be infected by HIV-1, it has been reported that primary neural cells cannot be infected after they differentiate. However, pediatric AIDS is often the result of HIV-1 infection occurring during fetal development and early postnatal life, when neural cells are not yet differentiated. Here we show that primary cell cultures derived from the human fetal olfactory system which are representative of the developing CNS can be infected by both HIV-1 strains, the monocyte-macrophagotropic BaL and the lymphotropic HTLV-IIIB, although they do not express the CD4 molecule. In addition, the levels of viral replication are higher with the HIV-1 BaL than with the IIIB isolate. These results suggest that (1) during development immature neurons are susceptible to HIV-1 infection; (2) monocyte-macrophagotropic HIV-1 strains may preferentially be involved in the productive infection of the nervous system; and (3) a mechanism(s) other than the CD4-mediated viral entry is responsible for HIV-1 infection of immature neurons.
- Published
- 1995
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44. Cytokines from activated T cells induce normal endothelial cells to acquire the phenotypic and functional features of AIDS-Kaposi's sarcoma spindle cells.
- Author
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Fiorelli V, Gendelman R, Samaniego F, Markham PD, and Ensoli B
- Subjects
- Acquired Immunodeficiency Syndrome pathology, Animals, Antigens, Differentiation, Myelomonocytic biosynthesis, Biomarkers, Cell Adhesion Molecules biosynthesis, Culture Media, Conditioned pharmacology, Endothelium, Vascular pathology, Factor VIII biosynthesis, Fibroblast Growth Factor 2 pharmacology, G1 Phase physiology, Gene Products, tat pharmacology, Humans, Lymphocyte Activation, Mice, Mice, Nude, Platelet Endothelial Cell Adhesion Molecule-1, Protein Biosynthesis, RNA biosynthesis, Sarcoma, Kaposi complications, Sarcoma, Kaposi pathology, Umbilical Veins, tat Gene Products, Human Immunodeficiency Virus, Acquired Immunodeficiency Syndrome complications, Cytokines pharmacology, Endothelium, Vascular drug effects, Sarcoma, Kaposi etiology, T-Lymphocytes metabolism
- Abstract
Kaposi's sarcoma (KS) is a proliferative disease of vascular origin particularly frequent in HIV-1-infected homosexual men (AIDS-KS) and characterized by proliferating spindle-shaped cells, angiogenesis, and inflammatory cell infiltration. Previous work has suggested that KS spindle cells are of endothelial cell origin and that chronic immune activation via the release of inflammatory cytokines may cooperate with basic fibroblast growth factor (bFGF) and the HIV-1 Tat protein in the induction and progression of AIDS-KS. Here we show that KS spindle cells have features of activated endothelial cells, and that conditioned media from activated T cells, rich in the same inflammatory cytokines increased in HIV-1-infected individuals, induce normal endothelial cells to acquire the phenotypic and functional features of KS cells. These include (a) acquisition of a similar pattern of cell surface antigen expression; (b) similar proliferative response to bFGF; (c) induction of the responsiveness to the mitogenic effect of extracellular HIV-1 Tat protein that is now able to promote the G1-S transition of endothelial cell cycle; and (d) induction in nude mice of vascular lesions closely resembling early KS as well as the lesions induced by inoculation of KS cells. These results suggest that chronic immune activation, via release of inflammatory cytokines, may play a role in the induction of KS.
- Published
- 1995
- Full Text
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45. Block of AIDS-Kaposi's sarcoma (KS) cell growth, angiogenesis, and lesion formation in nude mice by antisense oligonucleotide targeting basic fibroblast growth factor. A novel strategy for the therapy of KS.
- Author
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Ensoli B, Markham P, Kao V, Barillari G, Fiorelli V, Gendelman R, Raffeld M, Zon G, and Gallo RC
- Subjects
- Acquired Immunodeficiency Syndrome pathology, Animals, Base Sequence, Cell Division drug effects, Dose-Response Relationship, Drug, Endothelium, Vascular cytology, Mice, Mice, Inbred BALB C, Mice, Nude, Molecular Sequence Data, Sarcoma, Kaposi pathology, Acquired Immunodeficiency Syndrome therapy, Fibroblast Growth Factor 2 physiology, Neovascularization, Pathologic prevention & control, Oligonucleotides, Antisense therapeutic use, Sarcoma, Kaposi therapy
- Abstract
Kaposi's sarcoma (KS) is the most frequent tumor of HIV-1-infected individuals (AIDS-KS). Typical features of KS are proliferating spindle-shaped cells, considered to be the tumor cells of KS, and endothelial cells forming blood vessels. Basic fibroblast growth factor (bFGF), a potent angiogenic factor, is highly expressed by KS spindle cells in vivo and after injection in nude mice it induces vascular lesions closely resembling early KS in humans. Similar lesions are induced by inoculating nude mice with cultured spindle cells from AIDS-KS lesions (AIDS-KS cells) which produce and release bFGF. Here we show that phosphorothioate antisense (AS) oligonucleotides directed against bFGF mRNA (ASbFGF) inhibit both the growth of AIDS-KS cells derived from different patients and the angiogenic activity associated with these cells, including the induction of KS-like lesions in nude mice. These effects are due to the block of the production of bFGF which is required by AIDS-KS cells to enter the cell cycle and which, after release, mediates angiogenesis. The effects of ASbFGF are specific, dose dependent, achieved at low (0.1-1 microM), nontoxic, oligomer concentrations, and are reversed by the addition of bFGF to the cells, suggesting that ASbFGF oligomers are promising drug candidates for KS therapy.
- Published
- 1994
- Full Text
- View/download PDF
46. Synergy between basic fibroblast growth factor and HIV-1 Tat protein in induction of Kaposi's sarcoma.
- Author
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Ensoli B, Gendelman R, Markham P, Fiorelli V, Colombini S, Raffeld M, Cafaro A, Chang HK, Brady JN, and Gallo RC
- Subjects
- Acquired Immunodeficiency Syndrome virology, Animals, Base Sequence, Cell Adhesion, Cell Line, Collagenases metabolism, Enzyme Activation, Extracellular Matrix Proteins physiology, Fibronectins physiology, Humans, Matrix Metalloproteinase 9, Mice, Mice, Inbred BALB C, Mice, Nude, Molecular Mimicry, Molecular Sequence Data, Palatine Tonsil pathology, Sarcoma, Kaposi pathology, Sarcoma, Kaposi virology, Skin pathology, tat Gene Products, Human Immunodeficiency Virus, Acquired Immunodeficiency Syndrome complications, Fibroblast Growth Factor 2 physiology, Gene Products, tat physiology, HIV-1 physiology, Sarcoma, Kaposi etiology
- Abstract
Basic fibroblast growth factor (bFGF) and human immunodeficiency virus type 1 (HIV-1) Tat protein synergize in inducing angiogenic Kaposi's sarcoma-like lesions in mice. Synergy is due to Tat, which enhances endothelial cell growth and type-IV collagenase expression in response to bFGF mimicking extracellular matrix proteins. The bFGF, extracellular Tat and Tat receptors are present in HIV-1-associated KS, which may explain the higher frequency and aggressiveness of this form compared to classical Kaposi's sarcoma where only bFGF is present.
- Published
- 1994
- Full Text
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47. Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation.
- Author
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Ensoli B, Buonaguro L, Barillari G, Fiorelli V, Gendelman R, Morgan RA, Wingfield P, and Gallo RC
- Subjects
- Animals, Biological Transport, Cell Compartmentation, Cell Line, Dose-Response Relationship, Drug, Gene Products, tat pharmacology, HIV Long Terminal Repeat genetics, HIV-1 genetics, Humans, Recombinant Proteins metabolism, Recombinant Proteins pharmacology, Regulatory Sequences, Nucleic Acid, Sarcoma, Kaposi metabolism, T-Lymphocytes drug effects, Transfection, tat Gene Products, Human Immunodeficiency Virus, Cell Communication, Gene Products, tat metabolism, HIV-1 metabolism, T-Lymphocytes microbiology, Transcriptional Activation drug effects
- Abstract
During acute human immunodeficiency virus type 1 (HIV-1) infection or after transfection of the tat gene, Tat protein is released into the cell culture supernatant. In this extracellular form, Tat stimulates both HIV-1 gene expression and the growth of cells derived from Kaposi's sarcoma (KS) lesions of HIV-1-infected individuals (AIDS-KS cells). Tat protein and its biological activities appear in the cell supernatants at the peak of Tat expression, when the rate of cell death is low (infection) or cell death is undetectable (transfection) and increased levels of cytoplasmic Tat are present. Tat-containing supernatants stimulate maximal AIDS-KS cell growth but only low to moderate levels of HIV-1 gene expression. This is due to the different concentrations of exogenous Tat required for the two effects. The cell growth-promoting effects of Tat peak at between 0.1 and 1 ng of purified recombinant protein per ml in the cell growth medium and do not increase with concentration. In contrast, both the detection of nuclear-localized Tat taken up by cells and the induction of HIV-1 gene expression or replication require higher Tat concentrations (> or = 100 ng/ml), and all increase linearly with increasing amounts of the exogenous protein. These data suggest that Tat can be released by a mechanism(s) other than cell death and that the cell growth-promoting activity and the virus-transactivating effect of extracellular Tat are mediated by different pathways.
- Published
- 1993
- Full Text
- View/download PDF
48. Silent HIV infection.
- Author
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Aiuti F, Ensoli F, Fiorelli V, Mezzaroma I, Pinter E, Guerra E, and Varani AR
- Subjects
- Blotting, Western, DNA, Viral analysis, Enzyme-Linked Immunosorbent Assay, HIV Infections immunology, HIV-1 isolation & purification, HIV-1 physiology, Humans, Lymphocytes microbiology, Polymerase Chain Reaction, Prospective Studies, Risk Factors, Substance Abuse, Intravenous, Viremia, HIV Antibodies blood, HIV Infections microbiology, HIV Seropositivity, HIV-1 immunology
- Abstract
The period of latency between infection by the human immunodeficiency virus type-1 (HIV-1) and the production of specific antibodies to viral antigens may be prolonged and, occasionally, may last for years. This condition of seronegative infection could represent a serious risk of viral transmission from subjects who are unaware of their status. However, whether these individuals are actually infectious, especially through body fluids, has not been clarified. We have performed a prospective study in 65 high-risk individuals seronegative for HIV-1 antibodies for a prolonged period of time. Twelve of them (18%) were shown to be carriers of HIV-1 proviral sequences by the polymerase chain reaction (PCR). The virus was isolated from mitogen-stimulated peripheral blood lymphocytes in five out of ten subjects tested since the first positive PCR. In two of them, virus could also be isolated from cell-free plasma, subsequently they remained seronegative during 10 months of follow-up. These data indicate that delayed seroconversions may be associated with productive infection, suggesting that mechanism(s) other than viral latency may be responsible for the absence of antibody responses to HIV-1 proteins. Furthermore, our findings suggest that prolonged seronegative individuals can transmit HIV infection through their body fluids.
- Published
- 1993
- Full Text
- View/download PDF
49. Effects of cytokines from activated immune cells on vascular cell growth and HIV-1 gene expression. Implications for AIDS-Kaposi's sarcoma pathogenesis.
- Author
-
Barillari G, Buonaguro L, Fiorelli V, Hoffman J, Michaels F, Gallo RC, and Ensoli B
- Subjects
- Cell Division, Cells, Cultured, Gene Expression Regulation, Viral drug effects, Gene Products, tat pharmacology, HTLV-II Infections pathology, Humans, In Vitro Techniques, Lymphocyte Activation, Virus Replication drug effects, tat Gene Products, Human Immunodeficiency Virus, Cytokines pharmacology, Endothelium, Vascular cytology, HIV-1 genetics, Muscle, Smooth, Vascular cytology, Sarcoma, Kaposi pathology, T-Lymphocytes physiology
- Abstract
Kaposi's sarcoma (KS) arises more frequently in homosexual and bisexual men than in other groups of HIV-1 infected individuals. Clinico-epidemiologic data indicate that homosexuals often are infected with multiple microbial agents and/or subjected to other antigenic stimuli, preceding or accompanying HIV-1 infection. Signs of immune activation, in fact, frequently have been detected in these individuals, and the onset of KS can precede any sign of immunodeficiency. These data have suggested that products from activated immune cells may affect the development of AIDS-KS. Here we report that conditioned media from activated or dysregulated T cells contain a variety of cytokines that promote the growth of spindle cells derived from KS lesions of AIDS patients (AIDS-KS cells) and induce normal vascular cells, potential cell progenitors of the AIDS-KS cells, to acquire features of the KS cell phenotype ("spindle" cell morphology and growth responsiveness to the mitogenic effect of extracellular HIV-1 Tat protein). The same conditioned media or cytokines promote HIV-1 gene expression and rescue defective HIV-1 proviruses, interrupting HIV-1 latency and increasing Tat production. The cellular and viral effects of cytokines are increased in an additive or synergistic manner by picomolar concentrations of extracellular Tat. These data suggest that cytokines produced by activated immune cells cooperate with HIV-1 infection in AIDS-KS pathogenesis.
- Published
- 1992
50. Plasma viraemia in seronegative HIV-1-infected individuals.
- Author
-
Ensoli F, Fiorelli V, Mezzaroma I, D'Offizi G, Rainaldi L, Luzi G, Fiorilli M, and Aiuti F
- Subjects
- DNA, Viral blood, Female, HIV Infections etiology, HIV Infections transmission, HIV Seropositivity immunology, HIV-1 isolation & purification, Humans, Male, Polymerase Chain Reaction, Prospective Studies, Risk Factors, Sexual Behavior, Substance-Related Disorders complications, Blood Cells microbiology, HIV Infections microbiology, HIV Seropositivity microbiology, HIV-1 pathogenicity, Viremia
- Abstract
It has been reported that the period of latency between HIV-1 infection and the production of antibodies against the virus is sometimes prolonged for greater than 6 months. However, the data supporting this are still controversial and it is not known whether these individuals are actually infectious, especially through body fluids. We have performed a prospective study of 65 high-risk HIV-1-antibody-negative individuals who were followed-up for a period of at least 1 year. Twelve of these individuals were shown by polymerase chain reaction (PCR) to be carriers of HIV-1 proviral sequences. The virus was isolated from lymphocytes in five out of 10 PCR-positive subjects and from cell-free plasma in two. Our data indicate that in some cases delayed seroconversions may be associated with productive infection, suggesting that mechanism(s) other than viral latency may be responsible for the absence of antibody responses to HIV-1 proteins.
- Published
- 1991
- Full Text
- View/download PDF
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