Clelia Palladino - Academia.edu (original) (raw)

Papers by Clelia Palladino

The Journal of Immunology

The Tat protein of HIV-1, a transactivator of viral gene expression, is released by acutely infec... more The Tat protein of HIV-1, a transactivator of viral gene expression, is released by acutely infected T cells and, in this form, exerts angiogenic activities. These have linked the protein to the pathogenesis of Kaposi’s sarcoma (KS), a vascular tumor frequent and aggressive in HIV-1-infected individuals (AIDS-KS). In this study, we show that a combination of the same inflammatory cytokines increased in KS lesions, namely IL-1β, TNF-α, and IFN-γ, synergizes with Tat to promote in nude mice the development of angioproliferative KS-like lesions that are not observed with each factor alone. Inflammatory cytokines induce the tissue expression of both basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), two angiogenic molecules highly produced in primary KS lesions. However, bFGF, but not VEGF, synergizes with Tat in vivo and induces endothelial cells to migrate, to adhere, and to grow in response to Tat in vitro. Tat angiogenic effects correlate with the e...

Molecular Cancer Therapeutics

Antiretrovirals belonging to the human immunodeficiency virus (HIV) protease inhibitor (HIV-PI) c... more Antiretrovirals belonging to the human immunodeficiency virus (HIV) protease inhibitor (HIV-PI) class exert inhibitory effects across several cancer types by targeting tumor cells and its microenvironment. Cervical carcinoma represents a leading cause of morbidity and mortality, particularly in women doubly infected with high-risk human papillomaviruses (HR-HPV) and HIV; of note, combined antiretroviral therapy has reduced cervical carcinoma onset and progression in HIV-infected women. We evaluated the effectiveness and mechanism(s) of action of HIV-PI against cervical carcinoma using a transgenic model of HR-HPV–induced estrogen-promoted cervical carcinoma (HPV16/E2) and found that treatment of mice with ritonavir-boosted HIV-PI, including indinavir, saquinavir, and lopinavir, blocked the growth and promoted the regression of murine cervical carcinoma. This was associated with inhibition of tumor angiogenesis, coupled to downregulation of matrix metalloproteinase (MMP)-9, reduction...

International Journal of Molecular Sciences, 2022

Kaposi’s sarcoma (KS) is an angioproliferative tumor showing an increased frequency and aggressiv... more Kaposi’s sarcoma (KS) is an angioproliferative tumor showing an increased frequency and aggressiveness in HIV-infected subjects (AIDS-KS), due to the combined effects of inflammatory cytokines (IC), angiogenic factors, and the HIV-1 Tat protein. While the introduction of effective combined antiretroviral regimens greatly improved AIDS-KS incidence and course, it continues to be an incurable disease and the development of new rational targeted therapies is warranted. We used the BKV/Tat transgenic mouse model to evaluate the effects of IC and anti-Tat antibodies (Abs) treatment on KS-like lesions arising in BKV/Tat mice. We demonstrated here that IC-treatment increases the severity and delays the regression of KS-like lesions. Further, anti-Tat Abs reduced KS-like lesion severity developing in IC-treated mice when anti-Tat Abs were administered at an early-stage of lesion development as compared to more advanced lesions. Early anti-Tat Abs treatment also accelerated KS-like lesion re...

International Journal of Molecular Sciences, 2020

Previous work has shown that the Tat protein of Human Immunodeficiency Virus (HIV)-1 is released ... more Previous work has shown that the Tat protein of Human Immunodeficiency Virus (HIV)-1 is released by acutely infected cells in a biologically active form and enters dendritic cells upon the binding of its arginine-glycine-aspartic acid (RGD) domain to the α5β1, αvβ3, and αvβ5 integrins. The up-regulation/activation of these integrins occurs in endothelial cells exposed to inflammatory cytokines that are increased in HIV-infected individuals, leading to endothelial cell dysfunction. Here, we show that inflammatory cytokine-activated endothelial cells selectively bind and rapidly take up nano-micromolar concentrations of Tat, as determined by flow cytometry. Protein oxidation and low temperatures reduce Tat entry, suggesting a conformation- and energy-dependent process. Consistently, Tat entry is competed out by RGD-Tat peptides or integrin natural ligands, and it is blocked by anti-α5β1, -αvβ3, and -αvβ5 antibodies. Moreover, modelling–docking calculations identify a low-energy Tat-αv...

Oncology Letters, 2017

A reduced incidence and decreased clinical progression of uterine cervical intraepithelial neopla... more A reduced incidence and decreased clinical progression of uterine cervical intraepithelial neoplasia (CIN) has been observed in women infected with human immunodeficiency virus (HIV) treated with HIV-protease inhibitors (PIs). The HIV-PIs saquinavir (SQV) and ritonavir (RTV) have been demonstrated to efficiently inhibit invasion of human primary CIN cells by downregulating the expression of matrix metalloproteinase (MMP)-9. The present study further investigated the molecular mechanisms underlying the activity of SQV and RTV in CIN. The results of the present study indicate that the treatment of human primary CIN

Oncology Letters, 2016

The infection of uterine cervical epithelial cells by oncogenic, high-risk human papilloma viruse... more The infection of uterine cervical epithelial cells by oncogenic, high-risk human papilloma viruses (HR-HPVs) may lead to the development of cervical carcinoma. Of note, the incidence of this tumor is significantly increased in women infected by both HR-HPV and human immunodeficiency virus (HIV)-1. In this regard, previous studies have linked the HIV-1 Tat protein, a trans-activator of viral gene expression, to the pathogenesis of HIV-associated malignancies. In particular, it has been shown that upon its release by acutely infected cells, Tat protein can enter human cells, thus modifying their phenotype. Based on these findings, the present study evaluated whether extracellular Tat protein could be taken up by human uterine cervical carcinoma cells, and whether this could affect the expression of HPV (E6 or E7) or cellular (p16 or p53) molecules, which are key to cervical carcinoma development or progression. The results indicated that extracellular, biologically active HIV-1 Tat protein is taken up by human uterine cervical carcinoma cells, and that this is followed by an increase in the expression of the E6 protein of HPV, and by a reduction in the protein levels of the cellular oncosuppressor p53. Since p53 loss is associated with cell dedifferentiation and immortalization, these findings suggest a possible link between extracellular Tat protein and the high incidence and clinical aggressiveness of uterine cervical carcinoma observed in HIV/HPV doubly infected women.

Journal of HIV therapy, 2006

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Recenti progressi in medicina, 2003

A reduced incidence or the regression of Kaposi's sarcoma (KS) has been described in HIV-infe... more A reduced incidence or the regression of Kaposi's sarcoma (KS) has been described in HIV-infected patients treated with HIV-protease inhibitors (PI). We have recently demonstrated that PI block the angiogenesis and the development of KS lesions induced experimentally in vivo by the inoculation of angiogenic factors or human primary KS cells. These effects of PI occur at the same drug concentrations in plasma of treated individuals, and they are due to the inhibition of cell invasion and of the activation of matrix metalloprotease-2, an enzyme that is key to angiogenesis and tumor growth and invasion. Since PI also block the production of cytokines involved in KS initiation and maintenance, this anti-inflammatory activity of PI may also contribute to the anti-KS effects observed in treated individuals. Thus, by direct and indirect activities PI can simultaneously block several pathways involved in tumor growth, invasion or metastasis. These data indicate that PI should also be in...

PLoS ONE, 2012

Use of Env in HIV vaccine development has been disappointing. Here we show that, in the presence ... more Use of Env in HIV vaccine development has been disappointing. Here we show that, in the presence of a biologically active Tat subunit vaccine, a trimeric Env protein prevents in monkeys virus spread from the portal of entry to regional lymph nodes. This appears to be due to specific interactions between Tat and Env spikes that form a novel virus entry complex favoring R5 or X4 virus entry and productive infection of dendritic cells (DCs) via an integrin-mediated pathway. These Tat effects do not require Tat-transactivation activity and are blocked by anti-integrin antibodies (Abs). Productive DC infection promoted by Tat is associated with a highly efficient virus transmission to T cells. In the Tat/Env complex the cysteine-rich region of Tat engages the Env V3 loop, whereas the Tat RGD sequence remains free and directs the virus to integrins present on DCs. V2 loop deletion, which unshields the CCR5 binding region of Env, increases Tat/Env complex stability. Of note, binding of Tat to Env abolishes neutralization of Env entry or infection of DCs by anti-HIV sera lacking anti-Tat Abs, which are seldom present in natural infection. This is reversed, and neutralization further enhanced, by HIV sera containing anti-Tat Abs such as those from asymptomatic or Tat-vaccinated patients, or by sera from the Tat/Env vaccinated monkeys. Thus, both anti-Tat and anti-Env Abs are required for efficient HIV neutralization. These data suggest that the Tat/Env interaction increases HIV acquisition and spreading, as a mechanism evolved by the virus to escape anti-Env neutralizing Abs. This may explain the low effectiveness of Env-based vaccines, which are also unlikely to elicit Abs against new Env epitopes exposed by the Tat/Env interaction. As Tat also binds Envs from different clades, new vaccine strategies should exploit the Tat/Env interaction for both preventative and therapeutic interventions.

Nature Medicine, 2002

Kaposi sarcoma (KS) is an angio-proliferative disease characterized by angiogenesis, endothelial ... more Kaposi sarcoma (KS) is an angio-proliferative disease characterized by angiogenesis, endothelial spindle-cell growth (KS cells), inflammatory-cell infiltration and edema 1,2. KS is associated with human herpesvirus 8 (HHV8) infection, and is particularly frequent and aggressive in HIV-1/HHV8 co-infected individuals (AIDS-KS) 1-3. KS development is associated with HHV8 reactivation and spread to blood and tissues. Reactivation, in turn, is induced by Th-1 type cytokines (interferon-γ, interleukin-1β and tumor necrosis factor-α) that are increased in KS patients or in at-risk individuals 1,2,4. Inflammatory cytokines (ICs) also activate vessels promoting the tissue extravasation of infected lympho-monocytes and spindle-cell progenitors 1,2. In early-developing lesions, HHV8 load is low or undetectable whereas it is high in late-nodular lesions, which mostly show latent infection 1,2,5. This finding suggests that HHV8 may have a key role in KS progression to a frank tumor as latently expressed viral genes may induce cell transformation 2 , a feature observed in some late-nodular AIDS-KS lesions 6. Increase of ICs can also induce production of angiogenic factors and other molecules that initiate lesion formation, as observed in HIV-1infected individuals that develop KS or show KS progression after systemic administration of interferon-γ and interleukin-2 or tumor necrosis factor-α 7. Other studies confirm that high HHV8 burden and expression of ICs and angiogenic factors are found in all forms of KS (refs. 1,2,7). Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are the most highly expressed angiogenic factors 8-10. They are also increased in sera of KS patients or in at-risk individuals 11,12 , and are expressed in early lesions by KS cells, endothelial cells and infiltrating cells in response to ICs (refs. 1,7,8,10,13,14). bFGF promotes in autocrine fashion the growth of KS cells and synergizes with VEGF to mediate the development of angioproliferative KS-like lesions induced by the inoculation of KS cells in nude mice 8,10,13,15-17. Such KSlike lesions are composed of mouse cells and are induced by the factors produced by KS cells, and they are highly vascularized, closely resemble early KS and regress as KS regresses in humans 1,7. Conversely, inoculation with bFGF in nude mice and its in vivo induction with ICs reproduces the vascular lesions promoted in mice by the inoculation of KS cells and those found in human KS (refs. 8,14). Finally, bFGF synergizes with the HIV-1 Tat protein released by infected cells and increases the frequency and aggressiveness of KS in HIV-1-infected individuals 8,18,19. Thus, bFGF and VEGF are crucial to the development and progression of all forms of KS as well as to the growth of solid tumors 20. Recent reports have described a reduced incidence 21 or the regression 22,23 of KS in HIV-1-infected patients treated with highly active antiretroviral therapy (HAART) that includes at least one HIV-protease inhibitor (PI) such as indinavir or saquinavir 24. PIs have also been shown to directly affect cell metabolism, interfere with host or fungal proteases and block T-cell activation and dendritic-cell function 25,32 , even though they were designed to selectively interfere with the catalytic site of HIV protease 24. Given that proteases are also essential for angiogenic and inflammatory processes and for tumor growth, we reasoned that at least part of the lower incidence and regression of KS observed in PI-treated patients resulted

Molecular Biology of the Cell, 2001

Previous studies indicated that the Tat protein of human immunodeficiency virus type-1 (HIV-1) is... more Previous studies indicated that the Tat protein of human immunodeficiency virus type-1 (HIV-1) is a progression factor for Kaposi's sarcoma (KS). Specifically, extracellular Tat cooperates with basic fibroblast growth factor (bFGF) in promoting KS and endothelial cell growth and locomotion and in inducing KS-like lesions in vivo. Here we show that Tat and bFGF combined increase matrix-metalloproteinase-2 (MMP-2) secretion and activation in endothelial cells in an additive/synergistic manner. These effects are due to the activation of the membrane-type-1-matrix-metalloproteinase and to the induction of the membrane-bound tissue inhibitor of metalloproteinase-2 (TIMP-2) by Tat and bFGF combined, but also to Tat-mediated inhibition of both basal or bFGF-induced TIMP-1 and -2 secretion. Consistent with this, Tat and bFGF promote vascular permeability and edema in vivo that are blocked by a synthetic MMP inhibitor. Finally, high MMP-2 expression is detected in acquired immunodeficien...

Journal of Virology, 2007

It was previously reported that human immunodeficiency virus type 1 (HIV-1) spreads in CD4 lympho... more It was previously reported that human immunodeficiency virus type 1 (HIV-1) spreads in CD4 lymphocytes through cell-to-cell transmission. Here we report that HIV-1-infected macrophages, but not lymphocytes, transmit HIV-1 products to CD4-negative cells of either epithelial, neuronal, or endothelial origin in the absence of overt HIV-1 infection. This phenomenon was detectable as early as 1 h after the start of cocultivation and depended on cell-to-cell contact but not on the release of viral particles from donor cells. Transfer of HIV-1 products occurred upon their polarization and colocalization within zones of cell-to-cell contact similar to virological synapses. Neither HIV-1 Env nor Nef expression was required but, interestingly, we found that an HIV-1-dependent increase in matrix metalloproteinase 9 production from donor cells significantly contributed to the cell-to-cell transmission of the viral products. The macrophage-driven transfer of HIV-1 products to diverse CD4-negativ...

The Journal of Immunology, 2000

Kaposi’s sarcoma (KS) is an angioproliferative disease characterized by proliferation of spindle-... more Kaposi’s sarcoma (KS) is an angioproliferative disease characterized by proliferation of spindle-shaped cells predominantly of endothelial cell origin, neoangiogenesis, inflammatory cell infiltration, and edema. At least in early stage, KS behaves as a reactive lesion sustained by the action of inflammatory cytokines and growth factors, has a polyclonal nature, and can regress. However, in time it can become monoclonal, especially in the nodular stage, evolving into a true sarcoma, likely in association with the increased expression of antiapoptotic oncogenes. We have recently demonstrated by immunohistochemical analysis that Bcl-2, a proto-oncogene known to prolong cellular viability and to antagonize apoptosis, is highly expressed in spindle cells and vessels of both AIDS-KS and classical KS lesions and that its expression increases with lesion stage. Paclitaxel, a microtubule-stabilizing drug known to inhibit Bcl-2 antiapoptotic activity and to be highly effective in the treatmen...

JAIDS: Journal of Acquired Immune Deficiency Syndromes, 1999

Anti-Cancer Drugs, 2002

Kaposi's sarcoma (KS) is an angioproliferative disease of multifactorial origin arising in di¡ere... more Kaposi's sarcoma (KS) is an angioproliferative disease of multifactorial origin arising in di¡erent clinic-epidemiologic forms, which show the same histopathological features. It generally starts as a hyperplastic reactive-in£ammatory and angiogenic process, which may evolve into monomorphic nodules of KS cells that can be clonal (late-stage lesions) and resemble a true sarcoma. Infection with the human herpesvirus 8, cytokine-and angiogenic factor-induced growth together with an immuno-dysregulated state represent fundamental conditions for the development of this tumor. Several local therapies are used to eradicate early and con¢ned skin lesions, whereas widely disseminated, progressive or symptomatic disease requires a more aggressive treatment. Although di¡erent chemotherapeutic agents have been used to treat aggressive KS, the growing understanding of the pathogenetic factors participating in KS development has provided a strong rationale for using less-or non-cytotoxic agents that block the mechanisms involved in KS pathogenesis. The angiogenic nature of KS makes it particularly suitable for using therapies based on anti-angiogenic agents. Of note on this goal, recent studies indicate that the highly active anti-retroviral therapy, including at least one human immunode¢ciency virus (HIV) protease inhibitor (PI), is associated with a dramatic decrease in the incidence of AIDS-KS and with a regression of KS in treated individuals. Consistent with this, results from preclinical studies indicate that PIs have potent and direct anti-angiogenic and anti-KS activities, suggesting that they should be further investigated, alone or combined with other therapies, as a novel treatment for KS in both HIV seropositive or seronegative individuals. [r 2002 Lippincott Williams & Wilkins.]

AIDS, 2012

Objective and design: Treatment of human immunodeficiency virus (HIV)-infected women with the hig... more Objective and design: Treatment of human immunodeficiency virus (HIV)-infected women with the highly active antiretroviral therapy (HAART) has reduced the onset of uterine cervical intraepithelial neoplasia (CIN), and halted its progression to cervical carcinoma. We and others demonstrated that the HIV protease inhibitors (HIV-PIs) used in HAART can exert direct antitumour activities also in HIV-free preclinical or clinical models. As uterine cervical carcinoma is a leading cause of death in women independently of HIV infection, herein we assessed the impact of therapeutic concentrations of HIV-PIs including indinavir (IDV), saquinavir (SQV) or ritonavir (RTV) on cells obtained from CIN or cervical carcinoma lesions of HIV-negative women. Methods: HIV-PI effects were evaluated by cell invasion, growth or toxicity assays, and by RNA, protein or zymogram analyses. Results: Both SQV and RTV inhibited CIN cell invasion, and this was paralleled by a reduced expression and proteolytic activity of the matrix metalloproteinase (MMP)-2 and 9 in treated cells. SQV and RTV also reduced CIN cell growth rate, but did not affect the invasion or growth of cells derived from highly progressed cervical carcinoma. Conclusion: As MMP-2 and MMP-9 have a key role in CIN evolution into cervical carcinoma, these results support the use of SQV or RTV for the block of CIN clinical progression in either HIV-infected or uninfected patients.