Inhibition of cervical cancer cell growth in vitro and in vivo with dual shRNAs

RNA interference (RNAi)-based gene silencing is widely used in laboratories for gene function studies and also holds a great promise for developing treatments for diseases. However, in vivo delivery of RNAi therapy remains a key issue. Lentiviral vectors have been employed for stable gene transfer and gene therapy and therefore are expected to deliver a stable and durable RNAi therapy. But this does not seem to be true in some disease models. Here, we showed that lentivirus delivered short-hairpin RNA (shRNA) against human papillomavirus (HPV) E6/E7 oncogenes were effective for only 2 weeks in a cervical cancer model. However, using this vector to carry two copies of the same shRNA or two shRNAs targeting at two different but closely related genes (HPV E6 and vascular endothelial growth factor) was more effective at silencing the gene targets and inhibiting cell or even tumor growth than their single shRNA counterparts. The cancer cells treated with dual shRNA were also more sensitive to chemotherapeutic drugs than single shRNA-treated cells. These results suggest that a multi-shRNA strategy may be a more attractive approach for developing an RNAi therapy for this cancer. Cancer Gene Therapy (2011) 18, 219-227; doi: 10.1038/cgt.2010.72; published online 19 November 201

A prophylactic and therapeutic AIDS vaccine containing as a component the innocuous Tat toxoid

Extracellular Tat can act as a viral toxin on uninfected cells of different tissues, including the CNS and the immune system, thus in order to immunize humans against Tat we have prepared a biologically inactivated but immunogenic Tat (Tat Toxoid). Tat Toxoid is not toxic in mice even at high doses. It triggers high levels of specific Tat Abs in the mouse and rabbit. Furthermore, in humans Tat Toxoid immunization was safe and induced in seronegatives persistent high levels of Tat Abs and in immunodeficient patients a significant rise of these specific Abs. Facing acute HIV-1 infection, the presence of high level of circulating Tat Abs promoted by Tat Toxoid vaccine should prevent Tat-induced immunosuppression and allow anti-HIV-1 cellular response to develop. As a consequence, early release of beta-chemokines could enhance host resistance towards HIV-1, and, in infected people, inhibit viral replication and evolution towards AID

Induction in mice of anti-Tat mucosal immunity by the intranasal and oral routes

Anti-Tat vaccination experiments were carried out in mice with a view to inducing systemic in addition to mucosal immunity. For this. three types of immunizing preparations were tested, which consisted of Tat toroid embedded in either an adjuvant oily structure (IMS), or nanoparticles of chitosan, or microparticles of polylactide-co-glycolide (PLG). Administered by either the intranasal or oral route all preparations triggered anti-Tat IgG and IgA antibodies. Sera from mice immunized with either of these preparations could also inhibit significantly the Tat transactivating activity. These results open up a new avenue to the development of an effective anti-AIDS protective vaccine. (C) 2001 Editions scientifiques et medicates Elsevier SAS

Clinical efficacy of selective JAK1 inhibition and transcriptome analysis of chronic discoid lupus erythematosus

International audienc

Anti-IFNα immunization raises the IFNα-neutralizing capacity of serum - An adjuvant to antiretroviral tritherapy

HAART (highly active antiretroviral therapy) suppresses but does not eradicate HIV-1 infection. However since the antiretroviral agents used in HAART may also be toxic in the long-term, immunotherapies which correct HIV- 1 immunosuppression or the cytokine dysregulation associated with it may be beneficial. In this respect, a double blind multicentric placebo-controlled phase II/III anti-IFNα vaccine trial has been carried out on 242 HIV-1 patients, the majority of whom were undergoing HAART treatment. In vaccinated patients (vaccinees) who responded to immunization by increased levels of IFNα Abs (whether under HAART or not) when compared to placebo or non- responder vaccinees, a strong correlation was found between an increased IFNα neutralizing capacity and the reduction of clinical manifestations.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Identification of immunodominant epitopes in inactivated tat-vaccinated healthy and HIV-1-infected volunteers

We analyzed the epitopes and the molecular forms of Tat recognized by the antibodies raised by Tat-toxoid vaccination in both healthy and HIV-infected volunteers. Tat-toxoid - vaccinated healthy volunteer sera reacted predominantly with peptides covering amino acids 1 through 24 and 46 through 60, corresponding to the N-terminus and basic domains of Tat. In contrast, whereas all sera from vaccinated HIV-1 - positive patients reacted with the N-terminus and (with a single exception) with the basic domain, most of these sera also recognized peptides encompassing distinct domains of Tat, particularly the C-terminus (79-86). The sera of vaccinated individuals recognized both monomeric and oligomeric forms of Tat 1 through 86 or of Tat 1 through 101 and also blocked the ability of cell-released extracellular Tat to transactivate the HIV-1 LTR promoter. Synthetic Tat preincubated with sera from vaccinated individuals lost its functional activity as well. This is probably because of its inability to enter the cells as a result of immune complex formation with anti-Tat IgG. These data demonstrate that Tat-toxoid vaccination induces an efficient antibody response blocking the functional activity of Tat