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Ahlers J.D.,Vaccine and Gene Therapy Institute of Florida
Discovery Medicine | Year: 2014

HIV-1 broadly neutralizing antibodies (BNAbs) develop after several years of infection through a recursive process of memory B cell adaptation and maturation against co-evolving virus quasispecies. Advances in single-cell sorting and memory B cell antibody cloning methods have identified many new HIV BNAbs targeting conserved epitopes on the HIV envelope (env) protein. 3D crystal structures and biophysical analyses of BNAbs bound to invariant virus structures expressed on monomeric gp120, epitope scaffolds, core structures, and native trimers have helped us to visualize unique binding interactions and paratope orientations that have been instrumental in guiding vaccine design. A paradigm shift in the approach to structure-based design of HIV-1 envelope immunogens came recently after several laboratories discovered that native viral envelopes or "env-structures" reverse-engineered to bind with high affinity to a handful of broadly neutralizing antibodies did not in fact bind the predicted germline precursors of these broadly neutralizing antibodies. A major challenge for HIV-1 B cell vaccine development moving forward is the design of new envelope immunogens that can trigger the selection and expansion of germline precursor and intermediate memory B cells to recapitulate B cell ontogenies associated with the maturation of a broadly neutralizing antibody response. Equally important for vaccine development is the identification of delivery systems, prime-boost strategies, and synergistic adjuvant combinations that can induce the magnitude and quality of antigen-specific T follicular helper (TFH) cell responses needed to drive somatic hypermutation (SHM) and B cell maturation against heterologous primary virus envelopes. Finding the combination of multi-protein envelope immunogens and immunization strategies that can evolve a potent broadly neutralizing antibody response portends to require a complex vaccine regimen that might be difficult to implement on any scale. This perspective strives to integrate recent insights into mechanisms associated with the evolution of an HIV-1 broadly neutralizing antibody response with current immunogen design and proffers a novel immunization strategy for skewing TH17/TFH cell responses that can drive B cell adaptation and affinity maturation associated with a broadly neutralizing antibody response. © Discovery Medicine.

Cubas R.,Vaccine and Gene Therapy Institute of Florida | Perreau M.,University of Lausanne
Current Opinion in HIV and AIDS | Year: 2014

PURPOSE OF REVIEW: T follicular helper (Tfh) cells play a critical role as providers of B-cell help and dysfunction in Tfh/B-cell interactions can lead to autoimmunity or immunodeficiency. These observations have generated a great deal of interest in understanding how these cells are affected during HIV infection and how their functional changes might affect antibody responses. RECENT FINDINGS: Recent studies have shown that HIV/simian immunodeficiency virus (SIV) infection affects both Tfh-cell frequency and function and suggest that Tfh-cell perturbations might contribute to the relative inefficiency of HIV-infected individuals to generate broadly neutralizing antibodies (bNAbs). SUMMARY: The present review will highlight these recent findings addressing the role of Tfh cells in HIV infection as well as the impact HIV infection has on Tfh and circulating memory Tfh (cTfh) cell frequency and function. © 2014 Wolters Kulwer Health.

Noto A.,Vaccine and Gene Therapy Institute of Florida
Journal of visualized experiments : JoVE | Year: 2013

Cytolytic activity of CD8+ T cells is rarely evaluated. We describe here a new cell-based assay to measure the capacity of antigen-specific CD8+ T cells to kill CD4+ T cells loaded with their cognate peptide. Target CD4+ T cells are divided into two populations, labeled with two different concentrations of CFSE. One population is pulsed with the peptide of interest (CFSE-low) while the other remains un-pulsed (CFSE-high). Pulsed and un-pulsed CD4+ T cells are mixed at an equal ratio and incubated with an increasing number of purified CD8+ T cells. The specific killing of autologous target CD4+ T cells is analyzed by flow cytometry after coculture with CD8+ T cells containing the antigen-specific effector CD8+ T cells detected by peptide/MHCI tetramer staining. The specific lysis of target CD4+ T cells measured at different effector versus target ratios, allows for the calculation of lytic units, LU30/10(6) cells. This simple and straightforward assay allows for the accurate measurement of the intrinsic capacity of CD8+ T cells to kill target CD4+ T cells.

Yu H.,Beckman Research Institute | Lee H.,Beckman Research Institute | Herrmann A.,Beckman Research Institute | Buettner R.,Beckman Research Institute | Jove R.,Vaccine and Gene Therapy Institute of Florida
Nature Reviews Cancer | Year: 2014

The Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) proteins, particularly STAT3, are among the most promising new targets for cancer therapy. In addition to interleukin-6 (IL-6) and its family members, multiple pathways, including G-protein-coupled receptors (GPCRs), Toll-like receptors (TLRs) and microRNAs were recently identified to regulate JAK-STAT signalling in cancer. Well known for its role in tumour cell proliferation, survival, invasion and immunosuppression, JAK-STAT3 signalling also promotes cancer through inflammation, obesity, stem cells and the pre-metastatic niche. In addition to its established role as a transcription factor in cancer, STAT3 regulates mitochondrion functions, as well as gene expression through epigenetic mechanisms. Newly identified regulators and functions of JAK-STAT3 in tumours are important targets for potential therapeutic strategies in the treatment of cancer. © 2014 Macmillan Publishers Limited. All rights reserved.

Belgnaoui S.M.,Lady Davis Institute for Medical Research | Belgnaoui S.M.,McGill University | Paz S.,Lady Davis Institute for Medical Research | Paz S.,McGill University | And 2 more authors.
Current Opinion in Immunology | Year: 2011

Sensing of RNA virus infection by the RIG-I-like receptors (RLRs) engages a complex signaling cascade that utilizes the mitochondrial antiviral signaling (MAVS) adapter protein to orchestrate the innate host response to pathogen, ultimately leading to the induction of antiviral and inflammatory responses mediated by type I interferon (IFN) and NF-κB pathways. MAVS is localized to the outer mitochondrial membrane, and has been associated with peroxisomes, the endoplasmic reticulum and autophagosomes, where it coordinates signaling events downstream of RLRs. MAVS not only plays a pivotal role in the induction of antiviral and inflammatory pathways but is also involved in the coordination of apoptotic and metabolic functions. This review summarizes recent findings related to the MAVS adapter and its essential role in the innate immune response to RNA viruses. © 2011 Elsevier Ltd.

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