scholarly journals Env-Expressing Autologous T Lymphocytes Induce Neutralizing Antibody and Afford Marked Protection against Feline Immunodeficiency Virus

2010 ◽  
Vol 84 (8) ◽  
pp. 3845-3856 ◽  
Author(s):  
Mauro Pistello ◽  
Francesca Bonci ◽  
Elisa Zabogli ◽  
Francesca Conti ◽  
Giulia Freer ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Feline Immunodeficiency Virus ◽  
Cd4 T Cells ◽  
Neutralizing Antibodies ◽  
Ex Vivo ◽  
Neutralizing Antibody ◽  
Viral Loads ◽  
Immunodeficiency Virus ◽  
Specific Pathogen

ABSTRACT The envelope (Env) glycoproteins of HIV and other lentiviruses possess neutralization and other protective epitopes, yet all attempts to induce protective immunity using Env as the only immunogen have either failed or afforded minimal levels of protection. In a novel prime-boost approach, specific-pathogen-free cats were primed with a plasmid expressing Env of feline immunodeficiency virus (FIV) and feline granulocyte-macrophage colony-stimulating factor and then boosted with their own T lymphocytes transduced ex vivo to produce the same Env and interleukin 15 (3 × 106 to 10 × 106 viable cells/cat). After the boost, the vaccinees developed elevated immune responses, including virus-neutralizing antibodies (NA). Challenge with an ex vivo preparation of FIV readily infected all eight control cats (four mock vaccinated and four naïve) and produced a marked decline in the proportion of peripheral CD4 T cells. In contrast, five of seven vaccinees showed little or no traces of infection, and the remaining two had reduced viral loads and underwent no changes in proportions of CD4 T cells. Interestingly, the viral loads of the vaccinees were inversely correlated to the titers of NA. The findings support the concept that Env is a valuable immunogen but needs to be administered in a way that permits the expression of its full protective potential.

scholarly journals Adoptive Immunotherapy of Feline Immunodeficiency Virus with Autologous Ex Vivo-Stimulated Lymphoid Cells Modulates Virus and T-Cell Subsets in Blood

2005 ◽  
Vol 12 (6) ◽  
pp. 736-745 ◽  
Author(s):  
J. Norman Flynn ◽  
Mauro Pistello ◽  
Patrizia Isola ◽  
Lucia Zaccaro ◽  
Barbara Del Santo ◽  
...  
Keyword(s):  
T Cells ◽  
Feline Immunodeficiency Virus ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Lymphoid Cells ◽  
T Cell Subsets ◽  
Slow Increase ◽  
Immunodeficiency Virus ◽  
Vaccinia Viruses ◽  
Specific Pathogen

ABSTRACT The potential of immunotherapy with autologous virus-specific T cells to affect the course of feline immunodeficiency virus (FIV) infection was explored in a group of specific-pathogen-free cats infected with FIV a minimum of 10 months earlier. Popliteal lymph node cells were stimulated by cocultivation with UV-inactivated autologous fibroblasts infected with recombinant vaccinia viruses expressing either FIV gag or env gene products, followed by expansion in interleukin-2. One or two infusions of both Gag- and Env-stimulated cells resulted in a slow increase in FIV-specific gamma interferon-secreting T cells in the circulation of cats. In the same animals, viral set points fluctuated widely during the first 2 to 3 weeks after adoptive transfer and then returned to pretreatment levels. The preexisting viral quasispecies was also found to be modulated, whereas no novel viral variants were detected. Circulating CD4+ counts underwent a dramatic decline early after treatment. CD4/CD8 ratios remained instead essentially unchanged and eventually improved in some animals. In contrast, a single infusion of Gag-stimulated cells alone produced no apparent modulations of infection.

scholarly journals AIDS Vaccination Studies Using an Ex Vivo Feline Immunodeficiency Virus Model: Reevaluation of Neutralizing Antibody Levels Elicited by a Protective and a Nonprotective Vaccine after Removal of Antisubstrate Cell Antibodies

2001 ◽  
Vol 75 (9) ◽  
pp. 4424-4429 ◽  
Author(s):  
Simone Giannecchini ◽  
Daniela Del Mauro ◽  
Donatella Matteucci ◽  
Mauro Bendinelli
Keyword(s):  
Infected Cell ◽  
Feline Immunodeficiency Virus ◽  
Neutralizing Antibodies ◽  
Ex Vivo ◽  
Neutralizing Antibody ◽  
Cell Vaccine ◽  
Immunodeficiency Virus ◽  
Fixed Cell ◽  
Antibody Levels

ABSTRACT In the feline immunodeficiency virus system, immunization with a fixed-infected-cell vaccine conferred protection against virulent homologous challenge but the immune effectors involved remained elusive. In particular, few or no neutralizing antibodies were detected in sera from vaccinated cats. Here we show that, when preadsorbed with selected feline cells, the same sera revealed clearly evident virus-neutralizing activity. Because high titers of neutralizing antibody in cell-adsorbed sera from 23 cats immunized with fixed-infected-cell or whole-inactivated-virus vaccines correlated with protection, it is likely that they were more important for protection than formerly realized. In vitro, the fixed-cell vaccine efficiently removed neutralizing antibody from immune sera while the whole-inactivated-virus vaccine was much less effective.

scholarly journals WFDC1/ps20 Is a Novel Innate Immunomodulatory Signature Protein of Human Immunodeficiency Virus (HIV)-Permissive CD4+ CD45RO+ Memory T Cells That Promotes Infection by Upregulating CD54 Integrin Expression and Is Elevated in HIV Type 1 Infection

2007 ◽  
Vol 82 (1) ◽  
pp. 471-486 ◽  
Author(s):  
R. Alvarez ◽  
J. Reading ◽  
D. F. L. King ◽  
M. Hayes ◽  
P. Easterbrook ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Integrin Expression ◽  
Small Interference Rna ◽  
Immunodeficiency Virus

ABSTRACT Understanding why human immunodeficiency virus (HIV) preferentially infects some CD4+ CD45RO+ memory T cells has implications for antiviral immunity and pathogenesis. We report that differential expression of a novel secreted factor, ps20, previously implicated in tissue remodeling, may underlie why some CD4 T cells are preferentially targeted. We show that (i) there is a significant positive correlation between endogenous ps20 mRNA in diverse CD4 T-cell populations and in vitro infection, (ii) a ps20+ permissive cell can be made less permissive by antibody blockade- or small-interference RNA-mediated knockdown of endogenous ps20, and (iii) conversely, a ps20low cell can be more permissive by adding ps20 exogenously or engineering stable ps20 expression by retroviral transduction. ps20 expression is normally detectable in CD4 T cells after in vitro activation and interleukin-2 expansion, and such oligoclonal populations comprise ps20positive and ps20low/negative isogenic clones at an early differentiation stage (CD45RO+/CD25+/CD28+/CD57−). This pattern is altered in chronic HIV infection, where ex vivo CD4+ CD45RO+ T cells express elevated ps20. ps20 promoted HIV entry via fusion and augmented CD54 integrin expression; both of these effects were reversed by anti-ps20 antibody. We therefore propose ps20 to be a novel signature of HIV-permissive CD4 T cells that promotes infection in an autocrine and paracrine manner and that HIV has coopted a fundamental role of ps20 in promoting cell adhesion for its benefit. Disrupting the ps20 pathway may therefore provide a novel anti-HIV strategy.

scholarly journals Cytokine interactions in human immunodeficiency virus-infected individuals: roles of interleukin (IL)-2, IL-12, and IL-15.

1995 ◽  
Vol 182 (4) ◽  
pp. 1067-1077 ◽  
Author(s):  
R A Seder ◽  
K H Grabstein ◽  
J A Berzofsky ◽  
J F McDyer
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Tetanus Toxoid ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Specific Antigen ◽  
Neutralizing Antibody ◽  
Dependent Manner ◽  
Ifn Gamma ◽  
Immunodeficiency Virus

Cytokines have been shown to be powerful regulators of the immune response. In this study, we analyze the effect that the newly recognized cytokine interleukin (IL)-15 has on proliferation and cytokine induction using peripheral blood mononuclear cells (PBMCs) and purified CD4+ T cells from patients infected with human immunodeficiency virus (HIV) who are at various stages in their disease. We observed that IL-15 enhances the proliferative response in a dose-dependent manner from PBMCs of HIV-infected individuals when stimulated by polyclonal mitogen, tetanus toxoid, or HIV-specific antigen. The effects of exogenous IL-15 are substantially diminished by adding a neutralizing antibody to the beta chain of the IL-2 receptor. Moreover, the ability of IL-15 to increase proliferation is enhanced by the presence of endogenous IL-2 produced in the cultures. The effect that exogenous IL-15 had on IL-2, IL-4, and interferon (IFN)-gamma induction from PBMC's or CD4+ T cells in response to mitogen or tetanus toxoid was also examined. This was compared to the effect that exogenous IL-2 and IL-12 had under the same conditions. Addition of IL-2 or IL-15 to short-term in vitro cultures of either PBMCs or CD4+ T cells had little effect on IL-2, IL-4, or IFN-gamma production. By contrast, IL-12 caused substantial enhancement of both IL-2 and IFN-gamma production from these cultures. The role that endogenous cytokines have on IFN-gamma induction was also studied. Addition of a neutralizing antibody to the alpha chain of the IL-2 receptor or IL-12 to antigen stimulated cultures caused a striking decrease in IFN-gamma production. Neutralization of endogenous IL-15 also resulted in diminished IFN-gamma production from cultures stimulated with mitogen. IL-4 and IFN-gamma protein production by PBMCs and CD4+ T cells stimulated with mitogen was assessed to see if we could detect a specific bias of cytokine production. Small amounts of IL-4 were detected from CD4+ T cells but not PBMCs from most individuals tested. IFN-gamma and IL-2, however, were also produced from these same cultures. These results further elucidate the mechanism of cytokine regulation in HIV-infected individuals, and they provide evidence that IL-15 may be a useful immune modulator.

Viral-Specific Cytotoxic T Lymphocytes Lyse Human Immunodeficiency Virus–Infected Primary T Lymphocytes by the Granule Exocytosis Pathway

Blood ◽  
1999 ◽  
Vol 94 (9) ◽  
pp. 3084-3093 ◽  
Author(s):  
Premlata Shankar ◽  
Zhan Xu ◽  
Judy Lieberman
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Lymphocytes ◽  
Cell Lines ◽  
Cytotoxic T Lymphocytes ◽  
Cd4 T Cells ◽  
Target Cells ◽  
Granule Exocytosis ◽  
Immunodeficiency Virus ◽  
Bystander Cells

Cytotoxic T lymphocytes (CTL) lyse antigen-bearing target cells by two distinct pathways. Whereas granule exocytosis targets any antigen-bearing cell, fas-mediated cytotoxicity kills only fas-expressing cells and does not require antigen expression. Fas pathway activation can potentially lead to lysis of uninfected bystander cells. We examined the relative usage of the two pathways by CTL clones and cell lines directed against four different human immunodeficiency virus (HIV) proteins in lysing primary HIV-infected targets. Although fas was expressed on HIV-infected primary CD4+ T cells, their lysis by antigen-specific CD8+ CTL was only by the granule pathway. Fas ligand (fasL) was not detectable on antigen-specific CD8 clones, T-cell lines, or circulating HIV-specific CD8 T cells from HIV-infected donors, stained with a tetrameric HLA-A2-HIV-peptide complex. FasL expression by HIV-specific CTL clones was not activated by exposure to HIV-presenting cells, but was after unphysiological stimulation with phorbol myristate acetate (PMA). CTL clones did not lyse bystander Jurkat cells, but HIV-infected primary CD4+ T cells lysed uninfected bystander cells by the fas-mediated pathway. These results suggest that HIV-specific CD8+ CTL do not cause HIV immunopathology by lysing bystander cells. On the contrary, fas-mediated lysis of uninfected cells by HIV-infected cells may contribute to CD4 decline.

scholarly journals Chromatin maturation of the HIV-1 provirus in primary resting CD4+ T cells

2019 ◽  
Author(s):  
Birgitta Lindqvist ◽  
Sara Svensson Akusjarvi ◽  
Anders Sonnerborg ◽  
Marios Dimitriou ◽  
J. Peter Svensson
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Ex Vivo ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Infected Cells ◽  
Active Transcription ◽  
Hiv 1

Human immunodeficiency virus type 1 (HIV-1) infection is a chronic condition, where viral DNA integrates into the genome. Latently infected cells form a persistent, heterogeneous reservoir. The reservoir that reinstates an active replication comprises only cells with intact provirus that can be reactivated. We confirmed that latently infected cells from patients exhibited active transcription throughout the provirus. To find transcriptional determinants, we characterized the establishment and maintenance of viral latency during proviral chromatin maturation in cultures of primary CD4+ T-cells for four months after ex vivo HIV-1 infection. As heterochromatin (marked with H3K9me3 or H3K27me3) gradually stabilized, the provirus became less accessible with reduced activation potential. In a subset of infected cells, active marks (i.e., H3K27ac) remained detectable, even after prolonged proviral silencing. After T-cell activation, the proviral activation occurred uniquely in cells with H3K27ac-marked proviruses. Our observations suggested that, after transient proviral activation, cells were actively returned to latency.

scholarly journals AIDS Vaccination Studies Using an Ex Vivo Feline Immunodeficiency Virus Model: Homologous Erythrocytes as a Delivery System for Preferential Immunization with Putative Protective Antigens

1998 ◽  
Vol 5 (2) ◽  
pp. 235-241 ◽  
Author(s):  
Laura Chiarantini ◽  
Donatella Matteucci ◽  
Mauro Pistello ◽  
Umberto Mancini ◽  
Paola Mazzetti ◽  
...  
Keyword(s):  
Feline Immunodeficiency Virus ◽  
Vaccine Development ◽  
Ex Vivo ◽  
Degree Of Protection ◽  
Aids Vaccine ◽  
Protective Antigens ◽  
Homologous Virus ◽  
Immunodeficiency Virus ◽  
Specific Pathogen

ABSTRACT Feline immunodeficiency virus (FIV) is a useful model for testing of criteria for AIDS vaccine development. In the protocol we adopted, we used a primary isolate of FIV as a source of antigen and, for challenge, plasma from cats infected with the homologous virus never passaged in vitro. Cat erythrocytes (RBC) were coated with the surface components of freshly harvested and purified FIV by means of biotin-avidin-biotin bridges and used to immunize specific-pathogen-free cats (four doses at monthly intervals; total amount of FIV antigen administered per cat, approximately 14 μg). Immunized cats developed moderate levels of antibodies directed mainly to surface components of the virion and clearly evident lymphoproliferative responses. Four months after the last dose of immunogen, FIV-immunized cats and control cats immunized with bovine serum albumin-coated RBC were challenged. Judged from the results of the subsequent 12-month follow-up, FIV-immunized cats exhibited at least some degree of protection. However, following rechallenge, most of the FIV-immunized animals became virus positive in spite of a booster immunogen dose given 2 months before the second challenge.

scholarly journals Evaluation of live feline immunodeficiency virus vaccines with modified antigenic properties

2005 ◽  
Vol 86 (9) ◽  
pp. 2495-2506 ◽  
Author(s):  
Sophie Broche-Pierre ◽  
Jennifer Richardson ◽  
Anne Moraillon ◽  
Pierre Sonigo
Keyword(s):  
B Cell ◽  
Feline Immunodeficiency Virus ◽  
Ex Vivo ◽  
Cell Epitope ◽  
Viral Loads ◽  
Degree Of Protection ◽  
Antigenic Properties ◽  
Immunodeficiency Virus ◽  
Attenuated Viruses

Live-attenuated viruses have typically been generated from pathogenic viruses by genetic modifications that modified their replicative capacity. The present study investigated whether modification of the antigenic properties of live-attenuated viruses might improve upon the protection that such vaccines afford against lentivirus infection. In a previous study, random amino acid substitutions were introduced into the transmembrane envelope glycoprotein of the feline immunodeficiency virus (FIV), within a highly conserved domain (principal immunodominant domain) bearing immunodominant B-cell epitopes. Amongst a wide set of mutants, mutations that modified antibody specificity without abolishing infectivity ex vivo were selected. In the present study, two such mutants, TN14 and TN92, were evaluated for their replicative capacities and pathogenic properties in vivo in comparison with the parental virus, FIV 34TF10. No significant differences in viral load were observed between mutant and parental viruses. After 1 year of infection, all animals were subjected to a heterologous intraclade superinfection with a primary strain of FIV. Whilst both parental and modified viruses protected cats from high viral loads after superinfection, the TN92 virus afforded a higher degree of protection (P=0·0079). Such improvement in protection might correlate with a decrease in the immunogenicity of a B-cell epitope potentially involved in antibody enhancement of infection.

Sign in / Sign up

Export Citation Format

Share Document