68 results found
Almond N, Berry N, Stebbings R, et al., 2019, Vaccination of Macaques with DNA Followed by Adenoviral Vectors Encoding Simian Immunodeficiency Virus (SIV) Gag Alone Delays Infection by Repeated Mucosal Challenge with SIV, JOURNAL OF VIROLOGY, Vol: 93, ISSN: 0022-538X
Tavano B, Tsipouri V, Hardy GAD, et al., 2017, Immune Response in the Central Nervous system Are Anatomically Segregated in a Non-Human Primate Model of Human Immunodeficiency Virus Infection, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
The human immunodeficiency virus (HIV) accesses the central nervous system (CNS) early during infection, leading to HIV-associated cognitive impairment and establishment of a viral reservoir. Here, we describe a dichotomy in inflammatory responses in different CNS regions in simian immunodeficiency virus (SIV)-infected macaques, a model for HIV infection. We found increased expression of inflammatory genes and perivascular leukocyte infiltration in the midbrain of SIV-infected macaques. Conversely, the frontal lobe showed downregulation of inflammatory genes associated with interferon-γ and interleukin-6 pathways, and absence of perivascular cuffing. These immunologic alterations were not accompanied by differences in SIV transcriptional activity within the tissue. Altered expression of genes associated with neurotoxicity was observed in both midbrain and frontal lobe. The segregation of inflammatory responses to specific regions of the CNS may both account for HIV-associated neurological symptoms and constitute a critical hurdle for HIV eradication by shielding the CNS viral reservoir from antiviral immunity.
Le Heron A, Patterson S, Yáñez-Muñoz RJ, et al., 2017, Chimeric Trojan Protein Insertion in Lentiviral Membranes Makes Lentiviruses Susceptible to Neutralization by Anti-Tetanus Serum Antibodies., Hum Gene Ther, Vol: 28, Pages: 242-254
This study describes the initial testing of a novel strategy for neutralization of lentiviruses using the fundamental biology of enveloped viruses' assembly and budding. In the field of gene therapy, viral vector surface proteins have been manipulated in order to redirect host cell specificity by alteration of pseudo-types. This study tested whether known viral pseudo-typing proteins or surface proteins known to be recruited to the human immunodeficiency virus (HIV) envelope could be engineered to carry neutralizing epitopes from another microorganism onto the lentiviral surface. The results identify ICAM1 as a novel vehicle for lentiviral pseudo-typing. Importantly, the study shows that in a model lentiviral system, ICAM1 can be engineered in chimeric form to result in expression of a fragment of the tetanus toxoid on the viral membrane and that these viruses can then be neutralized by human serum antibodies protective against tetanus. This raises the possibility of delivering chimeric antigens as a gene therapy in HIV-infected patients.
Herath S, Le Heron A, Colloca S, et al., 2016, Strain-dependent and distinctive T-cell responses to HIV antigens following immunisation of mice with differing chimpanzee adenovirus vaccine vectors, Vaccine, Vol: 34, Pages: 4378-4385, ISSN: 1873-2518
In vivo vaccination studies are conventionally conducted in a single mouse strain with results, only reflecting responses to a single immunogenetic background. We decided to examine the immune response to an HIV transgene (gag, pol and nef fusion protein) in 3 strains of mice (CBA, C57BL/6 and BALB/c) to determine the spectrum of responses and in addition to determine whether the serotype of the adenoviral vector used (ChAd3 and ChAd63) impacted the outcome of response. Our results demonstrated that all three strains of mice responded to the transgene and that the magnitude of responses were different between the strains. The C57BL/6 strain showed the lowest range of responses compared to the other strains and, very few responses were seen to the same peptide pool in all three strains of mice. In CBA and BALB/c mice there were significant differences in IFNγ production dependent on the adenoviral vector used. Our results suggest that employing a single strain of mouse may underestimate the efficacy and efficiency of vaccine products.
Herath S, Le Heron A, Colloca S, et al., 2015, Analysis of T cell responses to chimpanzee adenovirus vectors encoding HIV gag–pol–nef antigen, Vaccine, Vol: 33, Pages: 7283-7289, ISSN: 1873-2518
Benlahrech A, Duraisingham S, King D, et al., 2015, Human blood CD1c dendritic cells stimulate IL-12-independent IFN-gamma responses and have a strikingly low inflammatory profile, JOURNAL OF LEUKOCYTE BIOLOGY, Vol: 97, Pages: 873-885, ISSN: 0741-5400
Herath S, Benlahrech A, Papagatsias T, et al., 2014, Fusion of Ubiquitin to HIV Gag Impairs Human Monocyte-Derived Dendritic Cell Maturation and Reduces Ability to Induce Gag T Cell Responses, PLOS ONE, Vol: 9, ISSN: 1932-6203
Chen J, Benlahrech A, Kelleher P, et al., 2013, Increased Activity of Extrinsic and Intrinsic Apoptosis Pathways in Different Mononuclear Cell Types in HIV Type 1-Infected Patients Regardless of Whether They Are Depleted in Disease, AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol: 29, Pages: 709-717, ISSN: 0889-2229
Bachy V, Hervouet C, Becker PD, et al., 2013, Langerin negative dendritic cells promote potent CD8(+) T-cell priming by skin delivery of live adenovirus vaccine microneedle arrays, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 3041-3046, ISSN: 0027-8424
Benlahrech A, Yasmin A, Westrop SJ, et al., 2012, Dysregulated immunophenotypic attributes of plasmacytoid but not myeloid dendritic cells in HIV-1 infected individuals in the absence of highly active anti-retroviral therapy, Clinical and Experimental Immunology, Vol: 170, Pages: 212-221, ISSN: 0009-9104
Dendritic cells (DC) in HIV-1-infected individuals are decreased and their dysfunction has been implicated in HIV-1 immunopathogenesis. The mechanism of their dysfunction remains unclear, thus we analysed the expression of membrane molecules associated with immune regulation and DC activation in myeloid (mDC) and plasmacytoid DC (pDC) in therapy-naive and highly active anti-retroviral therapy (HAART)-treated HIV-1+ patients. DC from healthy controls, untreated HIV-1+ and HAART-treated patients were assessed by flow cytometry for expression of: anergy and apoptosis inducing molecules [programmed death (PD)-1 and its ligands PD-L1 and PD-L2], inhibitory and regulatory T cell-inducing molecules [immunoglobulin-like transcript (ILT)-3 and ILT-4], interferon (IFN)-α inhibitory receptor (ILT-7) and co-stimulatory molecules (CD80, CD83, and CD86). pDC from untreated HIV-1+ patients expressed significantly lower levels of ILT-7 compared to healthy controls, while HAART-treated patients showed normal expression. pDC were also found to express moderately higher levels of PD-L1 and ILT-3 and lower levels of PD-L2 receptors in untreated patients compared to controls and HAART-treated patients. No significant changes were observed in mDC. There were no associations between the percentages and levels of expression of these molecules by pDC and viral load or CD4 T cell count. In conclusion, pDC but not mDC from HIV-1+ patients with active viraemia display higher levels of apoptosis and T regulatory-inducing molecules and may be predisposed to chronically produce IFN-α through down-regulation of ILT-7. HAART restored normal expression levels of these receptors.
Benlahrech A, Meiser A, Herath S, et al., 2012, Fragmentation of SIV-gag Vaccine Induces Broader T Cell Responses, PLOS ONE, Vol: 7, ISSN: 1932-6203
Pillay S, Patterson S, 2012, Expression of a versatile DC-targeting fusion protein using an Adenovirus expression system., Protein Expr Purif, Vol: 84, Pages: 270-279
The importance of viral and tumour vaccines in eliciting elicit strong CD8+ T-cell responses has been widely acknowledged. Strategies exploring ways to enhance CD8+ T-cell responses have been developed, including targeting of vaccine antigens to dendritic cell (DC) receptors to access to the cross presentation pathway. Many DC endocytic receptors could potentially lead to augmented CD8+ T-cell responses if antigens were targeted directly to them, however only a few receptors have been explored because current targeting reagents are limited in the number of receptors that they are able to target. Consequently, this study describes the production and purification of a streptavidin-fusion protein that provides a versatile and efficient means to target antigen to more than one DC receptor. A model antigen gene, CMV pp65, and a streptavidin core gene, were spliced together using an overlap-extension PCR technique. The resulting fusion gene was cloned into a vector allowing expression in an Adenovirus-based expression system. Expression was verified and optimised before Ni-NTA affinity chromatography purification. Evaluation of pp65-streptavidin immunogenicity revealed that it elicits similar levels of CD8+ T-cell proliferative responses as pp65 and is able to effectively target specific DC receptors when used in addition to biotinylated receptor-specific antibodies. Additionally, enhancement of CD8+ T-cell responses was shown after directing pp65-strep to selected DC receptors in preliminary in vitro experiments. Collectively, this highlights the ease of production of a streptavidin-fusion protein, and demonstrates its use as a promising strategy to evaluate numerous DC receptors as potential targets in vaccine strategies.
Benlahrech A, Patterson S, 2011, HIV-1 infection and induction of interferon alpha in plasmacytoid dendritic cells, CURRENT OPINION IN HIV AND AIDS, Vol: 6, Pages: 373-378, ISSN: 1746-630X
Benlahrech A, Gotch F, Kelleher P, et al., 2011, Loss of NK Stimulatory Capacity by Plasmacytoid and Monocyte-Derived DC but Not Myeloid DC in HIV-1 Infected Patients, PLOS ONE, Vol: 6, ISSN: 1932-6203
Duraisingham SS, Hornig J, Gotch F, et al., 2010, CD34-derived human Langerhans cells stimulate a T helper type 2 response independently of extracellular-signal-regulated kinase phosphorylation, IMMUNOLOGY, Vol: 131, Pages: 210-219, ISSN: 0019-2805
Benlahrech A, Harris J, Meiser A, et al., 2009, Adenovirus vector vaccination induces expansion of memory CD4 T cells with a mucosal homing phenotype that are readily susceptible to HIV-1, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 106, Pages: 19940-19945, ISSN: 0027-8424
Benlahrech A, Harris J, Meiser A, et al., 2009, OA07-02. Adenovirus vectors induce expansion of memory CD4 T cells with a mucosal homing phenotype that are readily susceptible to HIV-1 infection, Retrovirology, Vol: 6
Duraisingham SS, Hornig J, Gotch F, et al., 2009, TLR-Stimulated CD34 Stem Cell-Derived Human Skin-Like and Monocyte-Derived Dendritic Cells Fail to Induce Th17 Polarization of Naive T Cells but Do Stimulate Th1 and Th17 Memory Responses, JOURNAL OF IMMUNOLOGY, Vol: 183, Pages: 2242-2251, ISSN: 0022-1767
Buisson S, Benlahrech A, Gazzard B, et al., 2009, Monocyte-Derived Dendritic Cells from HIV Type 1-Infected Individuals Show Reduced Ability to Stimulate T Cells and Have Altered Production of Interleukin (IL)-12 and IL-10, JOURNAL OF INFECTIOUS DISEASES, Vol: 199, Pages: 1862-1871, ISSN: 0022-1899
Benlahrech A, Donaghy H, Rozis G, et al., 2009, Human NK Cell Up-regulation of CD69, HLA-DR, Interferon gamma Secretion and Cytotoxic Activity by Plasmacytoid Dendritic Cells is Regulated through Overlapping but Different Pathways, SENSORS, Vol: 9, Pages: 386-403, ISSN: 1424-8220
Patterson S, Papagatsias T, Benlahrech A, 2009, Use of adenovirus in vaccines for HIV., Handb Exp Pharmacol, Pages: 275-293, ISSN: 0171-2004
The best hope of controlling the HIV pandemic is the development of an effective vaccine. In addition to the stimulation of virus neutralising antibodies, a vaccine will need an effective T-cell response against the virus. Vaccines based on recombinant adenoviruses (rAd) are promising candidates to stimulate anti-HIV T-cell responses. This review discusses the different rAd vector types, problems raised by host immune responses against them and strategies that are being adopted to overcome this problem. Vaccines need to target and stimulate dendritic cells and thus the tropism and interaction of rAd-based vaccines with these cells is covered. Different rAd vaccination regimes and the need to stimulate mucosal responses are discussed together with data from animal studies on immunogenicity and virus challenge experiments. The review ends with a discussion of the recent disappointing Merck HIV vaccine trial.
Benlahrech A, Donaghy H, Rozis G, et al., 2009, Human NK Cell Up-regulation of CD69, HLA-DR, Interferon Secretion and Cytotoxic Activity by Plasmacytoid Dendritic Cells is Regulated Through Overlapping but Different Pathways, Sensors, Vol: 9, Pages: 386-403
Rozis G, Benlahrech A, Duraisingham S, et al., 2008, Human Langerhans' cells and dermal-type dendritic cells generated from CD34 stem cells express different toll-like receptors and secrete different cytokines in response to toll-like receptor ligands, IMMUNOLOGY, Vol: 124, Pages: 329-338, ISSN: 0019-2805
Papagatsias T, Rozis G, Athanasopoulos T, et al., 2008, Activity of different vaccine-associated promoter elements in human dendritic cells, IMMUNOLOGY LETTERS, Vol: 115, Pages: 117-125, ISSN: 0165-2478
Papagatsias T, Rozis G, Athanasopoulos T, et al., 2008, Activity of different vaccine-associated promoter elements in human dendritic cells., Immunology Letters, Vol: 115, Pages: 117-125
Patterson S, Donaghy H, Kelleher P, 2007, Loss, infection, and dysfunction of dendritic cells in HIV infection, New York, Publisher: Springer, ISBN: 9780387337845
Rozis G, de Silva S, Benlahrech A, et al., 2005, Langerhans cells are more efficiently transduced than dermal dendritic cells by adenovirus vectors expressing either group C or group B fibre protein: Implications for mucosal vaccines, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 35, Pages: 2617-2626, ISSN: 0014-2980
Kebba A, Stebbing J, Rowland S, et al., 2005, Expression of the common heat-shock protein receptor CD91 is increased on monocytes of exposed yet HIV-1-seronegative subjects, JOURNAL OF LEUKOCYTE BIOLOGY, Vol: 78, Pages: 37-42, ISSN: 0741-5400
Patterson S, Donaghy H, Amjadi P, et al., 2005, Human BDCA-1-positive blood dendritic cells differentiate into phenotypically distinct immature and mature populations in the absence of exogenous maturational stimuli: Differentiation failure in HIV infection, JOURNAL OF IMMUNOLOGY, Vol: 174, Pages: 8200-8209, ISSN: 0022-1767
Prakash M, Patterson S, Kapembwa MS, 2005, Topic II: Hormonal influences on HIV acquisition - Hormonal upregulation of CCR5 expression on T lymphocytes as a possible mechanism for increased HIV-1 risk, Conference on Fertility Regulation and Systemic Hormones in HIV-infected and At-Risk Women, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: S14-S16, ISSN: 1525-4135
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