Adel Benlahrech

Publications of Adel Benlahrech

• HIV-1 infection and induction of interferon alpha in plasmacytoid dendritic cells.

  Authors: Adel Benlahrech, Steven Patterson

  Current opinion in HIV and AIDS. 09/2011; 6(5):373-8.

  Loss of blood plasmacytoid dendritic cell (pDC) in HIV-1 infection is thought to impact on adaptive immune responses whilst the virus also induces aberrant interferon alpha (IFN-α) production thatLoss of blood plasmacytoid dendritic cell (pDC) in HIV-1 infection is thought to impact on adaptive immune responses whilst the virus also induces aberrant interferon alpha (IFN-α) production that may fuel chronic immune activation and drive disease progression. Recent attention has focussed on the pathway of HIV-induced IFN-α production by pDC and the new data are reviewed here together with the pathway leading to infection. Attachment to CD4 and chemokine co-receptors is essential for HIV-1 infection. Although CD4, but not co-receptor binding, is a major route for passage to endosomes and triggering of IFN-α secretion this may also occur by CD4-independent mechanisms involving other receptors. In contrast to other Toll-like receptor (TLR)-7 ligands and RNA viruses that stimulate pDC to secrete IFN-α for 2-3  h, HIV-1-stimulated pDC can give sustained IFN-α production for up to 48  h which may contribute to chronic immune activation. This may reflect retention of HIV in early endosomes which also seems to be associated with incomplete maturation induced by HIV. HIV-1-pDC interactions contribute to pathogenesis through depletion and aberrant IFN-α production. New data on the pathway of pDC HIV-stimulated IFN-α secretion may facilitate therapy to reduce chronic immune activation and slow disease progression.

• Loss of NK stimulatory capacity by plasmacytoid and monocyte-derived DC but not myeloid DC in HIV-1 infected patients.

  Authors: Adel Benlahrech, Frances Gotch, Peter Kelleher, Steven Patterson

  PloS one. 01/2011; 6(3):e17525.

  Dendritic cells (DC) are potent inducers of natural killer (NK) cells. There are two distinct populations in blood, myeloid (mDC) and plasmacytoid (pDC) but they can also be generated In vitro fromDendritic cells (DC) are potent inducers of natural killer (NK) cells. There are two distinct populations in blood, myeloid (mDC) and plasmacytoid (pDC) but they can also be generated In vitro from monocytes (mdDC). Although it is established that blood DC are lost in HIV-1 infection, the full impact of HIV-1 infection on DC-NK cell interactions remains elusive. We thus investigated the ability of pDC, mDC, and mdDC from viremic and anti-retroviral therapy-treated aviremic HIV-1+ patients to stimulate various NK cell functions. Stimulated pDC and mdDC from HIV-1+ patients showed reduced secretion of IFN-α and IL-12p70 respectively and their capacity to stimulate expression of CD25 and CD69, and IFN-γ secretion in NK cells was also reduced. pDC activation of NK cell degranulation in response to a tumour cell line was severely reduced in HIV-1+ patients but the ability of mDC to activate NK cells was not affected by HIV-1 infection, with the exception of HLA-DR induction. No differences were observed between viremic and aviremic patients indicating that anti-retroviral therapy had minimal effect on restoration on pDC and mdDC-mediated activation of NK cells. Results from this study provide further insight into HIV-1 mediated suppression of innate immune functions.

• Adenovirus vector vaccination induces expansion of memory CD4 T cells with a mucosal homing phenotype that are readily susceptible to HIV-1.

  Authors: Adel Benlahrech, Julian Harris, Andrea Meiser, Timos Papagatsias, Julia Hornig, Peter Hayes, Andre Lieber, Takis Athanasopoulos, Veronique Bachy, Eszter Csomor, Rod Daniels, Kerry Fisher, Frances Gotch, Len Seymour, Karen Logan, Romina Barbagallo, Linda Klavinskis, George Dickson, Steven Patterson

  Proceedings of the National Academy of Sciences of the United States of America. 11/2009;

  In the recently halted HIV type 1 (HIV-1) vaccine STEP trial, individuals that were seropositive for adenovirus serotype 5 (Ad5) showed increased rates of HIV-1 infection on vaccination with an Ad5In the recently halted HIV type 1 (HIV-1) vaccine STEP trial, individuals that were seropositive for adenovirus serotype 5 (Ad5) showed increased rates of HIV-1 infection on vaccination with an Ad5 vaccine. We propose that this was due to activation and expansion of Ad5-specific mucosal-homing memory CD4 T cells. To test this hypothesis, Ad5 and Ad11 antibody titers were measured in 20 healthy volunteers. Dendritic cells (DCs) from these individuals were pulsed with replication defective Ad5 or Ad11 and co-cultured with autologous lymphocytes. Cytokine profiles, proliferative capacity, mucosal migration potential, and susceptibility to HIV infection of the adenovirus-stimulated memory CD4 T cells were measured. Stimulation of T cells from healthy Ad5-seropositive but Ad11-seronegative individuals with Ad5, or serologically distinct Ad11 vectors induced preferential expansion of adenovirus memory CD4 T cells expressing alpha(4)beta(7) integrins and CCR9, indicating a mucosal-homing phenotype. CD4 T-cell proliferation and IFN-gamma production in response to Ad stimulation correlated with Ad5 antibody titers. However, Ad5 serostatus did not correlate with total cytokine production upon challenge with Ad5 or Ad11. Expanded Ad5 and Ad11 memory CD4 T cells showed an increase in CCR5 expression and higher susceptibility to infection by R5 tropic HIV-1. This suggests that adenoviral-based vaccination against HIV-1 in individuals with preexisting immunity against Ad5 results in preferential expansion of HIV-susceptible activated CD4 T cells that home to mucosal tissues, increases the number of virus targets, and leads to a higher susceptibility to HIV acquisition.

• 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.

  Authors: Sandrine Buisson, Adel Benlahrech, Brian Gazzard, Frances Gotch, Peter Kelleher, Steven Patterson

  The Journal of infectious diseases. 07/2009; 199(12):1862-71.

  Monocyte-derived dendritic cells (MDDCs) have been used in therapeutic vaccination for cancer. A small number of studies have employed a similar approach to vaccinate human immunodeficiency virusMonocyte-derived dendritic cells (MDDCs) have been used in therapeutic vaccination for cancer. A small number of studies have employed a similar approach to vaccinate human immunodeficiency virus (HIV)-infected individuals. We have thus analyzed the functional properties of MDDCs generated from HIV-infected individuals who either are receiving highly active antiretroviral therapy or are therapy naive. There was no difference in the MDDC phenotype or efficiency of MDDC generation between HIV-infected individuals and healthy control subjects. Despite this, the MDDCs derived from both groups of infected individuals were severely impaired in their ability to stimulate the proliferation of allogeneic T cells. Furthermore, production of interferon-gamma was reduced in T cells stimulated by MDDCs. These functional changes may be at least partly explained by reduced interleukin-12 and increased interleukin-10 secretion on stimulation with lipopolysaccharide and CD40 ligand. Our findings suggest that MDDCs used in therapeutic vaccination of HIV-infected individuals may show reduced potency.

• Use of Adenovirus in Vaccines for HIV.

  Authors: Steven Patterson, Timos Papagatsias, Adel Benlahrech

  Handbook of experimental pharmacology. 02/2009;

  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-cellThe 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.

• Human NK Cell Up-regulation of CD69, HLA-DR, Interferon γ Secretion and Cytotoxic Activity by Plasmacytoid Dendritic Cells is Regulated through Overlapping but Different Pathways.

  Authors: Adel Benlahrech, Heather Donaghy, George Rozis, Martin Goodier, Linda Klavinskis, Frances Gotch, Steven Patterson

  Sensors (Basel, Switzerland). 01/2009; 9(1):386-403.

  Human plasmacytoid dendritic cells secrete high levels of IFNα and are thus implicated in the activation of NK cells. Activated NK cells are characterised by the up-regulation of CD69 and MHC classHuman plasmacytoid dendritic cells secrete high levels of IFNα and are thus implicated in the activation of NK cells. Activated NK cells are characterised by the up-regulation of CD69 and MHC class II DR expression, secretion of IFN γ and enhanced cytotoxicity. We show that pDC mediate these processes by different mechanisms, some of which overlap. Human NK cells were analysed after co-culture with immature or CpG-matured blood pDC or with supernatant from these cells. Maximal CD69 expression by NK cells was mediated by supernatant from mature pDC and did not require pDC contact. Up-regulation was due in part to IFNα but also to factors in IFNα negative supernatant from immature DC. HLA-DR expression was independent of secreted molecules but required contact with immature or mature DC. Enhanced NK cytotoxicity, measured by killing of K562 targets and expression of CD107a, was mediated by multiple factors including type I IFN, supernatant from immature pDC cultures and contact with immature or mature pDC. These factors act cumulatively to enhance cytotoxcity. Thus different parameters of pDC mediated NK cell activation are regulated by distinct pathways.

• 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.

  Authors: George Rozis, Adel Benlahrech, Sai Duraisingham, Frances Gotch, Steven Patterson

  Immunology. 08/2008; 124(3):329-38.

  Langerhans' cells (LC) and dermal dendritic cells (dDC) are located in the superficial and deeper layers of the skin respectively and represent the main dendritic cell (DC) populations of the skin.Langerhans' cells (LC) and dermal dendritic cells (dDC) are located in the superficial and deeper layers of the skin respectively and represent the main dendritic cell (DC) populations of the skin. LC-like and dDC-like DC can be generated from CD34 stem cells and this system is widely used as a model for investigating these cells and in therapeutic vaccination. Here we report toll-like receptor (TLR) expression in human LC and dDC derived from CD34 stem cells. In vitro-generated DC expressed TLR-1, 2, 4, 6, 8 and 10. LC, but not dDC, expressed TLR-5, whereas only dDC expressed TLR-3. Maturation of LC was mediated by TLR-2, 4 and 5 ligands, but not by a TLR-3 ligand. dDC maturation was induced by TLR-3 and -4, but not with TLR-5 ligand and only weakly by a TLR-2 ligand. Stimulated LC secreted interleukin (IL)-1beta, low levels of tumour necrosis factor-alpha (TNF-alpha) and IL-8, but not IL-6 or IL-10. dDC secreted TNF-alpha, IL-6, IL-8 and IL-10, but little IL-1beta. IL-12p70 was not produced by ligand-stimulated dDC or LC, but was secreted by monocyte-derived DC (mdDC) stimulated with lipopolysaccharide (LPS). Thus, in vitro-generated LC and dDC detect different pathogen-associated molecules and show different cytokine-secretion profiles in response to TLR ligands.

• 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.

  Authors: George Rozis, Shamika de Silva, Adel Benlahrech, Timos Papagatsias, Julian Harris, Frances Gotch, George Dickson, Steven Patterson

  European journal of immunology. 10/2005; 35(9):2617-26.

  Vaccines against viruses need to target dendritic cells (DC) and stimulate mucosal immunity. Most vaccine studies have focussed on monocyte-derived or dermal DC (dDC) but recent evidence suggestsVaccines against viruses need to target dendritic cells (DC) and stimulate mucosal immunity. Most vaccine studies have focussed on monocyte-derived or dermal DC (dDC) but recent evidence suggests that Langerhans cells (LC) may stimulate mucosal immunity more effectively. New chimeric adenovirus vectors expressing fibre protein from group B adenoviruses (rAd5/11), which utilise CD46 rather than the Coxsackie adenovirus receptor (CAR), have been developed as vaccines to improve transduction and overcome problems of pre-existing vector immunity. Transduction of LC and dDC by rAd5/11 and standard rAd5 expressing green fluorescent protein (GFP) showed that both DC types were more efficiently transduced by rAd5/11 than by rAd5. Although expression of CD46 and the integrins alphavbeta3 and alphavbeta5, which recognise the adenovirus penton base and mediate virus internalisation, was similar in LC and dDC, LC expressed higher levels of GFP. Transduction by electroporation of plasmid also resulted in higher GFP expression in LC, suggesting differences between the two DC populations at a post-entry stage. Transduction with either vector did not induce maturation of LC or dDC and did not affect their ability to stimulate T cells. These findings suggest that vaccine strategies that target LC with adenovirus vectors may be worthy of exploration.

• Natural killer cells are not infected by Kaposi's sarcoma-associated herpesvirus in vivo, and natural killer cell counts do not correlate with the risk of developing Kaposi's sarcoma.

  Authors: Justin Stebbing, Brian Gazzard, Ornella Flore, Claire Thomas, Adel Benlahrech, Sundhiya Mandalia, Mark Bower, Frances Gotch, Steve Patterson

  AIDS (London, England). 10/2003; 17(13):1998-2000.

  Although the innate immune system is implicated in the control of Kaposi's sarcoma (KS), the risk of developing KS is not associated with the nadir natural killer (NK) cell count, and NK cell countsAlthough the innate immune system is implicated in the control of Kaposi's sarcoma (KS), the risk of developing KS is not associated with the nadir natural killer (NK) cell count, and NK cell counts do not significantly increase or decrease during KS resolution. KS-associated herpesvirus replication was not demonstrated in vivo or in vitro within NK cells, suggesting that NK cells do not contribute to the resolution of KS. Their role appears limited to events occurring during early infection.