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Shah N, Imami N, Johnson MR, 2015, Changes in T Cell, Dendritic Cell and NK Cell Phenotype, and T Cell Function From Mid To Late Pregnancy Indicate a Shift From Immune Tolerance To Increased Immune Activation., REPRODUCTIVE SCIENCES, Vol: 22, Pages: 279A-279A, ISSN: 1933-7191
Mletzko S, Robey R, Dalla Pria A, et al., 2015, Programmed death ligand 1 (PD-L1) expression is not upregulated in antiretroviral therapy-refractory Kaposi's sarcoma, 21st Annual Conference of the British HIV Association
Herasimtschuk A, Downey J, Nelson M, et al., 2014, Therapeutic immunisation plus cytokine and hormone therapy improves CD4 T-cell counts, restores anti-HIV-1 responses and reduces immune activation in treated chronic HIV-1 infection, VACCINE, Vol: 32, Pages: 7005-7013, ISSN: 0264-410X
BackgroundThis randomised, open label, phase I, immunotherapeutic study investigated the effects of interleukin (IL)-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), recombinant human growth hormone (rhGH), and therapeutic immunisation (a Clade B DNA vaccine) on combination antiretroviral therapy (cART)-treated HIV-1-infected individuals, with the objective to reverse residual T-cell dysfunction.MethodsTwelve HIV-1+ patients on suppressive cART with baseline CD4 T-cell counts >400 cells/mm3 blood were randomised into one of three groups: (1) vaccine, IL-2, GM-CSF and rhGH (n = 3); (2) vaccine alone (n = 4); or (3) IL-2, GM-CSF and rhGH (n = 5). Samples were collected at weeks 0, 1, 2, 4, 6, 8, 12, 16, 24 and 48. Interferon (IFN)-γ, IL-2, IL-4 and perforin ELISpot assays performed at each time point quantified functional responses to Gag p17/p24, Nef, Rev, and Tat peptides; and detailed T-cell immunophenotyping was undertaken by flow cytometry. Proviral DNA was also measured.ResultsMedian baseline CD4 T-cell count was 757 cells/mm3 (interquartile range [IQR] 567–886 cells/mm3), median age 48 years (IQR 42–51 years), and plasma HIV-1-RNA <50 copies/ml for all subjects. Patients who received vaccine plus IL-2, GM-CSF and rhGH (group 1) showed the most marked changes. Assessing mean changes from baseline to week 48 revealed significantly elevated numbers of CD4 T cells (p = 0.0083) and improved CD4/CD8 T-cell ratios (p = 0.0033). This was accompanied by a significant reduction in expression of CD38 on CD4 T cells (p = 0.0194), significantly increased IFN-γ and IL-2 production in response to Gag (p = 0.0122) and elevated IFN-γ production in response to Tat (p = 0.041) at week 48 compared to baseline. Subjects in all treatment groups showed significantly reduced PD-1 expression at week 48 compared to baseline, with some reductions in proviral DNA.ConclusionsMultifarious immunotherapeutic approaches in the context of fully s
Grageda N, Herasimtschuk A, Nelson M, et al., 2014, Outcome of cART and immunotherapy on virus-specific CD8+T lymphocyte subsets, Third Joint Conference of the British HIV Association (BHIVA) with the British Association for Sexual Health and HIV (BASHH), Publisher: Wiley, Pages: 48-48, ISSN: 1464-2662
Herasimtschuk A, Mandalia S, Nelson M, et al., 2014, Beneficial effect of NNRTI over boosted PI first line cART on CD4 T-cell restoration in older HIV-1+patients, Third Joint Conference of the British HIV Association (BHIVA) with the British Association for Sexual Health and HIV (BASHH), Publisher: Wiley, Pages: 4-4, ISSN: 1464-2662
Shah N, Imami N, Johnson M, 2014, Antigenic Readiness, Enhanced Immune Response and Modified Tolerant Phenotypes Follows Flu Vaccination in Pregnancy, REPRODUCTIVE SCIENCES, Vol: 21, Pages: 411A-411A, ISSN: 1933-7191
Herasimtschuk AA, Hansen BR, Langkilde A, et al., 2013, Low-dose growth hormone for 40 weeks induces HIV-1-specific T cell responses in patients on effective combination anti-retroviral therapy, Clinical and Experimental Immunology, Vol: 173, Pages: 444-453, ISSN: 0009-9104
Recombinant human growth hormone (rhGH) administered to combination anti-retroviral therapy (cART)-treated human immunodeficiency virus-1 (HIV-1)-infected individuals has been found to reverse thymic involution, increase total and naive CD4 T cell counts and reduce the expression of activation and apoptosis markers. To date, such studies have used high, pharmacological doses of rhGH. In this substudy, samples from treated HIV-1+ subjects, randomized to receive either a physiological dose (0·7 mg) of rhGH (n = 21) or placebo (n = 15) daily for 40 weeks, were assessed. Peptide-based enzyme-linked immunospot (ELISPOT) assays were used to enumerate HIV-1-specific interferon (IFN)-γ-producing T cells at baseline and week 40. Individuals who received rhGH demonstrated increased responses to HIV-1 Gag overlapping 20mer and Gag 9mer peptide pools at week 40 compared to baseline, whereas subjects who received placebo showed no functional changes. Subjects with the most robust responses in the ELISPOT assays had improved thymic function following rhGH administration, as determined using CD4+ T cell receptor rearrangement excision circle (TREC) and thymic density data from the original study. T cells from these robust responders were characterized further phenotypically, and showed decreased expression of activation and apoptosis markers at week 40 compared to baseline. Furthermore, CD4 and CD8 T cell populations were found to be shifted towards an effector and central memory phenotype, respectively. Here we report that administration of low-dose rhGH over 40 weeks with effective cART resulted in greater improvement of T lymphocyte function than observed with cART alone, and provide further evidence that such an approach could also reduce levels of immune activation.
Mletzko S, Rai A, Westrop S, et al., 2013, The role of interleukin-6 and interleukin-6 receptor in multicentric Castleman's disease (MCD): frequency of polymorphism, HIV MEDICINE, Vol: 14, Pages: 26-26, ISSN: 1464-2662
Herasimtschuk A, Downey J, Nelson M, et al., 2013, Therapeutic immunisation in conjunction with IL-2, GM-CSF and rhGH improves CD4 T-cell counts and reduces immune activation in cART-treated HIV-1-positive patients: a Phase I clinical study, HIV MEDICINE, Vol: 14, Pages: 10-10, ISSN: 1464-2662
Benlahrech A, Yasmin A, Westrop S, et al., 2013, Antiretroviral therapy restores HIV-1-induced abnormal expression of immunoregulatory molecules by plasmacytoid DC, HIV MEDICINE, Vol: 14, Pages: 25-25, ISSN: 1464-2662
Grageda N, Westrop SJ, Nelson M, et al., 2013, Differences in cART-mediated immune reconstitution are revealed by distinct exhaustive phenotypes of HIV-1-and CMV-specific CD8+T cells, HIV MEDICINE, Vol: 14, Pages: 23-24, ISSN: 1464-2662
Shah N, Westrop S, Low-Beer N, et al., 2013, Expanded CD56+subset in HIV-1-positive mothers on HAART is associated with premature delivery, HIV MEDICINE, Vol: 14, Pages: 32-32, ISSN: 1464-2662
Shah N, Westrop S, Low-Beer N, et al., 2013, Premature Delivery in HIV plus Mothers on HAART Is Associated with an Expanded Peripheral Blood CD56+Subset, 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI), Publisher: SAGE PUBLICATIONS INC, Pages: 197A-197A, ISSN: 1933-7191
Shah N, Imami N, Johnson M, 2013, Pregnancy Is Associated with Greater PIBF Expression on Peripheral Blood CD8+T-Cells In-Vitro, 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI), Publisher: SAGE PUBLICATIONS INC, Pages: 323A-323A, ISSN: 1933-7191
Imami N, Westrop SJ, Grageda N, et al., 2013, Long-term non-progression and broad HIV-1-specific proliferative T-cell responses, FRONTIERS IN IMMUNOLOGY, Vol: 4, ISSN: 1664-3224
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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.
Westrop SJ, Moyle G, Jackson A, et al., 2012, CCR5 antagonism impacts vaccination response and immune profile in HIV-1 infection., Molecular Medicine, Vol: 18, Pages: 1240-1248, ISSN: 1076-1551
Maraviroc (MVC) is the first licensed antiretroviral therapeutic agent to target a host cell surface molecule, and successful HIV-1 entry blockade by this C-C chemokine receptor type 5 (CCR5)-antagonist potentiates immunomodulation. We hypothesized that MVC intensification impacts immunization responses, T-cell phenotype, function and delayed type hypersensitivity (DTH) in HIV-1+ subjects. A 24-wk, double-blinded, placebo-controlled study of the addition of MVC to suppressive antiretroviral therapy in HIV-1+ persons was performed. Subjects received DTH tests, intramuscular tetanus, meningococcal and oral cholera immunizations. Antibody titers, T-cell function and phenotype were assessed. Of 157 patients referred, 47 were randomized 1:1; MVC:placebo. MVC enhanced meningococcal neo-immunization, blunted cholera response and expedited lymphoproliferation to tetanus boost, without affecting recall humoral response. Anti-HIV-1 group-specific antigen (Gag) and tetanus toxoid (TTox) function improved significantly, HIV-1-associated CD8 T-cell skewing normalized, and the percentage of late-stage and major histocompatibility complex (MHC) class II expressing CD4 T-cells increased. Activated CD4+ CD38+ human leukocyte antigen (HLA)-DR+ T-cells declined, and costimulation shifted to coinhibition. DTH was unchanged. Maraviroc intensification, through antagonism of the cell surface molecule CCR5, favorably influences immune profiles of HIV-1+ patients, supporting its immunomodulatory use in HIV-1 infection and potentially in other immunologically relevant settings.
Westrop SJ, Lagos D, Boshoff C, et al., 2012, African ancestry and innate immunity contribute to the incidence of multicentric Castleman’s disease in HIV-1/Kaposi’s sarcoma herpesvirus-coinfected individuals, Future Virology, Vol: 7, Pages: 729-734
Shah N, Imami N, Johnson M, 2012, T-cell phenotypic profile in pregnancy: link between immune activation and exhaustion, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 119, Pages: 62-62, ISSN: 1470-0328
Shah N, Benlarech A, Imami N, et al., 2012, Phenotypic analysis of dendritic cell lineage and maturity, and T-Cell exhaustion indicate dampened immune activation in pregnancy, Joint International Congress of the American-Society-for-Reproductive-Immunology (ASRI) and the European-Society-for-Reproductive-Immunology (ESRI), Publisher: ELSEVIER IRELAND LTD, Pages: 50-50, ISSN: 0165-0378
Herasimtschuk A, Thaventhiran T, Nelson M, et al., 2012, Distinct HIV-1 Gag-and Nef- specific responses correlate with immunophenotype in treated chronic HIV-1 infection, HIV MEDICINE, Vol: 13, Pages: 32-32, ISSN: 1464-2662
Guergnon J, Dalmasso C, Broet P, et al., 2012, Single-nucleotide polymorphism-defined Class I and Class III major histocompatibility complex genetic subregions contribute to natural long-term nonprogression in HIV infection, Journal of Infectious Diseases, Vol: 205, Pages: 718-724, ISSN: 0022-1899
We performed a genome-wide association study comparing a cohort of 144 human immunodeficiency virus (HIV type 1–infected, untreated white long-term nonprogressors (LTNPs) with a cohort of 605 HIV-1–infected white seroconverters. Forty-seven single-nucleotide polymorphisms (SNPs), located from class I to class III major histocompatibility complex (MHC) subregions, show statistical association (false discovery rate, <0.05) with the LTNP condition, among which 5 reached genome-wide significance after Bonferonni correction. The MHC LTNP–associated SNPs are ordered in ≥4 linkage disequilibrium blocks; interestingly, an MHC class III linkage disequilibrium block (defined by the rs9368699 SNP) seems specific to the LTNP phenotype.
Mandalia S, Westrop SJ, Beck EJ, et al., 2012, Are long-term non-progressors very slow progressors? Insights from the Chelsea and Westminster HIV Cohort, 1988–2010, PLOS One, Vol: 7, ISSN: 1932-6203
Define and identify long-term non-progressors (LTNP) and HIV controllers (HIC), and estimate time until disease progression. LTNP are HIV-1+ patients who maintain stable CD4+ T-cell counts, with no history of opportunistic infection or antiretroviral therapy (ART). HIC are a subset of LTNP who additionally have undetectable viraemia. These individuals may provide insights for prophylactic and therapeutic development. Records of HIV-1+ individuals attending Chelsea and Westminster Hospital (1988–2010), were analysed. LTNP were defined as: HIV-1+ for >7 years; ART-naïve; no history of opportunistic infection and normal, stable CD4+ T-cell counts. MIXED procedure in SAS using random intercept model identified long-term stable CD4+ T-cell counts. Survival analysis estimated time since diagnosis until disease progression. Subjects exhibiting long-term stable CD4+ T-cell counts with history below the normal range (<450 cells/µl blood) were compared to LTNP whose CD4+ T-cell count always remained normal. Within these two groups subjects with HIV-1 RNA load below limit of detection (BLD) were identified. Of 14,227 patients, 1,204 were diagnosed HIV-1+ over 7 years ago and were ART-naïve. Estimated time until disease progression for the 20% (239) whose CD4+ T-cell counts remained within the normal range, was 6.2 years (IQR: 2.0 to 9.6); significantly longer than 4.0 years (IQR: 1.0 to 7.3) for patients with historical CD4+ T-cell count below normal (Logrank chi-squared = 21.26; p<0.001). Within a subpopulation of 312 asymptomatic patients, 50 exhibited long-term stable CD4+ T-cell counts. Of these, 13 were LTNP, one of whom met HIC criteria. Of the remaining 37 patients with long-term stable low CD4+ T-cell counts, 3 controlled HIV-1 RNA load BLD. Individuals with stable, normal CD4+ T-cell counts progressed less rapidly than those with low CD4+ T-cell counts. Few LTNP and HIC identified in this and other studies, endorse the need for universal
Malnati MS, Heltai S, Cosma A, et al., 2012, A new antigen scanning strategy for monitoring HIV-1 specific T-cell immune responses, Journal of Immunological Methods, Vol: 375, Pages: 46-56, ISSN: 0022-1759
Delineation of the immune correlates of protection in natural infection or after vaccination is a mandatory step for vaccine development. Although the most recent techniques allow a sensitive and specific detection of the cellular immune response, a consensus on the best strategy to assess their magnitude and breadth is yet to be reached. Within the AIDS Vaccine Integrated Project (AVIP http://www.avip-eu.org) we developed an antigen scanning strategy combining the empirical-based approach of overlapping peptides with a vast array of database information. This new system, termed Variable Overlapping Peptide Scanning Design (VOPSD), was used for preparing two peptide sets encompassing the candidate HIV-1 vaccine antigens Tat and Nef. Validation of the VOPSD strategy was obtained by direct comparison with 15mer or 20mer peptide sets in a trial involving six laboratories of the AVIP consortium. Cross-reactive background responses were measured in 80 HIV seronegative donors (HIV-), while sensitivity and magnitude of Tat and Nef-specific T-cell responses were assessed on 90 HIV+ individuals. In HIV−, VOPSD peptides generated background responses comparable with those of the standard sets. In HIV-1+ individuals the VOPSD pools showed a higher sensitivity in detecting individual responses (Tat VOPSD vs. Tat 15mers or 20mers: p ≤ 0.01) as well as in generating stronger responses (Nef VOPSD vs. Nef 20mers: p < 0.001) than standard sets, enhancing both CD4 and CD8 T-cell responses. Moreover, this peptide design allowed a marked reduction of the peptides number, representing a powerful tool for investigating novel HIV-1 candidate vaccine antigens in cohorts of HIV-seronegative and seropositive individuals.
Herasimtschuk A, Thaventhiran T, Nelson M, et al., 2012, Distinct HIV-1 Gag-and Nef- specific responses correlate with immunophenotype in treated chronic HIV-1 infection, 18th Annual Conference of the British HIV Association
Grageda N, Westrop SJ, Jackson A, et al., 2012, Discordant reconstitution of HIV-1- and CMV-specific responses in cART-treated HIV-1+ patients – what can we learn from co-infection?, 18th Annual Conference of the British HIV Association
Westrop SJ, Moyle G, Nelson M, et al., 2012, Intensification of suppressive ART with maraviroc reduces CD4 T-cell activation, increases early stage CD8 T cells and improves anti-HIV-1 function, without detriment to humoral recall response, 18th Annual Conference of the British HIV Association
Westrop SJ, Madalia S, Moyle G, et al., 2012, Immunological manifestations of increasing age, ART duration and time since diagnosis within the ageing HIV-1+ cohort, 18th Annual Conference of the British HIV Association
Grageda N, Westrop SJ, Jackson A, et al., 2012, Functional and Phenotypic Characterization of CMV-specific T Cells in HIV-1+: Profiling of Total and Multimer-specific CD8 T Cells during ART, 19th Conference on Retroviruses and Opportunistic Infections
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