Publications
191 results found
Lagos D, Vart RJ, Gratix F, et al., 2008, Toll-like receptor 4 mediates innate immunity to Kaposi sarcoma herpesvirus., Cell Host & Microbe, Vol: 4, Pages: 470-483
The involvement of Toll-like receptor 4 (TLR4) in immunity against human herpesviruses has not been previously demonstrated. We show that infection of endothelial cells with Kaposi sarcoma herpesvirus (KSHV), a human oncogenic virus, leads to rapid suppression of TLR4 expression. This is a mechanism of immune escape as TLR4 mediates innate immunity against KSHV. In vitro, cells lacking TLR4 are more susceptible to KSHV infection, whereas activation of TLR4 protects cells from infection. In vivo, HIV-1-infected individuals carrying a mutant TLR4 allele appear more likely to have multicentric Castleman's disease, a lymphoproliferation associated with enhanced KSHV replication. ERK activation by KSHV structural proteins and the KSHV-encoded vGPCR plays a key role in the TLR4 downregulation, whereas the KSHV vIRF1 also contributes to this effect. Our findings reveal a role for TLR4 in innate immunity against herpesviruses and suggest the potential use of TLR4 agonists for the treatment of KSHV-related neoplasms.
Herasimtschuk AA, Westrop SJ, Moyle GJ, et al., 2008, Effects of recombinant human growth hormone on HIV-1-specific T-cell responses, thymic output and proviral DNA in patients on HAART: 48-week follow-up, Journal of Immune Based Therapies and Vaccines, Vol: 6, ISSN: 1476-8518
BackgroundEfficacious immune-based therapy in treated chronic HIV-1 infection requires the induction of virus-specific CD4+ T cells and subsequent maturation and maintenance of specific memory CD8+ T cells. Concomitant daily administration of recombinant human growth hormone (rhGH) with highly active antiretroviral therapy (HAART) was used in chronically infected patients with lipodystrophy in an attempt to reconstitute these virus-specific T-cell responses.MethodsIndividuals with chronic HIV-1 infection on HAART were enrolled on a randomized, double-blinded, placebo-controlled study to receive rhGH therapy. We assessed HIV-1-specific proliferative CD4+ and interferon-gamma (IFN-γ)-producing CD8+ T-cell responses, quantified thymic output and proviral HIV-1 DNA at the following time points: baseline; after 12 weeks of rhGH therapy; at 24 weeks, after randomization into three groups [placebo weeks 12–24 (Group A), alternate-day dosing weeks 12–24 (Group B), and twice-per-week dosing weeks 12–24 (Group C)]; and at 48 weeks after all patients had received HAART alone for the final 24 weeks.ResultsWe found significant increases in both proliferative CD4+ and IFN-γ-producing CD8+ HIV-1-specific T-cell responses after daily administration of rhGH. This increase was focused on HIV-1 Gag-specific T-cell responses. Following subsequent randomisation into different dosing regimens, HIV-1-specific proliferative CD4+ T-cell responses declined in patients receiving less frequent dosing of rhGH, while virus-specific IFN-γ-producing CD8+ T-cell responses were maintained for longer periods of time. There was no significant change in thymic output and the cell-associated HIV-1 DNA remained stable in most patients. An increased anti-HIV-1 Nef-specific CD4+ T-cell proliferative response was correlated to a decrease in proviral load, and an increased HIV-1 Gag-specific IFN-γ-producing CD8+ T-cell response correlated with an increase in proviral
Malnati MS, Heltay S, Cosma A, et al., 2008, A New Antigen-Scanning Strategy to Monitor T-Cell Immune Responses, AIDS Vaccine 2008 Conference, Publisher: MARY ANN LIEBERT INC, Pages: 136-136, ISSN: 0889-2229
Gudmundsdotter L, Bostrom A-C, Burton C, et al., 2008, Long-term increase of CD4<SUP>+</SUP> central memory cells in HIV-1-infected individuals by therapeutic HIV-1 rgp160 immunization, VACCINE, Vol: 26, Pages: 5107-5110, ISSN: 0264-410X
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- Citations: 3
Burton CT, Goodall RL, Samri A, et al., 2008, Restoration of anti-tetanus toxoid responses in patients initiating highly active antiretroviral therapy with or without a boost immunization: an INITIO substudy, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 152, Pages: 252-257, ISSN: 0009-9104
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- Citations: 12
Westrop SJ, Constantinou DS, Nelson M, et al., 2008, Lack of Evidence for CD8+ T Cell-mediated Selection Pressure on Proviral Gag p17 and p24 in Chronically Infected HIV-1+ Individuals, 15th Conference on Retroviruses and Opportunistic Infection
Imami N, Westrop S, Cranage A, et al., 2007, Combined use of cytokines, hormones and therapeutic vaccines during effective antiretroviral therapy, Future HIV Therapy, Vol: 1, Pages: 171-179
Immune-based therapies using vaccines, cytokines and hormones are being considered in the context of effective antiretroviral therapy to induce immunologically defined long-term nonprogressor status in chronically infected HIV-1 patients. Such immunotherapy must allow induction or regeneration of anti-HIV-1 immune responses with the potential to control viremia, activate and eradicate viral reservoirs, and alleviate the immunosuppression caused by HIV-1, eventually possibly reaching the status of a virologically defined ‘elite controller’ with an absence of detectable viremia and no progression to disease over a long period of time. This article summarizes pilot studies utilizing therapeutic vaccines, cytokines and/or hormones in treated HIV-1 infection, and focuses on novel agents and immunotherapeutic options that may have the potential to augment or replace existing antiretroviral therapy with the aim of inducing nonprogressor status in the infected host.
Imami N, Westrop S, Cranage A, et al., 2007, Combined use of cytokines, hormones and therapeutic vaccines during effective antiretroviral therapy, Future HIV Therapy, Vol: 1, Pages: 171-179
Rosignoli G, Cranage A, Burton C, et al., 2007, Expression of PD-L1, a marker of disease status, is not reduced by HAART in aviraemic patients, AIDS, Vol: 21, Pages: 1379-1381, ISSN: 0269-9370
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- Citations: 23
Hardy GA, Imami N, Nelson MR, et al., 2007, A phase I, randomized study of combined IL-2 and therapeutic immunisation with antiretroviral therapy, Journal of Immune Based Therapies and Vaccines, Vol: 5, ISSN: 1476-8518
BackgroundFully functional HIV-1-specific CD8 and CD4 effector T-cell responses are vital to the containment of viral activity and disease progression. These responses are lacking in HIV-1-infected patients with progressive disease. We attempted to augment fully functional HIV-1-specific CD8 and CD4 effector T-cell responses in patients with advanced chronic HIV-1 infection.DesignChronically infected patients with low CD4 counts T-cell counts who commenced antiretroviral therapy (ART) were subsequently treated with combined interleukin-2 and therapeutic vaccination.MethodsThirty six anti-retroviral naive patients were recruited and initiated on combination ART for 17 weeks before randomization to: A) ongoing ART alone; B) ART with IL-2 twice daily for 5 days every four weeks starting at week 17 for 3 cycles; C) ART with IL-2 as in group B and Remune HIV-1 vaccine administered once every 3 months, starting at week 17; and D) ART with Remune vaccine as in group C. Patients were studied for 65 weeks following commencement of ART, with an additional prior 6 week lead-in observation period. CD4 and CD8 T-cell counts, evaluations of HIV-1 RNA levels and proliferative responses to recall and HIV-1 antigens were complemented with assessment of IL-4-secretion alongside quantification of anti-HIV-1 CD8 T-cell responses and neutralizing antibody titres.ResultsNeither IL-2 nor Remune™ vaccination induced sustained HIV-1-specific T-cell responses. However, we report an inverse relationship between HIV-1-specific proliferative responses and IL-4 production which continuously increased in patients receiving immunotherapy, but not patients receiving ART alone.ConclusionInduction of HIV-1-specific cell-mediated responses is a major challenge in chronically HIV-1-infected patients even when combining immunisation with IL-2 therapy. An antigen-specific IL-4-associated suppressive response may play a role in attenuating HIV-specific responses.
Kebba A, Imami N, Bugembe-Lule D, et al., 2007, Recent HIV-1 infection in a high-risk Ugandan cohort: implications for Phase IIB test-of-concept HIV vaccine trials, PHARMACOGENOMICS, Vol: 8, Pages: 409-414, ISSN: 1462-2416
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- Citations: 3
Aspinall R, Pido-Lopez J, Imami N, et al., 2007, Old rhesus macaques treated with interleukin-7 show increased TREC levels and respond well to influenza vaccination, REJUVENATION RESEARCH, Vol: 10, Pages: 5-17, ISSN: 1549-1684
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- Citations: 59
Page M, Ojugo A, Imami N, et al., 2007, Specificity of anti-human leukocyte antigen antibody responses after immunization with Remune, an inactivated HIV-1 vaccine, AIDS, Vol: 21, Pages: 375-377, ISSN: 0269-9370
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- Citations: 5
Samri A, Goodall R, Burton C, et al., 2007, Three-year immune reconstitution in PI-sparing and PI-containing antiretroviral regimens in advanced HIV-1 disease, ANTIVIRAL THERAPY, Vol: 12, Pages: 553-558, ISSN: 1359-6535
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- Citations: 6
Imami N, Kebba A, Gotch F, 2006, An anniversary without celebration?, NATURE IMMUNOLOGY, Vol: 7, Pages: 893-893, ISSN: 1529-2908
Pao D, Smit E, Imami N, et al., 2006, A case of multidrug resistant primary HIV infection with delayed CD4 T-cell count decline despite low viral load, treated with interleukin-2, AIDS, Vol: 20, Pages: 1564-1565, ISSN: 0269-9370
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- Citations: 1
Burton CT, Gotch F, Imami N, 2006, Rapid qualitative and quantitative analysis of T-cell responses in HIV-1-infected individuals receiving successful HAART and HIV-1 sero-negative controls:: Concomitant assessment of perforin, IFN-γ and IL-4 secretion, JOURNAL OF IMMUNOLOGICAL METHODS, Vol: 308, Pages: 216-230, ISSN: 0022-1759
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- Citations: 12
Burton CT, Mela CM, Rosignoli G, et al., 2006, Immune modulation and reconstitution of HIV-1-specific responses: Novel approaches and strategies, CURRENT MEDICINAL CHEMISTRY, Vol: 13, Pages: 3203-3211, ISSN: 0929-8673
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- Citations: 5
Mela CM, Burton CT, Imami N, et al., 2005, Switch from inhibitory to activating NKG2 receptor expression in HIV-1 infection: lack of reversion with highly active antiretroviral therapy, AIDS, Vol: 19, Pages: 1761-1769, ISSN: 0269-9370
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- Citations: 77
Burton CT, Nelson MR, Hay P, et al., 2005, Immunological and virological consequences of patient-directed antiretroviral therapy interruption during chronic HIV-1 infection, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 142, Pages: 354-361, ISSN: 0009-9104
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- Citations: 12
Gotch F, Holmes H, Imami N, 2005, The importance of standardisation of laboratory evaluations in HIV vaccine trials, MICROBES AND INFECTION, Vol: 7, Pages: 1424-1432, ISSN: 1286-4579
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- Citations: 10
Pires A, Nelson M, Pozniak AL, et al., 2005, Mycobacterial immune reconstitution inflammatory syndrome in HIV-1 infection after antiretroviral therapy is associated with deregulated specific T-cell responses: beneficial effect of IL-2 and GM-CSF immunotherapy, Journal of Immune Based Therapies and Vaccines, Vol: 3, ISSN: 1476-8518
BackgroundWith the advent of antiretroviral therapy (ART) cases of immune reconstitution inflammatory syndrome (IRIS) have increasingly been reported. IRIS usually occurs in individuals with a rapidly rising CD4 T-cell count or percentage upon initiation of ART, who develop a deregulated immune response to infection with or without reactivation of opportunistic organisms. Here, we evaluated rises in absolute CD4 T-cells, and specific CD4 T-cell responses in 4 HIV-1+ individuals presenting with mycobacterial associated IRIS who received in conjunction with ART, IL-2 plus GM-CSF immunotherapy.MethodsWe assessed CD4 T-cell counts, HIV-1 RNA loads, phenotype for naïve and activation markers, and in vitro proliferative responses. Results were compared with those observed in 11 matched, successfully treated asymptomatic clinical progressors (CP) with no evidence of opportunistic infections, and uninfected controls.ResultsMedian CD4 T-cell counts in IRIS patients rose from 22 cells/μl before initiation of ART, to 70 cells/μl after 8 months of therapy (median 6.5 fold increase). This coincided with IRIS diagnosis, lower levels of naïve CD4 T-cells, increased expression of immune activation markers, and weak CD4 T-cell responses. In contrast, CP had a median CD4 T-cell counts of 76 cells/μl at baseline, which rose to 249 cells/μl 6 months post ART, when strong T-cell responses were seen in > 80% of patients. Higher levels of expression of immune activation markers were seen in IRIS patients compared to CP and UC (IRIS > CP > UC). Immunotherapy with IL-2 and GM-CSF paralleled clinical recovery.ConclusionThese data suggest that mycobacterial IRIS is associated with inadequate immune reconstitution rather than vigorous specific T-cell responses, and concomitant administration of IL-2 and GM-CSF immunotherapy with effective ART may correct/augment T-cell immunity in such setting resulting in clinical benefit.
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
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- Citations: 19
Burton CT, Gotch FM, Imami N, 2005, CCR2/64l mutation detection in a HIV-1-positive patient with slow CD4 T-cell decline and delay in disease progression, INTERNATIONAL JOURNAL OF STD & AIDS, Vol: 16, Pages: 392-394, ISSN: 0956-4624
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- Citations: 4
Nesrina Imami, Antonio Pires, 2005, Detection and Quantitation of HIV-1-Specific T Lymphocytes in HIV-1 Infected Individuals and Vaccine Recipients, Progress in AIDS Research, Editors: Liberman, New York, Publisher: Nova Science Publishers, Pages: 109-137, ISBN: 9781594541810
Hardy GAD, Imami N, Sullivan AK, et al., 2004, Tetanus vaccination with IL-2 during highly active antiretroviral therapy induces sustained and pronounced specific CD4 T-cell responses, AIDS, Vol: 18, Pages: 2199-2202, ISSN: 0269-9370
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- Citations: 4
Pires A, Hardy G, Gazzard B, et al., 2004, Initiation of antiretroviral therapy during recent HIV-1 infection results in lower residual viral reservoirs, JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES, Vol: 36, Pages: 783-790, ISSN: 1525-4135
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- Citations: 23
Kebba A, Kaleebu P, Rowland S, et al., 2004, Distinct patterns of peripheral HIV-1-specific interferon-γ responses in exposed HIV-1-seronegative individuals, JOURNAL OF INFECTIOUS DISEASES, Vol: 189, Pages: 1705-1713, ISSN: 0022-1899
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- Citations: 28
Hardy G, Worrell S, Hayes P, et al., 2004, Evidence of thymic reconstitution after highly active antiretroviral therapy in HIV-1 infection, HIV MEDICINE, Vol: 5, Pages: 67-73, ISSN: 1464-2662
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- Citations: 26
Goodier MR, Imami N, Moyle G, et al., 2004, Loss of the CD56(hi) CD16(-) NK cell subset and NK cell interferon-gamma production during antiretroviral therapy for HIV-1: partial recovery by human growth hormone (vol 134, pg 470, 2003), Clinical and Experimental Immunology, Vol: 135, Pages: 344-344, ISSN: 0009-9104
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