Publications
191 results found
Pires A, Pido-Lopez J, Moyle G, et al., 2004, Enhanced T-cell maturation, differentiation and function in HIV-1-infected individuals after growth hormone and highly active antiretroviral therapy, ANTIVIRAL THERAPY, Vol: 9, Pages: 67-75, ISSN: 1359-6535
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- Citations: 19
Imami N, Pires A, Burton C, 2004, The challenge of developing an effective HIV-1 vaccine, Drug Discovery Today: Therapeutic Strategies, Vol: 1, Pages: 461-467, ISSN: 1740-6773
An effective and safe vaccine against HIV-1 remains elusive. Animal and human studies reveal crucial insights into the pathogenesis of HIV-1 and potential successful approaches for preventive and therapeutic immunization. Such studies have focussed on dissecting correlates of immunity as well as highlighting the role of CD4-helper T lymphocytes in the regulation of the immune response. There are formidable challenges facing those behind the development of strategies for induction of effective HIV-1-specific T-lymphocytes and control of viral replication. © 2004 Elsevier Ltd. All rights reserved.
Portsmouth S, Imami N, Pires A, et al., 2004, Treatment of primary HIV-1 infection with nonnucleoside reverse transcriptase inhibitor-based therapy is effective and well tolerated, HIV MEDICINE, Vol: 5, Pages: 26-29, ISSN: 1464-2662
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- Citations: 9
Rutebemberwa A, Auma B, Gilmour J, et al., 2004, HIV type 1-specific inter- and intrasubtype cellular immune responses in HIV type 1-infected Ugandans, AIDS Res Hum Retroviruses, Vol: 20, Pages: 763-771, ISSN: 0889-2229
Kebba A, Kaleebu P, Serwanga J, et al., 2004, HIV type 1 antigen-responsive CD4+ T-lymphocytes in exposed yet HIV Type 1 seronegative Ugandans, AIDS Res Hum Retroviruses, Vol: 20, Pages: 67-75, ISSN: 0889-2229
Chadwick D, Pido-Lopez J, Pires A, et al., 2003, A pilot study of the safety and efficacy of thymosin α<sub>1</sub> in augmenting immune reconstitution in HIV-infected patients with low CD4 counts taking highly active antiretroviral therapy, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 134, Pages: 477-481, ISSN: 0009-9104
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- Citations: 28
Goodier MR, Imami N, Moyle G, et al., 2003, Loss of the CD56<SUP>hi</SUP>CD16<SUP>-</SUP> NK cell subset and NK cell interferon-γ production during antiretroviral therapy for HIV-1:: partial recovery by human growth hormone, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 134, Pages: 470-476, ISSN: 0009-9104
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- Citations: 38
Hardy GAD, Imami N, Sullivan AK, et al., 2003, Reconstitution of CD4<SUP>+</SUP> T cell responses in HIV-1 infected individuals initiating highly active antiretroviral therapy (HAART) is associated with renewed interleukin-2 production and responsiveness, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 134, Pages: 98-106, ISSN: 0009-9104
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- Citations: 27
Morlese JF, Orkin CM, Abbas R, et al., 2003, Plasma IL-6 as a marker of mycobacterial immune restoration disease in HIV-1 infection, AIDS, Vol: 17, Pages: 1411-1413, ISSN: 0269-9370
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- Citations: 25
Imami N, Gotch F, 2003, Twenty years of HIV-1 research: what the future holds, NATURE IMMUNOLOGY, Vol: 4, Pages: 501-501, ISSN: 1529-2908
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- Citations: 1
Sullivan AK, Burton CT, Nelson MR, et al., 2003, Restoration of human immunodeficiency virus-1-specific responses in patients changing from protease to non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy, Scandinavian Journal of Immunology, Vol: 57, Pages: 600-607, ISSN: 0300-9475
The effect of altering antiretroviral therapy (ART) on responses to viral, recall and human immunodeficiency virus (HIV)-1-specific recombinant antigens and interleukin-2 (IL-2) in HIV-1-infected patients was assessed. A longitudinal cohort study in eight HIV-1 infected individuals following a clinically indicated therapy change (seven for drug intolerance and one for virological failure) from protease inhibitor (PI) to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral regimens was performed. CD4 T-cell counts, viral loads, lymphoproliferative responses, cytokine production and latent proviral deoxyribonucleic acid (DNA) were measured at baseline and at weeks 12 and 24 after therapy substitution. Following therapy-switch there was a 33% proportional increase in mitogen response (95% confidence interval (CI), 3–33%) and a 31% increase (95% CI, 15–48%) in viral and recall-antigen responses. Six patients developed proliferative responses to low concentration IL-2 stimulation. All patients demonstrated an increase in median HIV-1-specific responses, as three had detectable virus at baseline (two being viral rebound); this may reflect an autovaccination effect. Proviral DNA changes largely reflected plasma HIV-1 ribonucleic acid (RNA). In conclusion, NNRTI substitution for a PI may favour immune reconstitution with an improvement in HIV-1-specific responses, which may reflect differential effects on antigen processing and presentation, an autovaccination effect or alternatively a potential suppressive effect of the PI.
Stebbing J, Bourboulia D, Johnson M, et al., 2003, Kaposi's sarcoma-associated herpesvirus cytotoxic T lymphocytes recognize and target Darwinian positively selected autologous K1 epitopes, Journal of Virology, Vol: 77, Pages: 4306-4314, ISSN: 0022-538X
Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of Kaposi's sarcoma (KS) and certain lymphoproliferations particularly in the context of human immunodeficiency virus (HIV) type 1-induced immunosuppression. The introduction of effective therapies to treat HIV has led to a decline in the incidence of KS, suggesting that immune responses may play a role in controlling KSHV infection and pathogenesis. Cytotoxic-T-lymphocyte (CTL) activity against KSHV proteins has been demonstrated; however, the identification of KSHV CTL epitopes remains elusive and problematic. Although the herpesvirus genomic layout is generally conserved, KSHV encodes a unique hypervariable protein, K1, with intense biological selection pressure at specific amino acid sites. To investigate whether this variability is partly driven by cellular immunity, we designed K1 peptides that match only the unique viral sequence for every individual studied here (autologous peptides). We identified functional CTL epitopes within K1's most variable areas, and we show that a given individual responds only to autologous peptides and not to peptides from other individuals. Furthermore, these epitopes are highly conserved sequences within KSHV isolates from a specific strain but are not conserved between different strains. We conclude that CTL recognition contributes to K1, and therefore to KSHV, evolution.
Sullivan AK, Hardy GAD, Nelson MR, et al., 2003, Interleukin-2-associated viral breakthroughs induce HIV-1-specific CD4 T cell responses in patients on fully suppressive highly active antiretroviral therapy, AIDS, Vol: 17, Pages: 628-629, ISSN: 0269-9370
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- Citations: 10
Pido-Lopez J, Burton C, Hardy G, et al., 2003, Thymic output during initial highly active antiretroviral therapy (HAART) and during HAART supplementation with interleukin 2 and/or with HIV type 1 immunogen (Remune), AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol: 19, Pages: 103-109, ISSN: 0889-2229
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- Citations: 18
Imami N, Hardy G, 2003, Timing of antiretroviral therapy: an immunological perspective., J HIV Ther, Vol: 8, Pages: 15-18, ISSN: 1462-0308
The success of an effective antiretroviral therapy regimen depends upon its effects on the viral load, the CD4 T-cell count and the ability to preserve and/or restore useful HIV-1-specific immune responses. Many new problems that limit the effectiveness of current treatment are arising during comparison of the differing positions taken in the British and American guidelines. A further difficulty is that many patients present for the first time in the clinic with AIDS-related illness and profound immunosuppression. Pitfalls such as a failure to eradicate the virus, the induction of side effects and a lack of regeneration of HIV-1-specific responses require frequent updates of the guidelines and reviews of the timing of initiation of effective antiretroviral therapy and of strategies for optimising the long-term success of antiretroviral therapy. Treatment guidelines encompass the choice of initial and subsequent regimens, treatment successes and failures, the timing of treatment and, finally, lay down the foundations for promising immune-based therapies and future drug regimens.
Huang A, Gilmour JW, Imami N, et al., 2003, Increased serum transforming growth factor-beta1 in human colorectal cancer correlates with reduced circulating dendritic cells and increased colonic Langerhans cell infiltration, Clin Exp Immunol, Vol: 134, Pages: 270-278, ISSN: 0009-9104
Burton CT, Hardy GAD, Sullivan AK, et al., 2002, Impact of NNRTI compared to PI-based highly active antiretroviral therapy on CCR5 receptor expression, <i>β</i>-chemokines and IL-16 secretion in HIV-1 infection, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 130, Pages: 286-292, ISSN: 0009-9104
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- Citations: 11
Pido-Lopez J, Imami N, Andrew D, et al., 2002, Molecular quantitation of thymic output in mice and the effect of IL-7, European Journal of Immunology, Vol: 32, Pages: 2827-2836, ISSN: 0014-2980
Aging of the murine thymus is accompanied by a measurable loss of weight and cellularity and a marked reduction in its output of T lymphocytes. This study employs a molecular approach to determine changes in the output of the murine thymus using a novel assay system based on the detection and quantitation of the excised TCRδ DNA locus from within the TCRα chain genes. In α β+ T cells such δ excision circles (δEC) are present at higher levels in naive T cells as compared with memory T cell populations, are non-replicating, and diluted within the total peripheral α β+ T cell pool with advancing age. This assay permits the assessment of thymic output in older animals where previous analysis was hampered by the transient nature ofthe naive T cell surface phenotype, and so allows the assessment of the efficacy of IL-7 as an agent to reverse thymic atrophy. Treatment of old mice with IL-7 although producing no overall change in the total number of α β+ T cells in the peripheral T cell pool altered the component subsets. Mice treated with IL-7 showed increases in the number of α β+TCR cells possessing δEC commensurate with improved thymic output, and the splenic T cells from IL-7-treated mice performed significantly better in in vitro functional assays compared to those from age-matched saline-treated controls.
Imami N, Pires A, Hardy G, et al., 2002, A balanced type 1/type 2 response is associated with long-term nonprogressive human immunodeficiency virus type 1 infection, Journal of Virology, Vol: 76, Pages: 9011-9023, ISSN: 0022-538X
Previous reports have emphasized the requirements for strong type 1 cell-mediated responses in the control of human immunodeficiency virus type 1 (HIV-1). HIV-1 Gag p24-specific CD4 helper T-lymphocyte (HTL) responses have been shown to inversely correlate with viral burden in HIV-1-infected individuals. In this study, peripheral blood mononuclear cells from 70 individuals with chronic progressive HIV-1 infection (clinical progressors), 10 clinical nonprogressors, and 3 immunologically discordant progressors were assessed for HTL proliferation and type 1/type 2 cytokine production. Clinical progressors lacked functional HIV-1-specific HTLs with proliferative and cytokine-producing capacity. Clinical nonprogressors were found to respond to a wide range of HIV-1 antigens from different clades, producing both type 1 and type 2 cytokines. Immunologically discordant progressors responded strongly to clade B Gag p24 with a type 1 cytokine profile but not to other antigens. Thus, in contrast to clinical nonprogressors, neither progressors nor immunologically discordant progressors secreted interleukin-4 (IL-4) in response to HIV-1 antigens. Both clinical nonprogressors and immunologically discordant progressors responded broadly to B clade Gag p24-overlapping peptides. However, IL-4 production in the nonprogressors was restricted to a limited number of p24 peptides. No HIV-1-specific T-cell responses were seen in 20 seronegative controls. Additionally, we observed a rapid type 1 to type 2 shift in the response of one immunologically discordant progressor upon onset of clinical symptoms. These results suggest that a balanced type 1/type 2 profile correlates with successful long-term control of HIV-1.
Imami N, Hardy G, Pires A, et al., 2002, Immune reconstitution in HIV-1-infected patients., Curr Opin Investig Drugs, Vol: 3, Pages: 1138-1145, ISSN: 1472-4472
HIV-1-specific CD8 cytotoxic and CD4 helper T-lymphocytes, which are respectively the central effector and regulatory cells in viral infections, together with fully functional antigen-presenting cells, are essential at all stages of HIV-1 infection to control viral activity. Recent studies indicate that such protective HIV-1-specific immune responses can be preserved/induced in HIV-1-infected individuals, utilizing strategies such as treatment interruption after early HAART. Despite successful combination antiretroviral drug therapy, strong anti-HIV-1 T-cell responses are often not apparent in chronic HIV-1 infection, diminishing the probability of viral eradication. Thus, the therapeutic use of immunization and cytokines are required to induce and steer immunity towards a desirable outcome. Here, we review and discuss therapeutic immunization and immunotherapy with regard to their potential use in the treatment of chronic HIV-1 infection.
Imami N, Gotch F, 2002, Mechanisms of loss of HIV-1-specific T-cell responses., J HIV Ther, Vol: 7, Pages: 30-34, ISSN: 1462-0308
Virus-specific T-cell responses, important for the control of HIV-1 infection, are seen in HIV-1-infected subjects in the early stages of infection. A progressive variable decline in HIV-1-specific CD4 and CD8 T-cell responses during the course of the infection is not reversed by the administration of potent antiretroviral drugs. The mechanisms responsible for this HIV-1-inflicted loss are complex, involving processes ranging from T-cell ontogeny to the final stages of antigen presentation and T-cell differentiation. HIV-1-specific CD4 and CD8 T cells are present in most patients, but have been rendered anergic, either directly by HIV-1 or indirectly by clonal inactivation, exhaustion and/or suppression. The absence of functional HIV-1-specific T cells in chronic infection, even after the initiation of antiretroviral therapy, indicates that additional immunomodulatory therapy is required. To induce or maintain such cellular responses in an immunosuppressed environment of chronic infection is proving difficult to achieve. The induction of virus-specific CD4 T-cell and, subsequently, CD8 T-cell responses may require different novel approaches based on an appreciation of the complex mechanisms involved in the loss of these responses.
Huang A, Gilmour J, Imami N, et al., 2002, Dendritic cells are redistributed from the circulation into the colonic mucosa in patients with colorectal cancer, BRITISH JOURNAL OF SURGERY, Vol: 89, Pages: 638-638, ISSN: 0007-1323
Hardy GA, Imami N, Gotch FM, 2002, Improving HIV-specific immune responses in HIV-infected patients., J HIV Ther, Vol: 7, Pages: 40-45, ISSN: 1462-0308
Deficiencies in potentially highly protective HIV-1-specific immune responses have led to interventions with immunotherapeutic strategies such as post-exposure vaccination. The application of exogenous antigen to the HIV-infected individual by therapeutic vaccination might be expected to induce renewed virus-specific effector T-cell and neutralising-antibody responses. However, the nature of HIV-1 immunopathogenicity precludes this approach: high levels of viral turnover, persistent expression and presentation of HIV-1 antigen to the immune system, T-cell hyperactivation and exhaustion and clonal T-cell anergy all successfully counter any effect of exogenous antigen. Even with the use of highly active antiretroviral therapy (HAART), when HIV-1 activity is profoundly restricted, the induction of immune responses remains problematic. Different vaccine strategies are currently being tested, including a whole killed virus preparation (Remune), a yeast virus-like particle (p24 VLP), whole antigen preparations (VaxSyn), canarypox immunogens (ALVAC) and DNA plasmids. Therapeutic vaccine strategies currently in the earliest stages of development include adenovirus vectors and a topical DNA preparation, DermaVir.
Powles T, Imami N, Nelson M, et al., 2002, Effects of combination chemotherapy and highly active antiretroviral therapy on immune parameters in HIV-1 associated lymphoma, AIDS, Vol: 16, Pages: 531-536, ISSN: 0269-9370
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- Citations: 72
Wilkinson J, Cope A, Gill J, et al., 2002, Identification of Kaposi's sarcoma-associated herpesvirus (KSHV)-specific cytotoxic T-lymphocyte epitopes and evaluation of reconstitution of KSHV-specific responses in human immunodeficiency virus type 1-infected patients receiving highly active antiretroviral therapy, Journal of Virology, Vol: 76, Pages: 2634-2640, ISSN: 0022-538X
Following the introduction of highly active antiretroviral therapy (HAART), the incidence of Kaposi's sarcoma (KS) has significantly declined in human immunodeficiency virus type 1 (HIV-1)-positive (HIV-1+) individuals and clinical remission is often observed. We hypothesize that these effects are partly due to anti-KS-associated herpesvirus (KSHV) immune restoration. Here, 15-mer overlapping peptides from proteins K12 and K8.1 were used to identify novel KSHV-specific cytotoxic T-lymphocyte epitopes. Three immunogenic peptides, two lytic and one latent, were subsequently used to monitor the anti-KSHV CD8+ T-cell responses in a cohort of 19 HIV-1+ KSHV+/− KS+/− individuals during 52 weeks of HAART. KSHV and HIV-1 loads, KSHV antibody titers, and both CD4+ and CD8+ T-lymphocyte counts were enumerated. Prior to HAART, the total number of spot-forming cells (SFC) for all three peptides correlated with both CD4+ and CD8+ T-lymphocyte counts (P ≤ 0.05) in the KSHV-positive KS-positive cohort (n = 11). Following 52 weeks of HAART, significant decreases in HIV-1 and KSHV loads were associated with significant increases in CD4+ T-lymphocyte counts and number of SFC for the three KSHV-specific peptides. Although these increases were modest in comparison to the number of SFC observed with the HIV-1 gag peptide SLYNTVATL, they represented a fourfold increase from the baseline, continuing an upward trend to week 52.
Imami N, Gotch F, 2002, Prospects for immune reconstitution in HIV-1 infection, Clinical and Experimental Immunology, Vol: 127, Pages: 402-411, ISSN: 0009-9104
Pido-Lopez J, Pires A, Nelson M, et al., 2002, Thymic activity in late-stage HIV-1 infected individuals receiving highly active antiretroviral therapy: potential effect of steroid therapy, HIV Medicine, Vol: 3, Pages: 56-61, ISSN: 1464-2662
OBJECTIVE: Our objective was to monitor the effect of steroid therapy on the thymic output and function of late-stage HIV-1-infected patients undergoing highly active antiretroviral therapy (HAART). DESIGN: The indirect measurement of T cells that have recently emigrated from the thymus as a means of quantifying thymic output, and therefore thymic function, was achieved through use of the polymerase chain reaction-based signal joint T cell receptor rearrangement excision circles (sjTREC) assay. Proliferative capacity and interleukin (IL)-2 and IL-4 production by T cells after antigenic, mitogenic and IL-2 stimulation were also analysed. METHOD: Measurements were made of sjTREC levels in peripheral blood mononuclear cell DNA samples from five HIV-1 infected patients (one on steroid therapy prior to and at the time of sample extraction) receiving HAART. IL-2 and IL-4 production and proliferative capacity were also measured in three patients, including the patient receiving steroids. RESULT: The sjTREC assay gave an extremely weak result for the patient on steroids but, under the same assay conditions, provided clear, positive readings for the four patients not on steroids. Comparison of the patients' cytokine profiles revealed that IL-2 production was generally low or absent in all three patients tested but that IL-4 production was significantly higher in the patient given steroids. Functional potential as revealed by proliferation assays showed very low or absent cellular proliferation. CONCLUSION: The thymic contribution to the restoration of T lymphocyte numbers, particularly during the treatment of HIV-1 infection, may become compromised if thymic inhibitory factors such as steroids are used. Furthermore, the use of steroids may also favour the development of a T helper 2 response, which could prove particularly undesirable during HIV-1 infection.
Gotch F, Hardy G, Imami N, et al., 2002, The effects of immunotherapy with cytokines and/or vaccines in HAART treated patients, 14th International AIDS Conference, Publisher: MEDIMOND S R L, Pages: 279-284
Imami N, Hardy G, Burton C, et al., 2001, Immune responses and reconstitution in HIV-1 infected individuals: impact of anti-retroviral therapy, cytokines and therapeutic vaccination, IMMUNOLOGY LETTERS, Vol: 79, Pages: 63-76, ISSN: 0165-2478
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- Citations: 25
Imami N, Sullivan AK, Gotch FM, 2001, Immunomodulation in HIV-1 infection in the HAART era., J HIV Ther, Vol: 6, Pages: 77-84, ISSN: 1462-0308
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