185 results found
Macharia GN, Yue L, Staller E, et al., 2020, Infection with multiple HIV-1 founder variants is associated with lower viral replicative capacity, faster CD4(+)T cell decline and increased immune activation during acute infection, PLoS Pathogens, Vol: 16, Pages: 1-22, ISSN: 1553-7366
HIV-1 transmission is associated with a severe bottleneck in which a limited number of variants from a pool of genetically diverse quasispecies establishes infection. The IAVI protocol C cohort of discordant couples, female sex workers, other heterosexuals and men who have sex with men (MSM) present varying risks of HIV infection, diverse HIV-1 subtypes and represent a unique opportunity to characterize transmitted/founder viruses (TF) where disease outcome is known. To identify the TF, the HIV-1 repertoire of 38 MSM participants’ samples was sequenced close to transmission (median 21 days post infection, IQR 18–41) and assessment of multivariant infection done. Patient derived gag genes were cloned into an NL4.3 provirus to generate chimeric viruses which were characterized for replicative capacity (RC). Finally, an evaluation of how the TF virus predicted disease progression and modified the immune response at both acute and chronic HIV-1 infection was done. There was higher prevalence of multivariant infection compared with previously described heterosexual cohorts. A link was identified between multivariant infection and replicative capacity conferred by gag, whereby TF gag tended to be of lower replicative capacity in multivariant infection (p = 0.02) suggesting an overall lowering of fitness requirements during infection with multiple variants. Notwithstanding, multivariant infection was associated with rapid CD4+ T cell decline and perturbances in the CD4+ T cell and B cell compartments compared to single variant infection, which were reversible upon control of viremia. Strategies aimed at identifying and mitigating multivariant infection could contribute toward improving HIV-1 prognosis and this may involve strategies that tighten the stringency of the transmission bottleneck such as treatment of STI. Furthermore, the sequences and chimeric viruses help with TF based experimental vaccine immunogen design and can be used in functional assays to pr
Cocker A, Shah N, Raj I, et al., 2020, Pregnancy gestation impacts on HIV-1-specific granzyme B response and central memory CD4 T cells, Frontiers in Immunology, Vol: 11, ISSN: 1664-3224
Pregnancy induces alterations in peripheral T-cell populations with both changes in subset frequencies and anti-viral responses found to alter with gestation. In HIV-1 positive women anti-HIV-1 responses are associated with transmission risk, however detailed investigation into both HIV-1-specific memory responses associated with HIV-1 control and T-cell subset changes during pregnancy have not been undertaken. In this study we aimed to define pregnancy and gestation related changes to HIV-1-specific responses and T-cell phenotype in ART treated HIV-1 positive pregnant women. Eleven non-pregnant and 24 pregnant HIV-1 positive women were recruited, peripheral blood samples taken, fresh cells isolated, and compared using ELISpot assays and flow cytometry analysis. Clinical data were collected as part of standard care, and non-parametric statistics used. Alterations in induced IFNγ, IL-2, IL-10, and granzyme B secretion by peripheral blood mononuclear cells in response to HIV-1 Gag and Nef peptide pools and changes in T-cell subsets between pregnant and non-pregnant women were assessed, with data correlated with participant clinical parameters and longitudinal analysis performed. Cross-sectional comparison identified decreased IL-10 Nef response in HIV-1 positive pregnant women compared to non-pregnant, while correlations exhibited reversed Gag and Nef cytokine and protease response associations between groups. Longitudinal analysis of pregnant participants demonstrated transient increases in Gag granzyme B response and in the central memory CD4 T-cell subset frequency during their second trimester, with a decrease in CD4 effector memory T cells from their second to third trimester. Gag and Nef HIV-1-specific responses diverge with pregnancy time-point, coinciding with relevant T-cell phenotype, and gestation associated immunological adaptations. Decreased IL-10 Nef and both increased granzyme B Gag response and central memory CD4 T cells implies that amplified a
Shah NM, Edey LF, Imami N, et al., 2020, Human labour is associated with altered regulatory T cell function and maternal immune activation, Clinical & Experimental Immunology, Vol: 199, Pages: 182-200, ISSN: 0009-9104
During human pregnancy, regulatory T cell (Treg) function is enhanced and immune activation is repressed allowing the growth and development of the feto–placental unit. Here, we have investigated whether human labour is associated with a reversal of the pregnancy‐induced changes in the maternal immune system. We tested the hypothesis that human labour is associated with a decline in Treg function, specifically their ability to modulate Toll‐like receptor (TLR)‐induced immune responses. We studied the changes in cell number, activation status and functional behaviour of peripheral blood, myometrial (myoMC) and cord blood mononuclear cells (CBMC) with the onset of labour. We found that Treg function declines and that Treg cellular targets change with labour onset. The changes in Treg function were associated with increased activation of myoMC, assessed by their expression of major histocompatibility complex (MHC) class II molecules and CBMC inflammatory cells. The innate immune system showed increased activation, as shown by altered monocyte and neutrophil cell phenotypes, possibly to be ready to respond to microbial invasion after birth or to contribute to tissue remodelling. Our results highlight changes in the function of the adaptive and innate immune systems that may have important roles in the onset of human labour.
Sayed AAA, Cooper N, Malik A, et al., 2019, Eltrombopag: more than just a thrombopoietin receptor agonist (TPO-RA) in immune thrombocytopenia (ITP), 61st Annual Meeting and exposition of the American Society for Hematology (ASH), Publisher: American Society of Hematology, ISSN: 0006-4971
Shah NM, Imami N, Kelleher P, et al., 2019, Pregnancy-related immune suppression leads to altered influenza vaccine recall responses, Clinical Immunology, Vol: 208, ISSN: 1521-6616
Pregnancy is a risk factor for severe influenza infection. Despite achieving seroprotective antibody titres post immunisation fewer pregnant women experience a reduction in influenza-like illness compared to non-pregnant cohorts. This may be due to the effects that immune-modulation in pregnancy has on vaccine efficacy leading to a less favourable immunologic response.To understand this, we investigated the antigen-specific cellular responses and leukocyte phenotype in pregnant and non-pregnant women who achieved seroprotection post immunisation. We show that pregnancy is associated with better antigen-specific inflammatory (IFN-γ) responses and an expansion of central memory T cells (Tcm) post immunisation, but low-level pregnancy-related immune regulation (HLA-G, PIBF) and associated reduced B-cell antibody maintenance (TGF-β) suggest poor immunologic responses compared to the non-pregnant.Thus far, studies of influenza vaccine immunogenicity have focused on the induction of antibodies but understanding additional vaccine-related cellular responses is needed to fully appreciate how pregnancy impacts on vaccine effectiveness.
Shah NM, Lai PF, Imami N, et al., 2019, Progesterone-related immune modulation of pregnancy and labor, Frontiers in Endocrinology, Vol: 10, ISSN: 1664-2392
Pregnancy involves a complex interplay between maternal neuroendocrine and immunological systems in order to establish and sustain a growing fetus. It is thought that the uterus at pregnancy transitions from quiescent to laboring state in response to interactions between maternal and fetal systems at least partly via altered neuroendocrine signaling. Progesterone (P4) is a vital hormone in maternal reproductive tissues and immune cells during pregnancy. As such, P4 is widely used in clinical interventions to improve the chance of embryo implantation, as well as reduce the risk of miscarriage and premature labor. Here we review research to date that focus on the pathways through which P4 mediates its actions on both the maternal reproductive and immune system. We will dissect the role of P4 as a modulator of inflammation, both systemic and intrinsic to the uterus, during human pregnancy and labor.
Cocker ATH, Greathead L, Herasimtschuk AA, et al., 2019, Therapeutic immunisation benefits mucosal-associated invariant T-cell recovery in contrast to IL-2, GM-CSF, and rhGH addition in HIV-1+ treated patients: individual case reports from phase I trial, AIDS Research and Human Retroviruses, Vol: 35, ISSN: 0889-2229
Mucosal-associated invariant T (MAIT) cell populations are reduced in frequency in HIV-1+ patients, and this disruption is associated with systemic immune activation. Reconstitution of MAIT frequency may benefit HIV-1-infected individuals; however, only recently has in vivo work been endeavored. Treatment with interleukin (IL)-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), and recombinant human growth hormone (rhGH) immunotherapy combined with an HIV-1 vaccine in the context of antiretroviral therapy (ART) has shown to reconstitute CD4 T cell population numbers and function. In this study cryopreserved peripheral blood mononuclear cells (PBMCs) from 12 HIV-1+ patients who were undergoing a combination of HIV-1 vaccine and/or IL-2, GM-CSF and rhGH immunotherapy in conjunction with ART were analyzed to assess the potential of this treatment to promote MAIT cell proliferation. PBMCs were thawed from study baseline, weeks 2 and 48 time points, fluorescently stained for MAIT cell markers, and assessed by flow cytometric analysis. Matched pairs and intergroup results were statistically compared using appropriate methods. MAIT cell frequency was increased from baseline at 48 weeks in participants who received vaccine only, whereas individuals receiving IL-2, GM-CSF, and rhGH immunotherapy with or without vaccine did not show additional benefit. Although IL-2, GM-CSF, and rhGH treatment promotes CD4 T cell reconstitution and HIV-1-specific T cell function, it does not support MAIT cell recovery in patients on suppressive ART. Therapeutic immunization however has a positive effect, highlighting the importance of aiming for balanced promotion of T cell population reconstitution to impact on HIV-1 transmission and pathogenesis.
Macharia G, Staller E, Yue L, et al., 2018, Infection With Multiple Transmitted/Founder (TF) HIV-1 Viruses Impacts Peak VL and HIV-1 Pathogenesis, HIV Research for Prevention 2018: AIDS Vaccine, Microbicide and ARV-based Prevention Science (HIVR4P)
Shah NM, Imami N, Johnson MR, 2018, Progesterone Modulation of Pregnancy-Related Immune Responses, FRONTIERS IN IMMUNOLOGY, Vol: 9, ISSN: 1664-3224
Progesterone (P4) is an important steroid hormone for the establishment and maintenance of pregnancy and its functional withdrawal in reproductive tissue is linked with the onset of parturition. However, the effects of P4 on adaptive immune responses are poorly understood. In this study, we took a novel approach by comparing the effects of P4 supplementation longitudinally, with treatment using a P4 antagonist mifepristone (RU486) in mid-trimester pregnancies. Thus, we were able to demonstrate the immune-modulatory functions of P4. We show that, in pregnancy, the immune system is increasingly activated (CD38, CCR6) with greater antigen-specific cytotoxic T cell responses (granzyme B). Simultaneously, pregnancy promotes a tolerant immune environment (IL-10 and regulatory-T cells) that gradually reverses prior to the onset of labor. P4 suppresses and RU486 enhances antigen-specific CD4 and CD8 T cell inflammatory cytokine (IFN-γ) and cytotoxic molecule release (granzyme B). P4 and RU486 effectively modulate immune cell-mediated interactions, by regulating differentiated memory T cell subset sensitivity to antigen stimulation. Our results indicate that P4 and RU486, as immune modulators, share a reciprocal relationship. These data unveil key contributions of P4 to the modulation of the maternal immune system and suggests targets for future modulation of maternal immune function during pregnancy.
Sassine AJ, Sivarajasingam SP, Cocker ATH, et al., 2018, Erythrocyte oleic acid is correlated with increasing natural killer cells in maternal blood, 65th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: Elsevier, Pages: 319A-319A, ISSN: 1933-7191
Westrop S, Grageda N, Imami N, 2018, Novel Approach to Recognition of Predicted HIV-1 Gag B*3501-Restricted CD8 T-Cell Epitopes by HLA-B*3501*Patients: Confirmation by Quantitative ELISpot Analyses and Characterisation Using Multimers, 2nd European Congress of Immunology (ECI)
Cocker A, Sivarajasingam S, Dermont S, et al., 2018, Gestational immunological adaptations and anti-viral responses are disrupted in HIV-1+pregnancies, 65th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: Elsevier, Pages: 318A-319A, ISSN: 1933-7191
Shah NM, Sooranna G, Imami N, et al., 2018, Progesterone suppressed ex vivo pregnancy immune responses are reversed with the progesterone antagonist RU486, 65th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: Sage, Pages: 314A-314A, ISSN: 1933-7191
Shah NM, Edey L, Sooranna G, et al., 2018, Labour is associated with a decline in Treg function and their modulation of TLR-Ligand induced immune responses, 65th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: Sage Publications Inc., Pages: 314A-314A, ISSN: 1071-5576
Sivarajasingam SP, Cocker ATH, Sassine AJ, et al., 2018, Disrupted immunological equilibrium of decidual natural killer cells and regulatory T cells with onset of labour, 65th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: Elsevier, Pages: 177A-177A, ISSN: 1071-5576
Shah NM, Herasimtschuk AA, Boasso A, et al., 2017, Changes in T Cell and Dendritic Cell Phenotype from Mid to Late Pregnancy Are Indicative of a Shift from Immune Tolerance to Immune Activation., Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
During pregnancy, the mother allows the immunologically distinct fetoplacental unit to develop and grow. Opinions are divided as to whether this represents a state of fetal-specific tolerance or of a generalized suppression of the maternal immune system. We hypothesized that antigen-specific T cell responses are modulated by an inhibitory T cell phenotype and modified dendritic cell (DC) phenotype in a gestation-dependent manner. We analyzed changes in surface markers of peripheral blood T cells, ex vivo antigen-specific T cell responses, indoleamine 2,3-dioxygenase (IDO) activity (kynurenine/tryptophan ratio, KTR), plasma neopterin concentration, and the in vitro expression of progesterone-induced blocking factor (PIBF) in response to peripheral blood mononuclear cell culture with progesterone. We found that mid gestation is characterized by reduced antigen-specific T cell responses associated with (1) predominance of effector memory over other T cell subsets; (2) upregulation of inhibitory markers (programmed death ligand 1); (3) heightened response to progesterone (PIBF); and (4) reduced proportions of myeloid DC and concurrent IDO activity (KTR). Conversely, antigen-specific T cell responses normalized in late pregnancy and were associated with increased markers of T cell activation (CD38, neopterin). However, these changes occur with a simultaneous upregulation of immune suppressive mechanisms including apoptosis (CD95), coinhibition (TIM-3), and immune regulation (IL-10) through the course of pregnancy. Together, our data suggest that immune tolerance dominates in the second trimester and that it is gradually reversed in the third trimester in association with immune activation as the end of pregnancy approaches.
Westrop SJ, Cocker ATH, Boasso A, et al., 2017, Enrichment of HLA types and single-nucleotide polymorphism associated with non-progression in a strictly defined cohort of HIV-1 controllers, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
HIV-1 controllers (HIC) are extremely rare patients with the ability to control viral replication, maintain unchanging CD4 T-cell count, and evade disease progression for extensive periods of time, in the absence of antiretroviral therapy. In order to establish the representation of key genetic correlates of atypical disease progression within a cohort of HIV-1+ individuals who control viral replication, we examine four-digit resolution HLA type and single-nucleotide polymorphisms (SNP) previously identified to be correlated to non-progressive infection, in strictly defined HIC. Clinical histories were examined to identify patients exhibiting HIC status. Genomic DNA was extracted, and high definition HLA typing and genome-wide SNP analysis was performed. Data were compared with frequencies of SNP in European long-term non-progressors (LTNP) and primary infection cohorts. HLA-B alleles associated with atypical disease progression were at very high frequencies in the group of five HIC studied. All four HIC of European ancestry were HLA-B*57+ and half were also HLA-B*27+. All HIC, including one of self-reported African ethnicity, had the HLA-Cw*0602 allele, and the HLA-DQ9 allele was present only in HIC of European ancestry. A median 95% of the top 19 SNP known to be associated with LTNP status was observed in European HIC (range 78–100%); 17/19 of the SNP considered mapped to chromosome 6 in the HLA region, whereas 2/19 mapped to chromosome 8. The HIC investigated here demonstrated high enrichment of HLA types and SNP previously associated with long-term non-progression. These findings suggest that the extreme non-progressive phenotype considered here is associated with a genetic signature characterized by a single-genetic unit centered around the HLA-B*57 haplotype and the possible additive effect of HLA-B*27.
Cocker A, Imami N, Johnson M, et al., 2017, HIV-1-positive pregnancies demonstrate altered IFN gamma and IL-10 responses to flu and CMV and disrupted DC, NK and T-cell profiles, 23rd Annual Conference of the British HIV Association, Publisher: Wiley, Pages: 28-28, ISSN: 1464-2662
Cocker A, Dermont S, Khan W, et al., 2017, Altered CD4 and NK cell profile with inverse IFN gamma and IL-10 antiviral response in HIV-1(+) pregnancies, 64th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: Elsevier, Pages: 294A-294A, ISSN: 1071-5576
Sivarajasingam SP, Das A, Herbert BR, et al., 2017, Immunological changes in the choriodecidua, placenta and amnion in preterm deliveries secondary to chorioamnionitis., 64th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: Elsevier, Pages: 174A-175A, ISSN: 1071-5576
Mletzko S, Pinato DJ, Robey RC, et al., 2017, Programmed death ligand 1 (PD-L1) expression influences the immune-tolerogenic microenvironment in antiretroviral therapy-refractory Kaposi's sarcoma: A pilot study., Oncoimmunology, Vol: 6, ISSN: 2162-4011
Upregulation of programmed death ligand 1 (PD-L1) is a mechanism of immune escape utilized by a variety of tumors. PD-L1 expression in tumor cells or in the surrounding infiltrate correlates with clinical responsiveness to novel therapies targeting the PD-1/PD-L1 immune checkpoint. In the context of HIV-1 infection, Kaposi's sarcoma (KS) is largely responsive to restoration of immunity following combination antiretroviral therapy (cART), but there is a subset that is not. We hypothesized that this subset of cART-refractory KS may utilize the PD-L1 pathway of immune escape. We found that PD-L1 expressing KS had a denser CD8+ T cell (p = 0.03) and PD-L1 positive macrophage peritumoral infiltrate (p = 0.04) to suggest the involvement of PD-L1 in shaping an immune-tolerogenic microenvironment in cART-refractory KS. The presence of PD-L1 expression in association with immune-infiltrating cells provides rationale for the clinical development PD-1/PD-L1-targeted checkpoint inhibitors in cART-refractory KS.
Sivarajasingam SP, Imami N, Johnson M, 2016, Cytokines and myometrial signalling in human labour, Journal of Endocrinology, Vol: 231, Pages: R101-R119, ISSN: 1479-6805
Human labour is an inflammatory event, physiologically driven by an interaction between hormonal and mechanical factors and pathologically associated with infection, bleeding and excessive uterine stretch. The initiation and communicators of inflammation is still not completely understood, however the role of cytokines and chemokine have been implicated. We summarise the current understanding of the nature and role of cytokines, chemokines and hormones and their involvement in signalling within the myometrium particularly during labour.
Cocker A, Hardy G, Herasimtschuk A, et al., 2016, Gag- and Nef-specific responses are associated with increased proportions of regulatory T cells in treated chronic HIV-1 infection, 22nd Annual Conference of the British HIV Association (BHIVA), Publisher: Wiley, Pages: 29-30, ISSN: 1464-2662
Hardy GAD, Cocker ATH, Imami N, 2015, A stepwise advance out of the shadows: leading HIV to its clearance, FUTURE VIROLOGY, Vol: 10, Pages: 1263-1266, ISSN: 1746-0794
Imami N, Herasimtschuk AA, 2015, Multifarious immunotherapeutic approaches to cure HIV-1 infection, Human Vaccines & Immunotherapeutics, Vol: 11, Pages: 2287-2293, ISSN: 2164-5515
Immunotherapy in the context of treated HIV-1 infection aims to improve immune responses to achieve better control of the virus. To date, multifaceted immunotherapeutic approaches have been shown to reduce immune activation and increase CD4 T-lymphocyte counts, further to the effects of antiretroviral therapy alone, in addition to improving HIV-1-specific T-cell responses. While sterilizing cure of HIV-1 would involve elimination of all replication-competent virus, a functional cure in which the host has long-lasting control of viral replication may be more feasible. In this commentary, we discuss novel strategies aimed at targeting the latent viral reservoir with cure of HIV-1 infection being the ultimate goal, an achievement that would have considerable impact on worldwide HIV-1 infection.
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
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