Os doentes transplantados renais têm alto risco para desenvolver queratoses actínicas e câncer de pele. Para verificar o efeito quimioprofilático da acitretina estudamos a evolução de 13 doentes transplantados renais com queratoses actínicas múltiplas e história de carcinomas cutâneos submetidos a tratamento por 12 meses (20mg/dia). Fez-se a avaliação clínica e laboratorial regularmente em todo o período do estudo. Realizou-se exame histopatológico, demonstração imuno-histoquímica de sub-populações de linfócitos T (CD4, CD8), células natural killer e células de Langerhans, sua quantificação e comparação em biopsias de pele, sem lesão, de área exposta e protegida do sol antes, após seis e 12 meses de tratamento. Observou-se melhora das lesões cutâneas e ausência de aparecimento de novos tumores em 12 dos 13 pacientes. Não ocorreram alterações laboratoriais relacionadas a função renal, hepatotoxicicidade e hiperlipidemia. Não houve diferenças significativas histopatológicas e da população de linfócitos T e células natural killer da pele exposta e protegida do sol com o tratamento. Verificou-se aumento numérico de células de Langerhans epidérmicas aos 12 meses quando comparado aos da pele antes e após seis meses de tratamento (p = 0,002 e p = 0,003). Em nossa casuística o uso de acitretina em doses baixas foi útil para melhorar o aspecto cutâneo e prevenir lesões cutâneas pré-cancerosas e carcinomas. O aumento das células de Langerhans epidérmicas estaria relacionado ao efeito imunomodular da acitretina. / Renal transplant recipients have an increased incidence of actinic keratosis and skin cancer. In order to examine the chemoprophylatic effects of low-dose acitretin on skin cancer development we submitted 13 renal transplanted patients to acitretin therapy (20 mg/day) for 12 month. The patients were assessed at monthly intervals during the first 6 months and every two months until the 12th month for new skin lesions and for acitretin toxicity. Normal skin biopsies of sun exposed and sun protected area were taken for histopathological exam and submitted to immunohistochemistry technique to demonstrate CD4+ and CD8+ T lymphocytes, natural killer cells and Langerhans cells wich were counted and compared in the beginning, after 6th month and 12th month of the treatment. There was an improvement of actinic keratosis and all patients but one did not develop new skin cancer. Side-effects were well-tolerated and no significant biochemical effects were observed. Although there were no differences in the microscopic aspects of the skin and in the number of CD4+ and CD8+ T lymphocytes and natural killer cells, there was a significant increase in the number of epidermal Langerhans cells after 12 months of acitretin therapy. The data obtained permit us to conclude that low dose acitretin therapy is safe, well-tolerated and partially effective in chemoprophylaxis of skin cancer in renal transplant recipients. The increase in epidermal Langerhans cells observed may be an expression of the immunomodulatory effect of acitretin.

A busca por uma construção vacinal contra o HIV-1 é urgente. Os linfócitos T CD4+ têm assumido um papel de destaque no campo de vacinas por participar no controle da replicação do HIV-1, seja auxiliando as funções efetoras de linfócitos T CD8+ e a produção de anticorpos por linfócitos B ou mesmo agindo de forma citotóxica sobre macrófagos infectados. A utilização de sequências consenso do grupo M do HIV-1 é apontada como uma das maneiras de se contornar os problemas relacionados à diversidade viral. Além disso, é preciso construir vacinas que apresentem potencial de induzir respostas imunes com grande cobertura populacional. Com o intuito de induzir respostas amplas de linfócitos T CD4+ contra diversos subtipos do HIV-1 em uma população geneticamente diversa para moléculas HLA-DR, identificamos em nosso trabalho prévio 34 peptídeos promíscuos (previstos de se ligarem a múltiplas moléculas HLA-DR) e conservados da sequência consenso do grupo M do HIV-1. Desenvolvemos uma vacina de DNA codificando 7 peptídeos de Env (HIVenv7) e outra vacina (HIVBr27) codificando os demais 27 peptídeos. A vacina HIVBr27 foi imunogênica em camundongos BALB/c, induzindo uma resposta ampla e polifuncional de linfócitos T CD4+ e CD8+. A vacina HIVenv7 foi pouco imunogênica e mostrou-se capaz de suprimir a resposta induzida pela HIVBr27 em regime de co-imunização. No presente trabalho demonstramos que a imunização com HIVBr27 induz uma resposta imune celular mediada por linfócitos T CD4+ e CD8+ contra peptídeos de diferentes subtipos do HIV-1. Além disso, a imunização com HIVBr27 mostrou-se parcialmente protetora contra a infecção pelo vírus Vaccinia recombinante codificando as proteínas Gag e Pol do HIV-1. Ensaios in vitro demonstraram que os peptídeos codificados pela HIVBr27 se ligam a múltiplas moléculas HLA de classe II e são reconhecidos por células de pacientes infectados pelo HIV-1. Demonstramos também que a vacina HIVenv7 não possui propriedades imunossupressoras consistentes, contrariando os resultados obtidos previamente. Os peptídeos codificados pela HIVenv7 se ligaram a múltiplas moléculas HLA de classe II, mas apresentaram baixa frequência de reconhecimento por células de pacientes infectados pelo HIV-1. Acreditamos que a vacina HIVBr27 possui potencial de induzir uma resposta imune de grande cobertura populacional e direcionada a diferentes variantes do HIV-1. Por outro lado, a vacina HIVenv7 se mostrou pouco imunogênica e não deve ser utilizada em estudos futuros / The search for an HIV-1 vaccine construct is urgent. The CD4+ T cells have assumed a prominent role in the vaccine field participating in the control of HIV-1 replication either by helping CD8+ T cell effector function and B cell-mediated antibody production or by acting as citotoxic cells on infected macrophages. The use of HIV-1 M-group consensus sequences is pointed as an alternative to overcome viral diversity. Besides, it is necessary to construct vaccines that would potentially induce immune responses with broad population coverage. Intending to induce a broad CD4+ T-cell immune response against different HIV-1 subtypes in a population bearing diverse HLA-DR molecules we have previously identified 34 promiscuous peptides (potentially binding to multiple HLA-DR molecules) and conserved within the HIV-1 M-group consensus sequence. We construct a DNA vaccine encoding 7 Env peptides (HIVenv7) and another vaccine (HIVBr27) encoding 27 peptides. The HIVBr27 vaccine was immunogenic in BALB/c mice, inducing a broad and polyfunctional CD4+ and CD8+ T-cell response. The HIVenv7 vaccine was much less immunogenic and suppressed HIVBr27-induced immune responses when co-immunized. Here, we have shown that HIVBr27 immunization leads to a cross-clade CD4+ and CD8+ T-cell immune response. Besides, HIVBr27 immunization has partially protected mice challenged with a recombinant Vaccinia virus encoding HIV-1 Gag e Pol. In vitro assays have shown that HIVBr27- encoded peptides bind to multiple HLA class II molecules and are recognized by HIV- 1-infected patients. We have also shown that HIVenv7 has no consistent immunosuppressive properties, contradicting our previous results. The HIVenv7- encoded peptides bound to multiple HLA class II molecules but were recognized by a low number of HIV-1-infected patients. We believe that our vaccine HIVBr27 has potential to induce an immune response with broad population coverage, towards different HIV-1 variants. On the other hand, the HIVenv7 vaccine was poorly immunogenic and should not be used in future studies

The prevalence of diabetes is approaching epidemic proportions worldwide. There is currently no cure for type 1 diabetes, and successful treatment requires constant monitoring of blood sugars and use of exogenous insulin to prevent hyperglycemia. Diabetes will be curable when pancreatic β-islet cells can be transplanted into diabetes patients without requiring long-term immunosuppression. This will require learning more about the induction of functional tolerance, a state that maintains the competence of the immune system to most antigens but protects graft-specific antigens from immune rejection, permitting transplantation. One known mechanism of peripheral tolerance is T cell anergy, a phenotype of hypo-reponsiveness in CD4+ T cells. The focus of this thesis is a description of factors shown to be specific to the induction and maintenance of T cell anergy, whose loss reverses the anergic phenotype, restoring the ability of the cells to proliferate in response to antigen. The first of these is Egr-2, a zinc-finger transcription factor, whose presence is required for the induction of anergy induced in T cell clones by TCR stimulation in the absence of costimulation. Egr-2 is shown to be important to anergy induction but not anergy maintenance. In contrast, a negative costimulation receptor, PD-1, is shown to be necessary for the maintenance of anergy. It is possible that learning more about the genetic factors that orchestrate T cell anergy will prove useful in the development of tolerance-based protocols for organ and tissue transplantation without the use of long-term immunosuppression.

A busca por uma construção vacinal contra o HIV-1 é urgente. Os linfócitos T CD4+ têm assumido um papel de destaque no campo de vacinas por participar no controle da replicação do HIV-1, seja auxiliando as funções efetoras de linfócitos T CD8+ e a produção de anticorpos por linfócitos B ou mesmo agindo de forma citotóxica sobre macrófagos infectados. A utilização de sequências consenso do grupo M do HIV-1 é apontada como uma das maneiras de se contornar os problemas relacionados à diversidade viral. Além disso, é preciso construir vacinas que apresentem potencial de induzir respostas imunes com grande cobertura populacional. Com o intuito de induzir respostas amplas de linfócitos T CD4+ contra diversos subtipos do HIV-1 em uma população geneticamente diversa para moléculas HLA-DR, identificamos em nosso trabalho prévio 34 peptídeos promíscuos (previstos de se ligarem a múltiplas moléculas HLA-DR) e conservados da sequência consenso do grupo M do HIV-1. Desenvolvemos uma vacina de DNA codificando 7 peptídeos de Env (HIVenv7) e outra vacina (HIVBr27) codificando os demais 27 peptídeos. A vacina HIVBr27 foi imunogênica em camundongos BALB/c, induzindo uma resposta ampla e polifuncional de linfócitos T CD4+ e CD8+. A vacina HIVenv7 foi pouco imunogênica e mostrou-se capaz de suprimir a resposta induzida pela HIVBr27 em regime de co-imunização. No presente trabalho demonstramos que a imunização com HIVBr27 induz uma resposta imune celular mediada por linfócitos T CD4+ e CD8+ contra peptídeos de diferentes subtipos do HIV-1. Além disso, a imunização com HIVBr27 mostrou-se parcialmente protetora contra a infecção pelo vírus Vaccinia recombinante codificando as proteínas Gag e Pol do HIV-1. Ensaios in vitro demonstraram que os peptídeos codificados pela HIVBr27 se ligam a múltiplas moléculas HLA de classe II e são reconhecidos por células de pacientes infectados pelo HIV-1. Demonstramos também que a vacina HIVenv7 não possui propriedades imunossupressoras consistentes, contrariando os resultados obtidos previamente. Os peptídeos codificados pela HIVenv7 se ligaram a múltiplas moléculas HLA de classe II, mas apresentaram baixa frequência de reconhecimento por células de pacientes infectados pelo HIV-1. Acreditamos que a vacina HIVBr27 possui potencial de induzir uma resposta imune de grande cobertura populacional e direcionada a diferentes variantes do HIV-1. Por outro lado, a vacina HIVenv7 se mostrou pouco imunogênica e não deve ser utilizada em estudos futuros / The search for an HIV-1 vaccine construct is urgent. The CD4+ T cells have assumed a prominent role in the vaccine field participating in the control of HIV-1 replication either by helping CD8+ T cell effector function and B cell-mediated antibody production or by acting as citotoxic cells on infected macrophages. The use of HIV-1 M-group consensus sequences is pointed as an alternative to overcome viral diversity. Besides, it is necessary to construct vaccines that would potentially induce immune responses with broad population coverage. Intending to induce a broad CD4+ T-cell immune response against different HIV-1 subtypes in a population bearing diverse HLA-DR molecules we have previously identified 34 promiscuous peptides (potentially binding to multiple HLA-DR molecules) and conserved within the HIV-1 M-group consensus sequence. We construct a DNA vaccine encoding 7 Env peptides (HIVenv7) and another vaccine (HIVBr27) encoding 27 peptides. The HIVBr27 vaccine was immunogenic in BALB/c mice, inducing a broad and polyfunctional CD4+ and CD8+ T-cell response. The HIVenv7 vaccine was much less immunogenic and suppressed HIVBr27-induced immune responses when co-immunized. Here, we have shown that HIVBr27 immunization leads to a cross-clade CD4+ and CD8+ T-cell immune response. Besides, HIVBr27 immunization has partially protected mice challenged with a recombinant Vaccinia virus encoding HIV-1 Gag e Pol. In vitro assays have shown that HIVBr27- encoded peptides bind to multiple HLA class II molecules and are recognized by HIV- 1-infected patients. We have also shown that HIVenv7 has no consistent immunosuppressive properties, contradicting our previous results. The HIVenv7- encoded peptides bound to multiple HLA class II molecules but were recognized by a low number of HIV-1-infected patients. We believe that our vaccine HIVBr27 has potential to induce an immune response with broad population coverage, towards different HIV-1 variants. On the other hand, the HIVenv7 vaccine was poorly immunogenic and should not be used in future studies

Os doentes transplantados renais têm alto risco para desenvolver queratoses actínicas e câncer de pele. Para verificar o efeito quimioprofilático da acitretina estudamos a evolução de 13 doentes transplantados renais com queratoses actínicas múltiplas e história de carcinomas cutâneos submetidos a tratamento por 12 meses (20mg/dia). Fez-se a avaliação clínica e laboratorial regularmente em todo o período do estudo. Realizou-se exame histopatológico, demonstração imuno-histoquímica de sub-populações de linfócitos T (CD4, CD8), células natural killer e células de Langerhans, sua quantificação e comparação em biopsias de pele, sem lesão, de área exposta e protegida do sol antes, após seis e 12 meses de tratamento. Observou-se melhora das lesões cutâneas e ausência de aparecimento de novos tumores em 12 dos 13 pacientes. Não ocorreram alterações laboratoriais relacionadas a função renal, hepatotoxicicidade e hiperlipidemia. Não houve diferenças significativas histopatológicas e da população de linfócitos T e células natural killer da pele exposta e protegida do sol com o tratamento. Verificou-se aumento numérico de células de Langerhans epidérmicas aos 12 meses quando comparado aos da pele antes e após seis meses de tratamento (p = 0,002 e p = 0,003). Em nossa casuística o uso de acitretina em doses baixas foi útil para melhorar o aspecto cutâneo e prevenir lesões cutâneas pré-cancerosas e carcinomas. O aumento das células de Langerhans epidérmicas estaria relacionado ao efeito imunomodular da acitretina. / Renal transplant recipients have an increased incidence of actinic keratosis and skin cancer. In order to examine the chemoprophylatic effects of low-dose acitretin on skin cancer development we submitted 13 renal transplanted patients to acitretin therapy (20 mg/day) for 12 month. The patients were assessed at monthly intervals during the first 6 months and every two months until the 12th month for new skin lesions and for acitretin toxicity. Normal skin biopsies of sun exposed and sun protected area were taken for histopathological exam and submitted to immunohistochemistry technique to demonstrate CD4+ and CD8+ T lymphocytes, natural killer cells and Langerhans cells wich were counted and compared in the beginning, after 6th month and 12th month of the treatment. There was an improvement of actinic keratosis and all patients but one did not develop new skin cancer. Side-effects were well-tolerated and no significant biochemical effects were observed. Although there were no differences in the microscopic aspects of the skin and in the number of CD4+ and CD8+ T lymphocytes and natural killer cells, there was a significant increase in the number of epidermal Langerhans cells after 12 months of acitretin therapy. The data obtained permit us to conclude that low dose acitretin therapy is safe, well-tolerated and partially effective in chemoprophylaxis of skin cancer in renal transplant recipients. The increase in epidermal Langerhans cells observed may be an expression of the immunomodulatory effect of acitretin.

Le sepsis est à l’origine d’une dysfonction immunitaire prolongée responsable d’infections nosocomiales et d’une mortalité tardive élevée. Sa physiologie complexe demeure mal connue et il n’existe aucun traitement spécifique en dehors de l’antibiothérapie et des thérapeutiques de suppléance d’organes. Nous nous sommes intéressés au rôle des cellules myéloïdes dans cette dysfonction immunitaire. Nous avons pu montrer qu’il existe chez les patients atteints de sepsis une augmentation du nombre de cellules suppressives d’origine myéloïde monocytaires (M-MDSC) CD14+HLA-DRlow/- et granulocytaires (G-MDSC) identifiées comme des granulocytes de faible densité CD14-CD15+. Ces cellules sont responsables d’une activité Indoléamine 2,3-dioxygénase (IDO) et arginase 1, et leur déplétion permet de restaurer la prolifération des lymphocytes T in vitro. L’augmentation précoce des G-MDSC prédit la survenue ultérieure d’infections nosocomiales. De même, l’augmentation de l’activité IDO et de l’arginase 1 plasmatique sont associées à un mauvais pronostic. Au total, nous avons pu démontrer que les cellules myéloïdes acquièrent un phénotype suppresseur en partie responsable de l’immunodépression acquise et du pronostic péjoratif chez les patients septiques. Afin de restaurer les capacités immunitaires des patients, les MDSC pourraient devenir une future cible thérapeutique. / Sepsis results in a sustained immune dysfunction responsible for poor prognosis and nosocomial infections. Sepsis physiology remains poorly understood and no treatment exists currently, excepted from antibiotherapy and life-support techniques. We asked if myeloid cells could play a role in this sustained immune dysfunction. We demonstrated that Peripheral CD14+HLA-DRlow/- monocytic-myeloid-derived suppressor cells (MDSCs) and CD14-CD15+ low-density granulocytes identified as granulocytic- (G-)MDSCs were increased in septic patients. In vitro, arginase and IDO activities relied on MDSCs and depletion of both subsets restored T-cell proliferation. The initial proportion of G-MDSC predicted occurrence of nosocomial infections. Similarly, high plasma Indoleamine 2,3-dioxygenase (IDO) activity and arginase 1 level were associated with poor outcome. Altogether, our results demonstrate that myeloid cells acquire suppressive functions during sepsis, partially responsible for the sustained immune dysfunction and poor outcome. MDSCs may become a future therapeutic target to restore the immune capacities of septic patients.

MA (Psychology) / Department of Psychology / Background: An estimated 70% of people in Sub-Saharan Africa out of 25 million are living with HIV. HIV is a debilitating disease, however, antiretroviral treatment helps promote effective viral suppression, reduces the risk of transmission and prevents death (WHO, 2013). To ensure positive treatment outcomes, high levels of Anti-Retroviral Therapy (ART) adherence, 95%, is necessary, however, research indicates that 23% of Africans are achieving less than 80% adherence, potentially impacting negatively on prognosis. Aim: The aim of this study was to determine adherence, explore perceptions and behaviour of patients on Antiretroviral Therapy attending Thohoyandou Health Centre, in Vhembe District, Limpopo, South Africa. Methodology: This was a mixed method which employed both quantitative and qualitative research approaches. In quantitative, triangulation was utilised through a questionnaire and patients’ file, simple random sampling was used to select 105 male and female patients aged 18-60 who are on ART at Thohoyandou Health Centre; data were collected and SPSSversion 25 was used to analyse the data through descriptive, cross tabulation and inferential statistics using Chi-square.Qualitative phase – phenomelogical research design was utilised, twenty participants were purposively sampled and individually interviewed, ATLAS. ti program was used to analyse the data collected. Results: 67% of respondents were females, 34% of the respondents’ age range was 50-60 years, 44.8% were single, 48.6% had tertiary education and 69.5% were unemployed. The self-report of ART adherence of 87.6% among patients was indicated, with 19.6% who reported defaulting ART, 14.3% admitted to missing medical appointments. The reasons for missing medical appointments were: forgetfulness, not a convenient time, patient feeling better, transportation challenges and being too sick to attend. The objective evaluation of patients’ CD4 count at baseline revealed that 40.9% of patients had a CD4 count of <200c/mm3, out of 40.9% respondents (15.2%) were those aged between 41-50 years, 31.4% of respondents did not know their CD4 count for various reasons (defaulted on treatment, missed appointments). CD4 count follow-up data after six months revealed that 33% of patients had a CD4 count <200c/mm3 and 39% accounted for unknown CD4 count. vi Three themes emerged from the data, namely: Knowledge of HIV were respondents presented a negaitive and positive perception of ths diagnosis; barriers to ART adherence where sub-themes included discrimination, strigma, rejection, inadequate knowledge about the diagnosis and treatment, side effects; coping strategies where acceptance, religion and social support serve as corner stones for patients. Association was examined and findings did not reveal any significant association between gender, marital status, education, occupation; however, age was significantly associated with non-adherence to ART with X2 = 3.69, df = 1, p = < .002. Recommendations: The study recommends intensification of health education campaign against stigma, discrimination, rejection and other barriers to enhance positive attitude towards HIV patients that wil consequently stimulate adherence and alleviate the burden associated with taking treatment unswervingly. Given the high percentage of infected older respondents, government must also focus its resources to educate illiterate and older people about HIV, adherence and management in order to achieve the golden standardrate of 95% adherence. Strategies to facilitate and normalise adherence among males is indicated. / NRF

<div>Cancer is responsible for the second highest cause of death in the United States, and lung cancer accounts for 13% of new cancer diagnoses, with the highest rate of cancer death at 24%. Almost 85% of these cases represent non-small cell lung cancer (NSCLC), which includes lung adenocarcinoma, the most common NSCLC subtype. Traditional cancer treatments often only temporarily stop the spread of the disease, but immunotherapies, which are becoming a standard of care, are much more promising. Natural killer (NK) cells are powerful effectors of innate immunity, and genetically engineered NK cells as immunotherapies have had encouraging clinical responses in the treatment of various cancers. However, more progress is needed for solid tumor treatment, especially for lung adenocarcinoma. The activation of cancer-associated ectoenzymes, CD39 and CD73 catalyze the phosphorylation of ATP to AMP to produce extracellular adenosine (ADO), which is a highly immunosuppressive mechanism contributing to the pathogenesis of solid tumors. Understanding adenosine effects on NK cells will help develop more robust immunotherapeutic treatments to improve cytotoxicity against solid tumors. Here, we established that tumor microenvironment ADO results in impaired metabolic and anti-tumor functions of cytokine-primed NK cells. Specifically, peripheral blood-derived NK cells stimulated with IL-2, IL-15, or a combination of IL-12 and IL-15 showed suppressed anti-tumor immunity due to ADO. This was observed by the downregulation of activation receptor expression, cytotoxicity inhibition, impairment of metabolic activity, and alterations in gene expression. To target ADO-producing CD73 on cancer cells, we redirected NK cells by fusing CD73 ScFv with intracellular and transmembrane regions of NK cell specific signaling components derived from FCyRIIIa (CD16). Engineered NK cells were shown to be cytotoxic against lung adenocarcinoma <i>in vitro</i> and impede tumor growth in a lung adenocarcinoma mouse model <i>in vivo</i>. Engineered cells also had higher levels of degranulation and cytokine release, as well as more infiltration into tumors and longer survival time in mice. In summary, the microenvironment of solid tumors is highly immunosupressive, and redirecting NK cell function using a NK-specific anti-CD73 targeting construct will help to promote anti-tumor immunity and</div><div>inhibit cancer growth for a potentially powerful new immunotherapy against solid tumors.</div>

Indiana University-Purdue University Indianapolis (IUPUI) / With effective antiretroviral therapy (ART), cardiovascular diseases (CVD), are emerging as a major cause of morbidity and death in the aging population with HIV infection. Although this increase in CVD could be partially explained by the toxic effects of combined anti-retroviral therapy (ART), more recently, HIV infection has emerged as an independent risk factor for CVD. However, it is unclear how HIV can contribute to CVD in patients on ART, when viral titers are low or non-detectable. Here, we provide several lines of evidence that HIV-Nef, produced in infected cells even when virus production is halted by ART, can lead to endothelial activation and dysfunction, and thus may be involved in CVD. We demonstrate that HIV-infected T cell-induced endothelial cell activation requires direct contact as well as functional HIV-Nef. Nef protein from either HIV-infected or Nef-transfected T cells rapidly transfers to endothelial cells while inducing nanotube-like conduits connecting T cells to endothelial cells. This transfer or transfection of endothelial cells results in endothelial apoptosis, ROS generation and release of monocyte attractant protein-1 (MCP-1). A Nef SH3 binding site mutant abolishes Nef-induced apoptosis and ROS formation and reduces MCP-1 production in endothelial cells, suggesting that the Nef SH3 binding site is critical for Nef effects on endothelial cells. Nef induces apoptosis of endothelial cells through both NADPH oxidase- and ROS-dependent mechanisms, while Nef-induced MCP-1 production is NF-kB dependent. Importantly, Nef can be found in CD4 positive and bystander circulating blood cells in patients receiving virally suppressive ART, and in the endothelium of chimeric SIV-infected macaques. Together, these data indicate that Nef could exert pro-atherogenic effects on the endothelium even when HIV infection is controlled and that inhibition of Nef-associated pathways may be promising new therapeutic targets for reducing the risk for cardiovascular disease in the HIV-infected population.

Myeloid-derived suppressor cells (MDSCs) prolong sepsis by promoting immunosuppression. We reported that sepsis MDSC development requires long non-coding RNA Hotairm1 interactions with S100A9. Using a mouse model that simulates the immunobiology of sepsis, we find that histone demethylase KDM6A promotes Hotairm1 transcription by demethylating transcription repression H3K27me3 histone mark. We show that chemical targeting of KDM6A by GSK-J4 represses Hotairm1 transcription, which coincides with decreases in transcription activation H3K4me3 histone mark and transcription factor PU.1 binding to the Hotairm1 promoter. We further show that immunosuppressive IL-10 cytokine promotes KDM6A binding at the Hotairm1 promoter. IL-10 knockdown repletes H3K27me3 and reduces Hotairm1 transcription. GSK-J4 treatment also relocalizes nuclear S100A9 protein to the cytosol. To support translation to human sepsis, we demonstrate that inhibiting H3K27me3 demethylation by KDM6A ex vivo in MDSCs from patients with protracted sepsis decreases Hotairm1 transcription. These findings suggest that epigenetic targeting of MDSCs in human sepsis might resolve post-sepsis immunosuppression and improve sepsis survival.