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espanolIntroduccion: muchas evidencias ratifican que la vitamina D puede estar asociada con la mejora de los niveles de celulas CD4 en individuos infectados por el VIH, tratados con terapia antirretroviral (ART) que se asocia a la disminucion de los niveles de 25(OH)D. Objetivo: realizar una revision sistematica sobre el efecto de la suplementacion de vitamina D en pacientes adultos infectados con VIH. Metodos: la investigacion fue realizada en las bases de datos Science Direct, PubMed, BVS, Scielo Cochrane y periodicos, de febrero a abril de 2018, con limite de publicacion de 2000 a 2018, sin restriccion de genero, etnicidad y que involucra a individuos con edad mayores de 18 anos. Para la evaluacion de la calidad de los estudios, se utilizo el protocolo Preferred Reporting Items for Systematic Reviews y Meta-Analyzes (PRISMA) y la escala de Jadad. Resultados: la encuesta inicialmente resulto en 198 articulos. Despues del proceso de seleccion, 5 articulos fueron identificados como elegibles, donde ponen de manifiesto que la suplementacion con vitamina D puede ser una intervencion asociada y eficaz para reducir la hipovitaminosis. La ART reduce niveles de la vitamina D3 y altera su metabolismo, estando asociada al riesgo de mortalidad. Sin embargo, los niveles adecuados de 25(OH)D estan asociados positivamente al numero de celulas CD4 + y la reduccion de los niveles de infecciones. Conclusion: la suplementacion de vitamina D promueve la recuperacion inmunologica. Sin embargo, los casos analizados fueron pocos, insuficientes para confirmar totalmente los beneficios y recomendar la suplementacion. Por lo tanto, estudios de intervencion son necesarios para elucidar la actuacion de la vitamina D en la proteccion humana contra las infecciones por el VIH. EnglishIntroduction: much evidence confirms that vitamin D may be associated with an improvement in CD4 cell counts in HIV-infected individuals, where antiretroviral therapy (ART) is used and associated with decreased 25(OH)D levels. Objective: to carry out a systematic review on the effect of vitamin D supplementation on HIV-infected adult patients. Methods: the research was conducted in the databases Science Direct, PubMed, BVS, Scielo Cochrane and Periods, from February to April 2018, with publication limit from 2000 to 2018, without restriction of gender, ethnicity and involving individuals with age older than 18 years. To evaluate the quality of the studies, we used the protocol Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) and the Jadad scale. Results: the search initially resulted in 198 articles. After the selection process 5 articles were identified as eligible, where they highlight that vitamin D supplementation may be an associated and effective intervention to reduce hypovitaminosis. ART reduces vitamin D3 levels and changes its metabolism, being associated with the risk of mortality. However, adequate levels of 25(OH)D are positively associated with the number of CD4 + cells and the reduction of infection levels. Conclusion: vitamin D supplementation promotes immune recovery. However, the cases analysed were few, insufficient to fully confirm the benefits and recommend supplementation. Therefore, intervention studies are needed to elucidate the role of vitamin D in human protection against HIV infections.

Lymphomas constitute the second most common indication for autologous hematopoietic cell transplantation (AHCT). Graft infusion is followed by a rapid hematological recovery and slower immune recovery. The number of natural killer cells and CD3

In clinical research and practice, there is often an interest in assessing the effect of time varying predictors, such as CD4/CD8 ratio, on immune recovery following antiretroviral therapy. Such predictors are measured with errors, and ignoring those measurement errors during data analysis may lead to biased results. Though parametric methods have been used for reducing biases, they usually depend on untestable assumptions. To relax those assumptions, this paper presents semiparametric mixed-effect models which deal with predictors having measurement errors and missing values. We develop a fully Bayesian approach for fitting these models and discriminating between patients who are potentially progressors or nonprogressors to severe disease condition (AIDS). The proposed methods are demonstrated using real data from an AIDS clinical study.

T cell development in the thymus requires constant interactions between developing thymocytes and the surrounding resident stromal cells (TSCs). These functional, non-hematopoietic-derived cells are predominantly of epithelial origin and constitute 1% of total thymus cellularity. Thymic function and naive T cell output are optimal in humans during the early years of life, but decline sharply after the first years of life and further after the onset of puberty, with progressive contraction of functional thymus tissue. The loss of thymic epithelial cells (TECs) eventually results in an altered microenvironment that affects normal T cell development, reducing naive T cell output and contributing to the overall demise of immune functions. Other extrinsic factors that exacerbate the effects of thymic involution include cytoreductive conditioning regimes in the context of cancer treatments and hematopoietic stem cell transplantation (HSCT). In these scenarios, elderly patients are incapable of full immune recovery. With such complications present, we describe herein various preclinical approaches that could lead to potential new treatment strategies to restore thymic function and, more importantly, T-cell mediated immunity following clinically induced damage (Fig. 13.1).

Terms and criteria to classify people living with HIV on antiretroviral therapy who fail to achieve satisfactory CD4 T-cell counts are heterogeneous, and need revision and summarization. Background: Terms and criteria to classify people living with HIV on antiretroviral therapy who fail to achieve satisfactory CD4+ T-cell counts are heterogeneous, and need revision and summarization. Methods: We performed a systematic review of PubMed original research articles containing a set of predefined terms, published in English between January 2009 and September 2018. The search retrieved initially 1360 studies, of which 103 were eligible. The representative terminology and criteria were extracted and analyzed. Results: Twenty-two terms and 73 criteria to define the condition were identified. The most frequent term was “immunological nonresponders” and the most frequent criterion was “CD4+ T-cell count, Supported by: FEDER, through the Competitiveness Factors Operational Program (COMPETE); by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-007038 and NORTE-01-0145-FEDER-000013; and by Programa Gilead GENESE (PGG/018/2017). R.R.-S. was supported by an FCT grant, in the context of PhDOC-Doctoral Program in Ageing and Chronic Diseases (PD/BD/106047/2015).

FEDER, through the Competitiveness Factors Operational Program (COMPETE); by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-00(7038) and by Programa Gilead GÉNESE (PGG/018/2017). RR-S and JC-G were supported by FCT grants, in the context of PhDOC—Doctoral Program in Aging and Chronic Diseases (PD/BD/106047/2015 and PD/BD/137433/2018, respectively). CN was also supported by a grant from FCT (SFRH/BPD/112001/2015). CA and EA were partially supported by Portuguese Funds through FCT within the project UID/MAT/00013/2013. AY was supported by Arthritis Research UK, Poor immunological responders (PIR) are HIV-infected patients with virologic suppression upon antiretroviral therapy (ART) but persistently low CD4+ T cell counts. Early identification of PIR is important given their higher morbimortality compared to adequate immune responders (AIR). In this study, 33 patients severely lymphopenic at ART onset, were followed for at least 36 months, and classified as PIR or AIR using cluster analysis grounded on their CD4+ T cell count trajectories. Based on a variety of immunological parameters, we built predictive models of PIR/AIR outcome using logistic regression. All PIR had CD4+ T cell counts consistently below 500 cells/μL, while all AIR reached this threshold. AIR showed a higher percentage of recent thymic emigrants among CD4+ T cells; higher numbers of sj-TRECs and greater sj/β TREC ratios; and significant increases in thymic volume from baseline to 12 months of ART. We identified mathematical models that correctly predicted PIR/AIR outcome after 36 months of therapy in 77-87% of the cases, based on observations made until 2-6 months after ART onset. This study highlights the importance of thymic activity in the immune recovery of severely lymphopenic patients, and may help to select the patients that will benefit from closer follow-up or novel therapeutic approaches.

Reconstitution of T cells after transplantation is a determinant of the long-term success of the procedure, and the correlation with T cell recovery and cytomegalovirus reactivation and disease is well known. We evaluated 110 patients who underwent transplantation: 55 received pre-emptive antiviral treatment, and in the other 55 patients, prophylaxis with letermovir was employed. A progressive statistically significant difference in T cell reconstitution between the 2 groups was observed, starting from day +60 with faster recovery in the pre-emptive group. Moreover, a higher incidence of cytomegalovirus reactivation was observed in prophylactic group after discontinuation of letermovir, and subsequent antiviral treatment has been necessary. Our findings confirm, as previously reported, that cytomegalovirus reactivation is a potent stimulator of T cell function.

Immune recovery folliculitis (IRF) is defined as the development of an inflammatory disorder of the facial pilo-sebaceous unit due to the immune reconstitution inflammatory syndrome (IRIS). Skin lesions can be related to an immune response against skin saprophyte bacteria (e.g. Demodex folliculorum, Cutibacterium acnes). The rapid reconstitution of T lymphocyte, with a CD8+ predominance, is considered a key pathogenic factor for this phenomenon. IRF is clinically similar to acne vulgaris and can be challenging to treat. Patients with facial pustules can experience social discomfort. Here we report two cases of IRF diagnosed at the human immunodeficiency virus (HIV) clinic of the National Institute of Infectious Diseases L. Spallanzani, in Rome, Italy. The first case occurred in an antiretroviral therapy (ART)-experienced patient, after a treatment simplification; the second one was registered in an ART-naïve patient, diagnosed with acute HIV infection shortly, after ART initiation. To date, an IRF secondary to an ART switch, has not been described yet. IRF should be ruled out and considered in differential diagnosis from antiretroviral drug-related skin effects.

OBJECTIVE To explore immune mechanisms and identify biomarkers associated with an inadequate immune recovery in patients with HIV with efficient antiretroviral therapy. DESIGN A cross-sectional study of 67 HIV-infected patients on antiretroviral therapy for ≥24 months with HIV RNA ≤20 copies per milliliter; 41 were defined as immunological nonresponders (INR) (CD4 600 cells per microliter). CD4 counts were also registered 2 years after inclusion. METHODS Cytokines, soluble markers of microbial translocation, and tryptophan catabolites were measured in plasma by multiplex assay, ELISA, or mass spectrometry. T-cell activation, differentiation, and regulatory T cells (Tregs) were analyzed by flow cytometry in 2 subgroups with comparable nadir CD4 counts. RESULTS Plasma interferon-inducible protein-10 (IP-10) levels were higher (P < 0.05), the T cells were more activated (CD38HLA-DR) (P < 0.05), the naive/effector memory T-cell ratio was lower (P < 0.01) and the proportion of resting Tregs (CD4CD45RAFoxP3) was reduced (P < 0.001) in INR patients compared with immunological responders. INR patients with CD4 counts ≤300 cells per microliter also demonstrated a higher fraction of activated Tregs (aTreg) (CD4CD147CD25) (P < 0.05). In the INR group, the aTreg percentages correlated with plasma IP-10 levels and inversely with CD4 counts (both P < 0.01). IP-10 levels (P < 0.05) and kynurenine/tryptophan ratio (P < 0.01) were negatively associated with the CD4 count 2 years after inclusion. CONCLUSION Patients with HIV with inadequate CD4 responses had higher levels of IP-10, more activated and differentiated T-cell phenotypes, as well as aTreg, compared with patients with satisfactory CD4 gain. High IP-10 levels were also associated with lower CD4 counts after 2 years.

Significant progress has been made over the past decade in haploidentical transplantation, with the development of novel methods to control intense alloreactive reactions generated in the major HLA-mismatched setting. Application of post-transplantation cyclophosphamide has gained worldwide acceptance as an effective and low-cost way to perform this type of transplantation, with outcomes now similar to those from HLA-matched unrelated donors. These advances have resulted in improved treatment-related mortality, whereas disease relapse has emerged as the most common cause of treatment failure. In addition, improvements in immunologic reconstitution after transplantation are much needed, not only in haploidentical transplantation but in all forms of stem cell transplantation. This symposium has focused on some of the most promising methods to control alloreactivity in this form of transplantation and application of cellular therapy to prevent disease relapse after transplantation, as well as understanding immunologic reconstitution and foreseeable approaches to improve immune recovery after transplantation.

T-cell recovery after allogeneic hematopoietic stem cell transplantation (allo-HCT) depends on both homeostatic peripheral expansion (HPE) of donor T cells contained in the graft [1], and T-cell ne...

Depressive symptoms are associated with poor HIV viral control and immune recovery among people living with HIV. However, no prior studies assessed this association exclusively among people co-infected with HIV-hepatitis C virus (HCV). While people with HIV only and those with HIV-HCV co-infection share many characteristics, co-infected people may become more susceptible to the effects of depressive symptoms on health outcomes. We assessed this association exclusively among people co-infected with HIV-HCV in Canada using data from the Food SecurityHIV-HCV Sub-Study (FS Sub-Study) of the Canadian Co-Infection Cohort (CCC). Stabilized inverse probability weighted marginal structural model was used to account for potential time-varying confounders. A total of 725 participants were enrolled between 2012 and 2015. At baseline, 52% of participants reported depressive symptoms, 75% had undetectable HIV viral load, and median CD4 count was 466 (IQR 300-665). People experiencing depressive symptoms had 1.32 times (95% CI: 1.07, 1.63) the risk of having detectable HIV viral load, but had comparable CD4 count to people who did not experience depressive symptoms (fold change of CD4 = 0.96, 95% CI: 0.91, 1.03). Presence of depressive symptoms is a risk factor for incomplete short-term HIV viral suppression among people co-infected with HIV-HCV. Therefore, depressive symptoms screening and related counseling may improve HIV related health outcomes and reduce HIV transmission.

Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a growing concern for advanced HIV/TB coinfected patients in an era where antiretroviral therapy (ART) is started shortly after TB treatment initiation. This perspective discusses potential mechanisms underlying TB-IRIS, focusing on recent studies that implicate coordinated recovery in adaptive and innate immune responses following ART initiation in TB-IRIS. More broadly, HIV/TB patients are probably a heterogeneous group whose outcomes are determined by the direction in which these immune responses change following ART initiation. Finally, in addition to treatment interventions that are in the pipeline for TB-IRIS, we highlight the need for holistic management of HIV/TB coinfected patients, which go beyond the current definition of TB-IRIS and take into consideration long-term consequences of robust immune recovery on ART.

Background HIV-infected patients with pulmonary TB (pTB) can have worsening of respiratory symptoms as part of TB-immune reconstitution inflammatory syndrome (TB-IRIS) following antiretroviral therapy (ART) initiation. Thus, reconstitution of immune function on ART could drive incident lung damage in HIV/TB. Methods We hypothesized that increases in matrix metalloproteinases (MMPs), which can degrade lung matrix, on ART are associated with TB-IRIS among a cohort of advanced, ART naïve, HIV-infected adults with pTB. Furthermore, we related early changes in immune measures and MMPs on ART to lung function in an exploratory subset of patients post-TB cure. This study was nested within a prospective cohort study. Rank sum and chi-square tests, Spearman's correlation coefficient, and logistic regression were used for analyses. Results Increases in MMP-8 following ART initiation were independently associated with TB-IRIS (p = 0.04; adjusted odds ratio 1.5 [95% confidence interval: 1.0–2.1]; n = 32). Increases in CD4 counts and MMP-8 on ART were also associated with reduced forced expiratory volume in one-second post-TB treatment completion (r = − 0.7, p = 0.006 and r = − 0.6, p = 0.02, respectively; n = 14). Conclusions ART-induced MMP increases are associated with TB-IRIS and may affect lung function post-TB cure. End-organ damage due to TB-IRIS and mechanisms whereby immune restoration impairs lung function in pTB deserve further investigation., Highlights • Matrix metalloproteinases (MMP), capable of degrading lung collagen, can increase rapidly on ART in HIV/TB patients. • Increases in plasma MMP-8 concentrations after ART initiation are associated with the development of paradoxical TB-IRIS. • Increases in CD4 T-cells and MMP-8 concentrations after ART initiation are correlated with decreased lung function post-TB cure. TB-associated pulmonary morbidity can persist after TB cure. However, causal mechanisms for lung damage, which may involve immune mechanisms and tissue proteases, in TB are unclear. Less is known in this regard among patients with HIV/TB, who are at risk for inflammatory reactions following ART initiation, otherwise known as TB-immune reconstitution inflammatory syndrome (IRIS). In this study, rapid ART-induced increases in certain tissue degrading proteins called matrix metalloproteinases (MMP) were associated with TB-IRIS. Furthermore, rapid recovery of CD4 T-cells and MMP-8 concentrations were associated with decreased lung function in an exploratory subset. In HIV/TB, robust increases in cellular immune function and MMPs on ART may underlie lung injury and long-term pulmonary deficits.

Purpose of review This manuscript reviews current reports about clinical aspects of immune reconstitution inflammatory responses (IRIS), with particular emphasis on IRIS in the setting of progressive multifocal leukoencephalopathy (PML) and to a lesser extent on cryptococcal meningitis (CM) and human immunodeficiency virus (HIV).

Objective T-cell activation independently predicts mortality, poor immune recovery and non-AIDS illnesses during combination antiretroviral therapy (cART). Atorvastatin showed anti-immune activation effects among HIV-infected cART-naive individuals. We investigated whether adjunct atorvastatin therapy reduces T-cell activation among cART-treated adults with suboptimal immune recovery. Methods A randomised double-blind placebo-controlled crossover trial, of atorvastatin 80 mg daily vs. placebo for 12 weeks, was conducted among individuals with CD4 increase

The oral poliovirus vaccine strains can revert to virulent forms and establish chronic infection in persons with a weakened immune system. The authors describe such infection in two children and clearance of infection through immune recovery.

La pobra recuperació immunològica que té lloc en una proporció d’individus VIH+ després d’iniciar TARGA s’ha associat a un perfil de maduració cel·lular alterat, un estat elevat d’inflamació, senescència accelerada i hiperactivació immunològica, però es desconeix l’impacte que totes aquestes alteracions tenen en la recuperació de la funcionalitat del compartiment de limfòcits T. En l’estudi dels mecanismes que poden associar-se a la resposta immunodiscordant s’ha descrit que la infecció per CMV contribueix a l’increment de l’activació immunológica, però es desconeix el paper que té la resposta CMV-especifica en les alteracions immunològiques d’individus immunodiscordants. A més, donat que l’apoptosi en cèl·lules T CD4 està altament associada amb una pobra recuperació immunològica, el procés d’autofàgia, associat a resposta inflamatòria i a mort cel·lular, podria estar també involucrat en la resposta immunodiscordant. Per això, els objectius d’aquesta tesi van ser determinar (i) el nivell funcional del compartiment T CD4 i CD8, (ii) la resposta immunitària, cel·lular i humoral contra CMV i (iii) la capacitat de les cèl·lules T CD4 d’activar autofàgia en un grup d’individus VIH+ virològicament suprimits per TARGA i amb resposta immunològica favorable o no favorable. Els nostres resultats mostren que els individus immunodiscordants mantenen la funcionalitat cel·lular policlonal i virus-específica en comparació amb individus immunoconcordants o amb població VIH-negativa. Els individus immunodiscordants presenten una major resposta cel·lular i humoral CMV-específica que estaria impulsada per reactivacions asimptomàtiques repetides al llarg del temps. S’ha observat també una autofàgia disminuïda en cèl·lules T CD4 d’individus immunodiscordants que podria estar contribuint a l’estat d’activació i inflamació elevat d’aquests individus. Així, els nostres resultats mostren en conjunt que el individus immunodiscordants, malgrat presentar alteracions immunològiques, tenen una diversitat funcional conservada. L’estat d’hiperactivació observat en individus immunodiscordants, a més, podria estar associat a un major nombre de reactivacions de CMV i una menor autofàgia al compartiment T CD4, que a la vegada conduiria a una elevada resposta immunitària CMV-especifica, contribuint al perfil de maduració alterat i el major risc de progressió clínica observada en aquest grup., La pobre recuperación inmunológica que se da en una proporción de individuos VIH+ después de iniciar TARGA se ha asociado a un perfil de maduración celular alterado, un estado elevado de inflamación, senescencia acelerada y hiperactivación immunològica; pero se desconoce el impacto que todas estas alteraciones tienen en la recuperación de la funcionalidad del compartimento de linfocitos T. En el estudio de los mecanismos que se asocian a la respuesta inmunodiscordante se ha descrito que la infección por CMV contribuye al incremento de la activación inmunológica, pero se desconoce el papel que tiene la respuesta CMV-especifica en las alteraciones inmunológicas de estos individuos. Además, dado que la apoptosis en células T CD4 está altamente asociada con una pobre recuperación inmune, el proceso de autofagia, asociado a inflamación y muerte celular, podría estar también involucrado en la respuesta inmunodiscordante. Por ello, los objetivos de esta tesis fueron determinar (i) el nivel funcional del compartimento T CD4 y CD8, (ii) la respuesta inmune celular y humoral contra CMV y (iii) la capacidad de las células T CD4 de activar autofagia en un grupo de individuos VIH+ en TARGA y virológicamente suprimidos con respuesta inmunológica favorable o no favorable. Nuestros resultados muestran que los individuos inmunodiscordantes mantienen la funcionalidad celular policlonal y virus-específica en comparación con individuos inmunoconcordantes o población VIH-negativa. Los individuos inmunodiscordantes presentan una mayor respuesta celular y humoral CMV-específica que estaría impulsada por reactivaciones asintomáticas repetidas a lo largo del tiempo. Se ha observado también una autofagia disminuida en células T CD4 de individuos inmunodiscordantes que podría estar contribuyendo al estado de activación y inflamación elevado de estos individuos. Nuestros resultados muestran en conjunto que los individuos inmunodiscordantes presentan una diversidad funcional conservada y que el estado de hiperactivación observado en estos individuos, podría estar asociado a un mayor número de reactivaciones de CMV y una menor autofagia en el compartimento T CD4, que a su vez conduciría a una elevada respuesta inmunitaria CMV-especifica, contribuyendo al perfil de maduración alterado y el mayor riesgo de progresión clínica observada en este grupo., Poor immune recovery after HAART observed in a proportion of HIV+ individuals has been associated with an altered cell maturation profile, elevated inflammation, accelerated senescence and immune hyperactivation. However, the impact that all of these alterations have on the T-cell functionality is unknown. Beside other mechanisms associated with the immunodiscordant response, it has been described that CMV infection contributes to an increased immune activation, although the role of the CMV-specific response among other immunological alterations related to immunodiscordant individuals is unknown. In addition, since apoptosis in CD4 T cells is highly associated with poor immune recovery, the autophagy process, which is involved in inflammation and cell death, may also contribute to the immunodiscordant response. Therefore, the objectives of this thesis were to determine (i) the functional level of the CD4 and CD8 T-cell compartments, (ii) the cellular and humoral immune response against CMV and (iii) the ability of CD4 T cells to activate autophagy in a group of virologically suppressed treated HIV+ individuals with favorable or unfavorable immune response. Our results show that immunodiscordant individuals maintain polyclonal and virus-specific cellular functionality as compared to immunoconcordant individuals or HIV-negative populations. Immunodiscordant individuals have a greater cellular and humoral CMV-specific response that would be driven by repeated asymptomatic reactivations over time. Decreased autophagy has also been observed in CD4 T cells from immunodiscordant individuals, and this fact may be contributing to the high activation and inflammation status of these individuals. Our results show that immunodiscordant individuals exhibit a conserved functional diversity and that the hyperactivation state observed in these individuals could be associated with a greater number of CMV reactivations and impaired autophagy in CD4 T cells, leading to a high CMV-specific immune response and driving the altered maturation profile and the increased risk of clinical progression observed in this group.

Background Highly Active Antiretroviral therapy (HAART) reverses the effect of Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) by durably suppressing viral replication. This allows CD4 gain to levels that are adequate enough to restore the body’s capability to fight against opportunistic infections (OIs). Patients with poor immune recovery have been shown to have higher risk of developing both AIDS and non AIDS related clinical events. This study aimed at assessing the proportions and risk factors of poor immune recovery in adult HIV-infected patients on 48 months of HAART attending care and treatment center (CTC) in northwestern Tanzania. Methods A retrospective analysis of adult HIV patients’ data attending CTC at Sekou Toure hospital and who initiated HAART between February 2004 and January 2008 was done. Poor immune recovery was defined as a CD4 count less than 350 cells/µl on follow up as used in other studies. Results A total of 734 patients were included in the study. In this study 50.25% of patients attending CTC at Sekou Toure hospital were found to have poor immune recovery. The risk of developing inadequate immune recovery was independently associated with male gender, age older than 50 years, low baseline CD4 counts, and advanced World Health Organization (WHO) clinical stage. Conclusions Poor immune recovery is prevalent among adult HIV patients attending CTC at Sekou Toure hospital in Northwestern part of Tanzania and opportunistic infections are common in this sub group of patients. Clinicians in resource limited countries need to identify these patients timely and plan them for targeted viral assessment and close clinical follow up to improve their long term clinical outcome.

Allogeneic stem cell transplantation (allo-SCT) offers an important curative therapy for hematological malignancies and other diseases. A number of studies have demonstrated the association of immune compositions in allografts with outcomes after allo-SCT, which promote graft engineering to improve transplant prognosis. This review summarizes the advances in investigating the correlation of the graft immune compositions with transplant outcomes in different transplant modalities, focusing on the immune subsets likely to have the greatest impact on clinical outcomes. The progress made in graft engineering in order to design novel transplant protocols, to decrease graft-versus-host disease and relapse and to improve immune recovery is also discussed. It is our belief that an adoptive immune subset transfer to improve clinical outcomes might represent a future direction.

Infection, relapse, and GVHD can complicate allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although the effect of poor immune recovery on infection risk is well-established, there are limited data on the effect of immune reconstitution on relapse and survival, especially following T-cell depletion (TCD). To characterize the pattern of immune reconstitution in the first year after transplant and its effects on survival and relapse, we performed a retrospective study in 375 recipients of a myeloablative TCD allo-HSCT for hematologic malignancies. We noted that different subsets recover sequentially, CD8 + T cells first, followed by total CD4 + and naïve CD4 + T cells, indicating thymic recovery during the first year after HSCT. In the multivariate model, a fully HLA-matched donor and recovery of T-cell function, assessed by PHA response at 6 months, were the only factors independently associated with OS and EFS. In conclusion, T-cell recovery is an important predictor of outcome after TCD allo-HSCT.

After allogeneic hematopoietic stem cell transplantation (HSCT), NK cell reconstitution, which is crucial for positive outcomes, is dominated by the CD56bright subset with low NK cell cytotoxicity (NKCC) activity. Moderate exercise has been described as a potent NK cell stimulus in adults with cancer. The purpose of this study is to determine the effects of a moderate-intensity exercise program on NK cell recovery early after HSCT and the feasibility of this intervention. Six children undergoing allogeneic HSCT were randomized to an exercise program (EP) or control (CT) group. The EP group performed a 10-week training combining in-hospital and home-based EP. We observed a significant increase in the posttraining/pretraining ratio of the CD56dim subset (EP = 1.27 ± 0.07; CT = 0.99 ± 0.08; P < .005) of the EP group. The ratio of NKCC was 8 times greater in the EP group. Data suggest that a moderate-intensity EP program performed early after HSCT is feasible and might redistribute the CD56dim/CD56brigh NK cell subset, improving NKCC. The results are still preliminary and must be interpreted with caution. Sin financiación 2.657 JCR (2017) Q1, 5/27 Integrative and Complementary Medicine; Q3, 137/223 Oncology 0.766 SJR (2017) Q1, 12/106 Complementary and Alternative Medicine; Q2, 184/378 Oncology No data IDR 2017 UEM

We analyzed the association of age at antiretroviral therapy (ART) initiation with CD4(+) T cell count recovery, death, and loss to follow-up (LTFU) among HIV-infected adults in Zambia. We compared baseline characteristics of patients by sex and age at ART initiation [categorized as 16-29 years, 30-39 years, 40-49 years, 50-59 years, and 60 years and older]. We used the medication possession ratio to assess adherence and analysis of covariance to measure the adjusted change in CD4(+) T cell count during ART. Using Cox proportional hazard regression, we examined the association of age with death and LTFU. In a secondary analysis, we repeated models with age as a continuous variable. Among 92,130 HIV-infected adults who initiated ART, the median age was 34 years and 6,281 (6.8%) were aged ≥50 years. Compared with 16-29 year olds, 40-49 year olds (-46 cells/mm(3)), 50-59 year olds (-53 cells/mm(3)), and 60+ year olds (-60 cells/mm(3)) had reduced CD4(+) T cell gains during ART. The adjusted hazard ratio (AHR) for death was increased for individuals aged ≥40 years (AHR 1.25 for 40-49 year olds, 1.56 for 50-59 year olds, and 2.97 for 60+ year olds). Adherence and retention in care were poorest among 16-29 year olds but similar in other groups. As a continuous variable, a 5-year increase in age predicted reduced CD4(+) T cell count recovery and increased risk of death. Increased age at ART initiation was associated with poorer clinical outcomes, while age30 years was associated with a higher likelihood of being lost to follow-up. HIV treatment guidelines should consider age-specific recommendations.

Background ARV treatment (ART) administered during acute HIV-infection presents several immunological benefits leading to a better CD4+ T-cell recovery and a diminished HIV reservoir. Methods Patients with acute HIV-infection, enrolled in the VIHIA cohort, had blood samples taken at diagnosis and at 2, 6 and 12 months after ART initiation. Flow-cytometry analysis was performed in fresh whole blood. Naïve-(Nv), central memory (CM), effector memory (EM) and terminally differentiated T-cells (TMRA), as well as activation markers were defined using CD3, CD4, CD8, CD45RA, CCR7, CD38, CD31 and HLA-DR markers. CD28 and CD57 were used to identify immunosenescent cells. Fox-P3, CD 25, CD127 and CD45RA were used to identify Regulatory T cells (Treg) and their subsets. To assess changes over time, Wilcoxon-matched-pairs signed rank test was used for each value between baseline and months 2 and 12 independently. Results Four patients were diagnosed at Fiebig stage II; 5 patients at Fiebig stage III, 24 patients at stage IV and 5 patients in stage V. All patients received treatment within the first 24 hours of HIV diagnosis. Only 13 patients had flow-cytometry data at baseline and 1 year of follow-up. All subjects were MSM with a mean age of 32 y.o. Mean CD4+ T-cell count was 439 cells/μL and mean viral load was 1.2 million copies/mL (23,379–10 × 106 copies/mL) at baseline. The change in T-cell differentiation patterns at 0 and 12 months is shown in Figure 1. Activation markers decreased in all studied subsets at 2 months and furthermore at 12 months. Total T-regs increased from 5.1% to 7.8% at 1 year of follow-up (Figure 2). Immunosenescence markers increased steadily throughout the study in all T-cell subsets, being statistically significant in the total T-cell CD8 population at 12 months of follow-up (Figure 3) unrelated to Fiebig stage. Conclusion It has been hypothesized that early ART decreases T-cell immunosenescence; however, in our cohort despite treatment during acute HIV, we observed that at 1 year follow-up immunosenescence markers increased despite a decrease in immune activation and a recovery of T-cell subsets. Disclosures All authors: No reported disclosures.

BackgroundTransitioning from paediatric to adult healthcare requires successful antiretroviral treatment (ART) for adolescents living with HIV (ADLHIV). Implementing such a policy implies monitoring ART response and selecting for therapeutic options for ADLHIV in resource-limited settings (RLS) like Cameroon.MethodsThe Ready study (EDCTP-CDF-1027) is conducted amongst ART-experienced ADLHIV (10–19 years old) in the Centre region, Cameroon. WHO-clinical staging, CD4-counts and viraemia were determined; in case of virological failure [VF] (viraemia ≥1000 copies/ml), HIV drug resistance (HIVDR) and subtyping were performed, and pResultsOut of 279 ADLHIV (212 urban vs 67 rural), the gender distribution was similar (54.5% female); median age was higher in urban (15 [IQR: 13–17] years) compared to rural (13 [IQR: 11–17] years), as well as the median duration on ART (7 [IQR: 3–10] years compared to 4 [IQR: 2–7] years, respectively); and the majority was on first-line ART (79.4% [162/204] urban vs 98.5% [66/67] rural, p3[urban] vs 332 cells/mm3[rural]) to 6 years after initiation (938 cells/mm3[urban] vs 548 cells/mm3[rural]) and rate of immunodeficiency (3) was 41.0% (87/208) in urban vs 47.5% (29/61) in rural, p=0.428. VF was 43.2% (41/95) in urban vs 60.9% (14/23) in rural, p=0.126. Among nine (9) sequences available from those experiencing VF, overall HIVDR was found in 88.8%, with 77.7% NNRTI, 55.6% NRTI and 22.2% PI/r. All were HIV-1 group M, with 55.6% CRF02_AG, 22.0% F1 and 22.4% others.ConclusionADLHIV appear clinically asymptomatic, with considerable immune recovery overtime. Despite differences in ART duration between urban and rural settings, VF was similarly high, associated with HIVDR mainly to NNRTI-based regimens. Thus, NNRTI-sparing regimens might be highly convenient when transitioning ADLHIV to adult ART-regimens in RLS like Cameroon.

We studied the immune response after starting antiretroviral treatment (ART) in 15,646 HIV-infected patients with or without tuberculosis (TB) at presentation in 3 ART programs in South Africa between 2003 and 2010. Patients presenting with TB had similar increases in CD4 cells compared with all other patients (adjusted difference 4.9 cells/µL per 6 months, 95% confidence interval: 0.2 to 9.7). Younger age, advanced clinical stage, female sex, and lower CD4 cell count at ART start were all associated with steeper CD4 slopes. In South Africa, HIV-infected patients presenting with TB experience immune recovery after starting ART that is no worse than in other patients.

The maintenance of chronic immune activation due to leishmaniasis or even due to microbial translocation is associated with immunosenescence and may contribute to frequent relapses. Our aim was to investigate whether patients with HIV-associated visceral leishmaniasis (VL/HIV) who experience a single episode of VL have different immunological behaviors in comparison to those who experience frequent relapses. VL/HIV patients were allocated to non-relapsing (NR, n = 6) and relapsing (R, n = 11) groups and were followed from the active phase of VL up to 12 months post-treatment (mpt). The patients were receiving highly active antiretroviral therapy (HAART) and secondary prophylaxis after VL therapy. During active VL, the two groups were similar in all immunological parameters, including the parasite load. At 6 and 12 mpt, the NR group showed a significant gain of CD4+ T cells, a reduction of lymphocyte activation, and lower soluble CD14 and anti-Leishmania IgG3 levels compared to the R group. The viral load remained low, without correlation with the activation. The two groups showed elevated but similar percentages of senescent T cells. These findings suggest a decreased ability of the R group to downmodulate immune activation compared to the NR group. Such functional impairment of the effector response may be a useful indicator for predicting clinical prognosis and recommending starting or stopping secondary prophylaxis.

Immune reconstitution was studied prospectively in 86 children who underwent allogeneic haematopoietic stem cell transplantation (HSCT). We analysed the risk of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation in correlation with the kinetics of immune recovery and in relation to other potential risk factors that may influence the reactivation of these viruses including: diagnosis, type of HSCT, source of stem cells, type of conditioning, or the occurrence of graft-versus-host disease (GvHD). The absolute number of lymphocyte subpopulations in peripheral blood was evaluated in seven timepoints following HSCT. Significantly lower values of both CD3+ and CD3+CD8+ lymphocytes on day +14 and significantly higher values of both these subsets on day +168 post-transplant in patients with CMV reactivation were observed. Significantly lower values of CD3+CD4+ subpopulation were noted in patients with CMV reactivation on day +28 post allo-HSCT. Significantly lower lymphocyte values in the group with EBV reactivation comparing with the group without EBV reactivation were confirmed only in the case of pan-B lymphocytes (CD19+) subpopulation on day +21, +28, and +84 post allo-HSCT. We identified the impact of CMV reactivation on occurrence of the intestinal acute GvHD, which occurred more frequently in the group with CMV reactivation compared with patients without reactivation. Higher incidence of chronic GvHD was also observed in patients with CMV reactivation compared to the group without reactivation. EBV reactivation occurred more frequently in patients receiving transplants from matched unrelated donors, in particular after peripheral blood stem cell transplantation and while implementing antithymocyte globulin as GvHD prophylaxis.

While changes in gut microbial populations have been described in human immuno-deficiency virus (HIV)-infected patients undergoing antiretroviral therapy (ART), the mechanisms underlying the contributions of gut bacteria and their molecular agents (metabolites and proteins) to immune recovery remain unexplored. To study this, we examined the active fraction of the gut microbiome, through examining protein synthesis and accumulation of metabolites inside gut bacteria and in the bloodstream, in 8 healthy controls and 29 HIV-infected individuals (6 being longitudinally studied). We found that HIV infection is associated to dramatic changes in the active set of gut bacteria simultaneously altering the metabolic outcomes. Effects were accentuated among immunological ART responders, regardless diet, subject characteristics, clinical variables other than immune recovery, the duration and type of ART and sexual preferences. The effect was found at quantitative levels of several molecular agents and active bacteria which were herein identified and whose abundance correlated with HIV immune pathogenesis markers. Although, we cannot rule out the possibility that some changes are partially a random consequence of the disease status, our data suggest that most likely reduced inflammation and immune recovery is a joint solution orchestrated by both the active fraction of the gut microbiota and the host., Graphical Abstract Image 1, Highlights • The active fraction of the gut microbiome is changed during HIV infection. • Changes are accentuated in immunological responders. • Alterations are both a consequence and a cause of immune recovery. • Immune system-bacteria synergism mediates solutions to immune recovery. With active antiretroviral therapy, changes in the active fraction of the gut microbiome may be both a consequence and a driver of the recovery of mucosal and systemic immunity in HIV-infected patients. Immune system-bacteria synergism likely exists to mediate solutions to inflammation and immune recovery. There is a need to assess the metabolic contributions of active gut bacteria to the recovery and maintenance of, or persistent defects in, innate and adaptive immunity across different diseases.