Alterations in immunoglobulin levels in uninfected children born to HIV infected women

Background Immunoglobulin levels are known to be elevated in HIV infected children. However, little is known about the effect of maternal HIV infection and the maternal altered immune system on immunoglobulin levels in uninfected children. As few data are available on immunoglobulins from young healthy children, we used data from uninfected children born to hepatitis C virus (HCV) infected women as a comparison. Methods Prospective data on immunoglobulin levels were available from birth to 5 years for children enrolled in the European Collaborative Study (ECS) of children born to HIV-1 infected women and from birth to 24 months for children enrolled in the European Paediatric HCV Network (EPHN). Children born to HIV/HCV co-infected women were excluded. Smoothers (running means) illustrated patterns of immunoglobulins over age by infection status. Associations between infant and maternal factors and child log10 total IgG, IgM and IgA levels were quantified in linear regression analyses allowing for repeated measures within child. Further analyses were performed using only data of HIV exposed uninfected children to investigate associations between child immunoglobulins and maternal immunological and virological factors and anti-retroviral therapy exposure. Results 1751 HIV uninfected, 190 HIV infected children (ECS), 173 HCV uninfected and 30 HCV infected children (EPHN) were included. HIV infected children had higher levels of all immunoglobulins compared to uninfected children over all ages. HIV uninfected children had significantly higher IgG, IgM and IgA levels than HCV uninfected children upto at least 24 months, adjusting for gender, prematurity and race. Prematurity was associated with significantly lower levels of immunoglobulins upto 24 months. Children born to African women had higher IgG and IgA levels upto 24 months than those born to white women but lower IgM in the first 6 months. Among HIV uninfected children higher IgG levels were associated with elevated maternal IgG levels, as well for measurements from 18 months to 5 years of age. No significant effect of maternal CD4 count was observed. ART exposure was associated with significantly lower IgG levels at 6-24 months. Race was not associated with immunoglobulin levels in multivariable analyses in this sub-group. Conclusions These findings indicate significant alterations in immunoglobulin levels in uninfected children born to HIV infected women. This suggests that exposure to an activated maternal immune system is associated with an altered humoral response in children without antigen stimulation, and warrants further research

The Farmer Life School: experience from an innovative approach to HIV education

The Farmer Life School (FLS) is an innovative approach to integrating HIV education into life skills and technical training for farmers. This study aims to gain insight into the strengths and weaknesses of this relatively new approach, through the implementation of an adapted version in South Africa. The results are presented of a pilot with three groups of community gardeners, predominantly women, attending weekly sessions. Impact was assessed in terms of three key elements: participation, learning, and empowerment. Data were collected through extensive session reports, follow-up interviews, and reflection exercises with facilitators and participating groups and individuals. The results suggest that a group-based discovery learning approach such as the FLS has great potential to improve food security and wellbeing, while allowing participants to explore issues around HIV/AIDS. However, the analysis also shows that HIV/AIDS-related illness and death, and the factors that drive the epidemic and its impact, undermine farmers\' ability to participate, the safety and trust required for learning, and the empowerment process. Participatory approaches such as the FLS require a thorough understanding of and adaptation to the context. Keywords: Farmer Life School, HIV/AIDS, participation, learning, empowerment.SAHARA J Vol. 5 (2) 2008: pp. 56-6

Co‐designing the Cabriotraining : a training for transdisciplinary teams

Accessible summary The research was conducted by a team of researchers. Some of the researchers have experience of living with a disability. The researchers created training for other research teams that include experts by experience. The training has six parts. To decide what happened in the training, the researchers read articles and asked the research teams they trained about what problems they had and what they wanted to know about. The article tells why and how the training was made. It also says what training is needed for researchers with and without disabilities to learn and work together in a way that feels safe and useful. In developing and providing the training, it was very crucial to search for a safe and welcome space for all people involved (Figure 8). As we don't know what is "safe" for the other, this means we have to search together, in respect and with enough time to get to know each other. Background Researchers collected questions and needs for training from 10 inclusive research projects in the Netherlands. Based on literature research and the information collected, six training modules were developed. Researchers sought to learn how to develop and provide training and coaching to inclusive teams on organising collaboration in the different stages of their research projects. Method An iterative training development process to support inclusive research projects was initiated by a research duo backed by a transdisciplinary team including researchers, trainers and designers. Some members of the team have experiential knowledge based on living with a disability. Results Literature research resulted in four guiding theories, including Universal Design for Learning, Derrida's concept of Hospitality, post-materialist theory looking at agency as an assemblage, and Romiszowski's model situated within Instructional Design theory. Insights gained during development of the training modules are documented with text, figures and vignettes. A core finding was the need to add "Level Zero" to Romiszowski's model: a collective term created for all the interacting issues trainers had to consider because of research group diversity. Conclusions Hospitality formed the heart of "Level Zero." Creating a failure-free space for learning is an important pre-condition for the development and organisation of training. Training can inspire exploration and reflection on collaboration and can illuminate how to conduct research within transdisciplinary teams. Essential practices included working with nonverbal research methods, as these are (more) fit for purpose when including the knowledge of experts by experience and incorporating practice- and stakeholder-based knowledge

Effect of Maternal HIV-1 Status and Antiretroviral Drugs on Haematological Profiles of South African Infants in Early Life

Maternal HIV-1 status and antiretroviral drug exposure may influence the haematological profiles of infants. We recruited infants from 118 uninfected control women and from 483 HIV-1 infected women who received no antiretroviral drugs (n=28), or received single-dose Nevirapine (sdNVP) (n=424) or triple-drug combination therapy (n=31) to reduce HIV-1 transmission. Blood was drawn from infants within 24 hours of delivery or 6-12 weeks post-delivery and full blood counts performed using a fully automated AcT-5-diff haematology analyser and reference controls. Exposed uninfected (EU; no NVP) differed from control infants only in having lower basophil counts and percentages. In all infant groups, leukocyte profiles showed characteristic quantitative changes with age in the first 6 weeks of life. HIV-1 infected infants displayed by 6 weeks elevations in white blood cells, lymphocyte, monocyte and basophil counts, and monocyte and basophil percentages, when compared to EU infants. At birth EU NVP-treated infants exhibited elevated monocyte percentages and counts and basophil counts that did not persist at 6 weeks. Interestingly, EU newborns of mothers with high CD4 counts (> 500 cells/μl) that had taken sdNVP had significantly elevated white blood cell, monocyte and basophil counts when compared to newborn infants of mothers with similar CD4 counts that had not taken sdNVP; this was not evident in infants of mothers with CD4 counts <200 cells/μl. These previously undescribed features may affect immune response capability in early life and clinical consequences of such changes need to be further investigated

Outcome of HIV-exposed uninfected children undergoing surgery

<p>Abstract</p> <p>Background</p> <p>HIV-exposed uninfected (HIVe) children are a rapidly growing population that may be at an increased risk of illness compared to HIV-unexposed children (HIVn). The aim of this study was to investigate the morbidity and mortality of HIVe compared to both HIVn and HIV-infected (HIVi) children after a general surgical procedure.</p> <p>Methods</p> <p>A prospective study of children less than 60 months of age undergoing general surgery at a paediatric referral hospital from July 2004 to July 2008 inclusive. Children underwent age-definitive HIV testing and were followed up post operatively for the development of complications, length of stay and mortality.</p> <p>Results</p> <p>Three hundred and eighty children were enrolled; 4 died and 11 were lost to follow up prior to HIV testing, thus 365 children were included. Of these, 38(10.4%) were HIVe, 245(67.1%) were HIVn and 82(22.5%) were HIVi children.</p> <p>The overall mortality was low, with 2(5.2%) deaths in the HIVe group, 0 in the HIVn group and 6(7.3%) in the HIVi group (p = 0.0003). HIVe had a longer stay than HIVn children (3 (2-7) vs. 2 (1-4) days p = 0.02). There was no significant difference in length of stay between the HIVe and HIVi groups. HIVe children had a higher rate of complications compared to HIVn children, (9 (23.7%) vs. 14(5.7%) (RR 3.8(2.1-7) p < 0.0001) but a similar rate of complications compared to HIVi children 34 (41.5%) (RR = 0.6 (0.3-1.1) p = 0.06).</p> <p>Conclusion</p> <p>HIVe children have a higher risk of developing complications and mortality after surgery compared to HIVn children. However, the risk of complications is lower than that of HIVi children.</p

Computed CD4 percentage as a low-cost method for determining pediatric antiretroviral treatment eligibility

<p>Abstract</p> <p>Background</p> <p>The performance of the WHO recommendations for pediatric antiretroviral treatment (ART) in resource poor settings is insufficiently documented in routine care.</p> <p>Methods</p> <p>We compared clinical and immunological criteria in 366 children aged 0 to 12 years in Kinshasa and evaluated a simple computation to estimate CD4 percent, based on CD4 count, total white blood cell count and percentage lymphocytes. Kappa (κ) statistic was used to evaluate eligibility criteria and linear regression to determine trends of CD4 percent, count and total lymphocyte count (TLC).</p> <p>Results</p> <p>Agreement between clinical and immunological eligibility criteria was poor (κ = 0.26). One third of children clinically eligible for ART were ineligible using immunological criteria; one third of children immunologically eligible were ineligible using clinical criteria. Among children presenting in WHO stage I or II, 54 (32%) were eligible according to immunological criteria. Agreement with CD4 percent was poor for TLC (κ = 0.04), fair for total CD4 count (κ = 0.39) and substantial for CD4 percent computational estimate (κ = 0.71). Among 5 to 12 years old children, total CD4 count was higher in younger age groups (-32 cells/mm³per year older), CD4 percent was similar across age groups.</p> <p>Conclusion</p> <p>Age-specific thresholds for CD4 percent optimally determine pediatric ART eligibility. The use of CD4 percent computational estimate may increase ART access in settings with limited access to CD4 percent assays.</p

The impact of maternal HIV infection on cord blood lymphocyte subsets and cytokine profile in exposed non-infected newborns

<p>Abstract</p> <p>Background</p> <p>Children born to HIV+ mothers are exposed intra-utero to several drugs and cytokines that can modify the developing immune system, and influence the newborn's immune response to infections and vaccines. We analyzed the relation between the distribution of cord blood lymphocyte subsets and cytokine profile in term newborns of HIV+ mothers using HAART during pregnancy and compared them to normal newborns.</p> <p>Methods</p> <p>In a prospective, controlled study, 36 mother-child pairs from HIV+ mothers and 15 HIV-uninfected mothers were studied. Hematological features and cytokine profiles of mothers at 35 weeks of pregnancy were examined. Maternal and cord lymphocyte subsets as well as B-cell maturation in cord blood were analyzed by flow cytometry. The non-stimulated, as well as BCG- and PHA-stimulated production of IL2, IL4, IL7, IL10, IL12, IFN-γ and TNF-alpha in mononuclear cell cultures from mothers and infants were quantified using ELISA.</p> <p>Results</p> <p>After one year follow-up none of the exposed infants became seropositive for HIV. An increase in B lymphocytes, especially the CD19/CD5+ ones, was observed in cord blood of HIV-exposed newborns. Children of HIV+ hard drug using mothers had also an increase of immature B-cells. Cord blood mononuclear cells of HIV-exposed newborns produced less IL-4 and IL-7 and more IL-10 and IFN-γ in culture than those of uninfected mothers. Cytokine values in supernatants were similar in infants and their mothers except for IFN-γ and TNF-alpha that were higher in HIV+ mothers, especially in drug abusing ones. Cord blood CD19/CD5+ lymphocytes showed a positive correlation with cord IL-7 and IL-10. A higher maternal age and smoking was associated with a decrease of cord blood CD4+ cells.</p> <p>Conclusions</p> <p>in uninfected infants born to HIV+ women, several immunological abnormalities were found, related to the residual maternal immune changes induced by the HIV infection and those associated with antiretroviral treatment. Maternal smoking was associated to changes in cord CD3/CD4 lymphocytes and maternal hard drug abuse was associated with more pronounced changes in the cord B cell line.</p

HLA-DPA1*02:01~B1*01:01 is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells

Objective Primary sclerosing cholangitis (PSC) is characterised by bile duct strictures and progressive liver disease, eventually requiring liver transplantation. Although the pathogenesis of PSC remains incompletely understood, strong associations with HLA-class II haplotypes have been described. As specific HLA-DP molecules can bind the activating NK-cell receptor NKp44, we investigated the role of HLA-DP/NKp44-interactions in PSC. Design Liver tissue, intrahepatic and peripheral blood lymphocytes of individuals with PSC and control individuals were characterised using flow cytometry, immunohistochemical and immunofluorescence analyses. HLA-DPA1 and HLA-DPB1 imputation and association analyses were performed in 3408 individuals with PSC and 34 213 controls. NK cell activation on NKp44/HLA-DP interactions was assessed in vitro using plate-bound HLA-DP molecules and HLA-DPB wildtype versus knock-out human cholangiocyte organoids. Results NKp44+NK cells were enriched in livers, and intrahepatic bile ducts of individuals with PSC showed higher expression of HLA-DP. HLA-DP haplotype analysis revealed a highly elevated PSC risk for HLA-DPA1*02:01~B1*01:01 (OR 1.99, p=6.7×10-50). Primary NKp44+NK cells exhibited significantly higher degranulation in response to plate-bound HLA-DPA1*02:01-DPB1*01:01 compared with control HLA-DP molecules, which were inhibited by anti-NKp44-blocking. Human cholangiocyte organoids expressing HLA-DPA1*02:01-DPB1*01:01 after IFN-γ-exposure demonstrated significantly increased binding to NKp44-Fc constructs compared with unstimulated controls. Importantly, HLA-DPA1*02:01-DPB1*01:01-expressing organoids increased degranulation of NKp44+NK cells compared with HLA-DPB1-KO organoids. Conclusion Our studies identify a novel PSC risk haplotype HLA-DP A1*02:01~DPB1*01:01 and provide clinical and functional data implicating NKp44+NK cells that recognise HLA-DPA1*02:01-DPB1*01:01 expressed on cholangiocytes in PSC pathogenesis

Natural killer cell-mediated ADCC in SARS-CoV-2-infected individuals and vaccine recipients.

COVID-19, caused by SARS-CoV-2, has emerged as a global pandemic. While immune responses of the adaptive immune system have been in the focus of research, the role of NK cells in COVID-19 remains less well understood. Here, we characterized NK cell-mediated SARS-CoV-2 antibody-dependent cellular cytotoxicity (ADCC) against SARS-CoV-2 spike-1 (S1) and nucleocapsid (NC) protein. Serum samples from SARS-CoV-2 resolvers induced significant CD107a-expression by NK cells in response to S1 and NC, while serum samples from SARS-CoV-2-negative individuals did not. Furthermore, serum samples from individuals that received the BNT162b2 vaccine induced strong CD107a expression by NK cells that increased with the second vaccination and was significantly higher than observed in infected individuals. As expected, vaccine-induced responses were only directed against S1 and not against NC protein. S1-specific CD107a responses by NK cells were significantly correlated to NK cell-mediated killing of S1-expressing cells. Interestingly, screening of serum samples collected prior to the COVID-19 pandemic identified two individuals with cross-reactive antibodies against SARS-CoV-2 S1, which also induced degranulation of NK cells. Taken together, these data demonstrate that antibodies induced by SARS-CoV-2 infection and anti-SARS-CoV-2 vaccines can trigger significant NK cell-mediated ADCC activity, and identify some cross-reactive ADCC-activity against SARS-CoV-2 by endemic coronavirus-specific antibodies