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Few studies have investigated immune cell ontogeny throughout the neonatal and early pediatric period, when there is often increased vulnerability to infections. In this study, we evaluated the dynamics of two critical T cell populations, T regulatory (Treg) cells and Th17 cells, over the first 36 wk of human life. First, we observed distinct CD4+ T cells phenotypes between cord blood and peripheral blood, collected within 12 h of birth, showing that cord blood is not a surrogate for newborn blood. Second, both Treg and Th17 cells expanded in a synchronous fashion over 36 wk of life. However, comparing infants exposed to HIV in utero, but remaining uninfected, with HIV-unexposed uninfected control infants, there was a lower frequency of peripheral blood Treg cells at birth, resulting in a delayed expansion, and then declining again at 36 wk. Focusing on birth events, we found that Treg cells coexpressing CCR4 and α4β7 inversely correlated with plasma concentrations of CCL17 (the ligand for CCR4) and intestinal fatty acid binding protein, IL-7, and CCL20. This was in contrast with Th17 cells, which showed a positive association with these plasma analytes. Thus, despite the stereotypic expansion of both cell subsets over the first few months of life, there was a disruption in the balance of Th17 to Treg cells at birth likely being a result of gut damage and homing of newborn Treg cells from the blood circulation to the gut.

As part of the CHAPS randomized clinical trial, we sequenced a segment of the bacterial 16S rRNA gene from foreskin tissue of 144 adolescents from South Africa and Uganda collected during surgical penile circumcision after receipt of 1 to 2 doses of placebo, emtricitabine with tenofovir disoproxil fumarate, or emtricitabine with tenofovir alafenamide. We found a large proportion ofCorynebacteriumin addition to other anaerobic species.Cutibacterium acneswas more abundant among participants from South Africa than Uganda, though this made no difference in surgical recovery. We did not find a difference in bacterial populations by treatment received nor bacterial taxa that were differentially abundant between participants who received placebo versus active drug. Using RNAseq libraries from foreskin tissue of the same participants, we found negative correlations between the relative abundance of bacterial taxa and the expression of genes downstream of the innate response to bacteria and regulation of the inflammatory response. When participants were divided into clusters based on bacterial community composition, two main clusters emerged which were distinguished by high and low bacterial diversity. Random forest classification showed higher expression ofNFATC3andSELENOSand lower expression ofSTAP1andNLRP6in the higher diversity group compared to the lower. Our results show no difference in the tissue microbiome of the foreskin with short-course PrEP but that bacterial taxa were largely inversely correlated with gene expression, consistent with non-inflammatory colonization.Author SummaryWe investigated the bacterial community of the foreskin of the penis. Previous studies found increased inflammation with certain anaerobic bacteria from swabs taken under the foreskin, but we found that higher relative abundances of the bacteria were correlated with lower expression of inflammatory genes. We did not find different bacteria in participants who received medicine to prevent HIV. Understanding the relationship between bacteria and inflammation in the penis will help us to understand how interventions like penile circumcision reduce the risk of acquiring sexually transmitted infections such as HIV.

The improvement of next-generation sequencing technologies has promoted the field of immunogenetics and produced numerous immunogenomics data. Modern data-driven research has the power to promote novel biomedical discoveries through secondary analysis of such data. Therefore, it is important to ensure data-driven research with great reproducibility and robustness for promoting a precise and accurate secondary analysis of the immunogenomics data. In scientific research, rigorous conduct in designing and conducting experiments is needed, specifically in scientific and articulate writing, reporting and interpreting results. It is also crucial to make raw data available, discoverable, and well described or annotated in order to promote future re-analysis of the data. In order to assess the data availability of published T cell receptor (TCR) repertoire data, we examined 11,918 TCR-Seq samples corresponding to 134 TCR-Seq studies ranging from 2006 to 2022. Among the 134 studies, only 38.1% had publicly available raw TCR-Seq data shared in public repositories. We also found a statistically significant association between the presence of data availability statements and the increase in raw data availability (p=0.014). Yet, 46.8% of studies with data availability statements failed to share the raw TCR-Seq data. There is a pressing need for the biomedical community to increase awareness of the importance of promoting raw data availability in scientific research and take immediate action to improve its raw data availability enabling cost-effective secondary analysis of existing immunogenomics data by the larger scientific community.

OBJECTIVE To examine the association between timing of antiretroviral treatment (ART) initiation in HIV-infected women and placental histopathology. DESIGN A nested substudy in a larger cohort of HIV-infected women which examined the association between ART status and birth outcomes. METHODS Placentas (n = 130) were examined for histopathology from two ART groups: stable (n = 53), who initiated ART before conception and initiating (n = 77), who started ART during pregnancy [median (interquartile range) 15 weeks gestation (11-18)]. Using binomial regression we quantified associations between ART initiation timing with placental histopathology and pregnancy outcomes. RESULTS One-third of all placentas were less than 10th percentile weight-for-gestation and there was no significant difference between ART groups. Placental diameter, thickness, cord insertion position and foetal-placental weight ratio were also similar by group. However, placentas from the stable group showed increased maternal vascular malperfusion (MVM) (39.6 vs. 19.4%), and decreased weight (392 vs. 422 g, P = 0.09). MVM risk was twice as high [risk ratios 2.03 (95% confidence interval: 1.16-3.57); P = 0.01] in the stable group; the increased risk remaining significant when adjusting for maternal age [risk ratios 2.04 (95% confidence interval: 1.12-3.72); P = 0.02]. Furthermore, MVM was significantly associated with preterm delivery and low birth weight (P = 0.002 and

Background Mechanisms underlying an association between human immunodeficiency virus (HIV) or antiretroviral therapy (ART) during pregnancy with risk of preterm delivery (PTD) and small-for-gestational-age (SGA) remain unclear. We explored the association between cellular immune activation and PTD or SGA in women with HIV initiating ART during or before pregnancy. Methods Women with HIV enrolled at median 15 weeks’ gestation, were analyzed for immune markers, and matched on ART initiation timing (15 women initiated pre- and 15 during pregnancy). There were 30 PTD (delivery 25th percentile) as outcomes. Lymphocytes, monocytes, and dendritic cell populations and their activation status or functionality were enumerated by flow cytometry. Results PTD cases initiating ART in pregnancy showed decreased CD8+ T cell, monocyte, and dendritic cell activation; increased classical (CD14+CD16–) and intermediate (CD14+CD16+) monocyte frequencies; and decreased inflammatory monocytes (CD14dimCD16+) compared with SGA cases and term controls (all P, Here, we show that low immune cell activation and lowered cytokine production by monocytes in response to toll-like receptor ligand stimulation in early pregnancy in women initiating antiretroviral therapy in pregnancy is associated with preterm but not small-for-gestational age delivery.

During human pregnancy, proinflammatory responses in the placenta can cause severe fetal complications, including growth restriction, preterm birth, and stillbirth. Villitis of unknown etiology (VUE), an inflammatory condition characterized by the infiltration of maternal CD8+ T cells into the placenta, is hypothesized to be secondary to either a tissue rejection response to the haploidentical fetus or from an undiagnosed infection. In this study, we characterized the global TCR β-chain profile in human T cells isolated from placentae diagnosed with VUE compared with control and infectious villitis–placentae by immunoSEQ. Immunosequencing demonstrated that VUE is driven predominantly by maternal T cell infiltration, which is significantly different from controls and infectious cases; however, these T cell clones show very little overlap between subjects. Mapping TCR clones to common viral epitopes (CMV, EBV, and influenza A) demonstrated that Ag specificity in VUE was equal to controls and significantly lower than CMV-specific clones in infectious villitis. Our data indicate VUE represents an allograft response, not an undetected infection. These observations support the development of screening methods to predict those at risk for VUE and the use of specific immunomodulatory therapies during gestation to improve outcomes in affected fetuses.

Background Implementation of universal antiretroviral therapy (ART) has significantly lowered vertical transmission rates but has also increased numbers of human immunodeficiency virus (HIV)–exposed uninfected children, who remain vulnerable to morbid effects. In the current study, we investigated whether T-cell alterations in the placenta contribute to altered immune status in HIV-exposed uninfected. Methods We analyzed T cells from term placenta decidua and villous tissue and paired cord blood from pregnant women living with HIV (PWH) who initiated ART late in pregnancy (n = 21) with pregnant women not living with HIV (PWNH) (n = 9). Results Placentas from PWH showed inverted CD4/CD8 ratios and higher proportions of tissue resident CD8+ T cells in villous tissue relative to control placentas. CD8+ T cells in the fetal capillaries, which were of fetal origin, were positively correlated with maternal plasma viremia before ART initiation, implying that imbalanced T cells persisted throughout pregnancy. In addition, the expanded memory differentiation of CD8+ T cells was confined to the fetal placental compartment and cord blood but was not observed in the maternal decidua. Conclusions T-cell homeostatic imbalance in the blood circulation of PWH is reflected in the placenta. The placenta may be a causal link between HIV-induced maternal immune changes during gestation and altered immunity in newborn infants in the absence of vertical transmission.

PurposePrematurity Immunology in Mothers living with HIV and their infants Study (PIMS) is a prospective cohort study in South Africa investigating the association between antiretroviral therapy (ART) use, preterm delivery (PTD) and small-for-gestational age (SGA) live births. PIMS main hypotheses are that ART initiation in pregnancy and ART-induced hypertension are associated with PTD and SGA respectively and that reconstitution of cellular immune responses in women on ART from before pregnancy results in increases in PTD of GA infants.ParticipantsPregnant women (n=3972) aged ≥18 years regardless of HIV status recruited from 2015 to 2016 into the overall PIMS cohort (2517 HIV-negative, 1455 living with HIV). A nested cohort contained 551 women living with HIV who were ≤24 weeks’ GA on ultrasound: 261 initiated ART before pregnancy, 290 initiated during the pregnancy.Findings to dateWomen in the overall cohort were followed antenatally through to delivery using routine clinical records; further women in the nested cohort were actively followed up until 12 months post partum, with data collected on maternal health (HIV care and ART use, clinical care and intercurrent clinical history). Other procedures conducted on the nested cohort included physical examinations (anthropometry, blood pressure measurement), assessment of fetal growth (ultrasound), maternal and infant phlebotomy for storage of plasma, RNA and peripheral blood mononuclear cells, collection of delivery specimens (placenta and cord blood) and infant 12-month developmental assessment. Preliminary findings have contributed to our understanding of risk factors for adverse birth outcomes, and the relationship between pregnancy immunology, HIV/ART and adverse birth outcomes.Future plansUsing specimens collected from study participants living with HIV throughout pregnancy and first year of life, the PIMS provides a valuable platform for answering a variety of research questions focused on temporal changes of immunology markers in women whose immune status is altered by HIV infection, and how ART initiated during the pregnancy affects immune responses. The relationship between these immunological changes with adverse birth outcomes as well as possible longer-term impact of exposure to ART in fetal and early life will be explored. Additionally, further active and passive follow-up of mothers and their infants is planned at school-going age and beyond to chart growth, morbidity and development, as well as changes in family circumstances.

Few studies have investigated immune cell ontogeny throughout the neonatal and early paediatric period, where there is often increased vulnerability to infections. Here, we evaluated the dynamics of two critical T cell populations, regulatory (Treg) cells and Th17 cells, over the first 36 weeks of life. Firstly, we observed distinct CD4+ T cells phenotypes between cord blood and peripheral blood, collected within 12 hours of birth, showing that cord blood is not a surrogate for newborn blood. Secondly, both Treg and Th17 cells expanded in a synchronous fashion over 36 weeks of life. However, comparing infants exposed to HIV in utero, but remaining uninfected (iHEU), with HIV-unexposed uninfected control infants (iHUU), there was a lower frequency of peripheral blood Treg cells at birth, resulting in a delayed expansion, and then declining again at 36 weeks. Focusing on birth events, we found that Treg cells co-expressing CCR4 and α4β7 inversely correlated with plasma concentrations of CCL17 (the ligand for CCR4) and intestinal fatty acid binding protein (iFABP), IL-7 and CCL20. This was in contrast to Th17 cells, which showed a positive association with these plasma analytes. Thus, despite the stereotypic expansion of both cell subsets over the first few months of life, there was a disruption in the balance of Th17 to Treg cells at birth likely being a result of gut damage and homing of newborn Treg cells from the blood circulation to the gut.Key pointsPhenotypic differences between cord and birth peripheral blood CD4 cells.Synchronous increase of Th17-Treg cells is disrupted by HIV/ART exposure.Intrauterine HIV exposure was associated with epithelial gut damage.

In this review, we discuss the often overlooked tissue-resident fetal macrophages, Hofbauer cells, which are found within the chorionic villi of the human placenta. Hofbauer cells have been shown to have a phenotype associated with regulatory and anti-inflammatory functions. They are thought to play a crucial role in the regulation of pregnancy and in the maintenance of a homeostatic environment that is crucial for fetal development. Even though the numbers of these macrophages are some of the most abundant immune cells in the human placenta, which are sustained throughout pregnancy, there are very few studies that have identified their origin, their phenotype, and functions and why they are maintained throughout gestation. It is not yet understood how Hofbauer cells may change in function throughout normal pregnancy, and especially in those complicated by maternal gestational diabetes, preeclampsia, and viral infections, such as Zika, cytomegalovirus, and human immunodeficiency virus. We review what is known about the origin of these macrophages and explore how common complications of pregnancy dysregulate these cells leading to adverse birth outcomes in humans. Our synthesis sheds light on areas for human studies that can further define these innate regulatory cells.

Determinants of the acquisition and maintenance of maternal microchimerism (MMc) during infancy and the impact of MMc on infant immune responses are unknown. We examined factors which influence MMc detection and level across infancy and the effect of MMc on T cell responses to BCG vaccination in a cohort of HIV exposed, uninfected and HIV unexposed infants in South Africa. MMc was measured in whole blood from 58 infants using a panel of quantitative PCR assays at day one and 7, 15, and 36 weeks of life. Infants received BCG at birth, and selected whole blood samples from infancy were stimulated in vitro with BCG and assessed for polyfunctional CD4+ T cell responses. MMc was present in most infants across infancy with levels ranging from 0-1,193/100,000 genomic equivalents and was positively impacted by absence of maternal HIV, maternal-infant HLA compatibility, infant female sex, and exclusive breastfeeding. Initiation of maternal antiretroviral therapy prior to pregnancy partially restored MMc level in HIV exposed, uninfected infants. Birth MMc was associated with an improved polyfunctional CD4+ T cell response to BCG. These data emphasize that both maternal and infant factors influence the level of MMc, which may subsequently impact infant T cell responses.Abstract Figure

Langerhans cells (LCs) reside in the epidermis as a dense network of immune system sentinels, coordinating both immunogenic and tolerogenic immune responses. To determine molecular switches directing induction of LC immune activation, we performed mathematical modelling of gene regulatory networks identified by single cell RNA sequencing of LCs exposed to TNF, a key pro-inflammatory signal produced by the skin. Our approach delineated three programmes of LC phenotypic activation (immunogenic, tolerogenic or ambivalent), and confirmed that TNF enhanced LC immunogenic programming. Through regulon analysis followed by mutual information modelling, we identified IRF1 as the key transcription factor for the regulation of immunogenicity in LCs. Application of a mathematical toggle switch model, coupling IRF1 with tolerance-inducing transcription factors, determined the key set of transcription factors regulating the switch between tolerance and immunogenicity, and correctly predicted LC behaviour in LCs derived from different body sites. Our findings provide a mechanistic explanation of how combinatorial interactions between different transcription factors can coordinate specific transcriptional programmes in human LCs, interpreting the microenvironmental context of the local tissue microenvironments.

BackgroundImplementation of universal antiretroviral therapy (ART) has significantly lowered vertical transmission rates but has also increased numbers of HIV-exposed uninfected children (HEU), who remain vulnerable to morbidities. Here, we investigated whether T cell alterations in the placenta contribute to altered immune status in HEU.MethodsWe analyzed T cells from term placentae decidua and villous tissue and paired cord blood from pregnant women with HIV (PWH) who initiated ART late in pregnancy (n=21) with pregnant women not living with HIV (PWNH) (n=9).ResultsPlacentae from PWH showed inverted CD4:CD8 ratios and higher proportions of tissue resident CD8+ T cells in villous tissue relative to control placentae. CD8+ T cells in the fetal capillaries, which were of fetal origin, positively correlated with maternal plasma viraemia prior to ART initiation, implying that imbalanced T cells persisted throughout pregnancy. Additionally, the expanded memory differentiation of CD8+ T cells was confined to the fetal placental compartment and cord blood but was not observed in the maternal decidua.ConclusionsT cell homeostatic imbalance in the blood circulation of PWH is reflected in the placenta. The placenta may be a causal link between HIV-induced maternal immune changes during gestation and altered immunity in newborn infants in the absence of vertical transmission.Lay SummaryThe effective prevention of HIV transmission during pregnancy with the rollout of antiretroviral therapy (ART) has resulted in increased numbers of HIV-exposed uninfected children (HEU). These children are vulnerable to infections and health problems and have distorted cellular immune systems at birth. We investigated whether these immune alterations originate in the placenta, as this fetal organ maintains life during pregnancy. After collecting placentae at term from pregnant women living with HIV (PWH), who started ART in the third trimester (n=21) and from pregnant women not living with HIV (PWNH) (n=9), we isolated T cells from dissected placental tissue and matching cord blood. Placentae from PWH showed inverted CD4:CD8 ratios in the placenta and cord blood with higher numbers of CD8+ T cells in the fetal part of the placenta. These CD8+ T cells mirrored events in the blood circulation of the mother and the altered balance of T cell immunity in the PWH was reflected in the placenta. Accordingly, the placenta may be a pivotal link between HIV-induced maternal immune changes and altered immunity in newborn infants in the absence of vertical transmission.

With the advent of high-throughput sequencing technologies, the fields of immunogenomics and adaptive immune receptor repertoire research are facing both opportunities and challenges. Adaptive immune receptor repertoire sequencing (AIRR-seq) has become an increasingly important tool to characterize T and B cell responses in settings of interest. However, the majority of AIRR-seq studies conducted so far were performed in individuals of European ancestry, restricting the ability to identify variation in human adaptive immune responses across populations and limiting their applications. As AIRR-seq studies depend on the ability to assign VDJ sequence reads to the correct germline gene segments, efforts to characterize the genomic loci that encode adaptive immune receptor genes in different populations are urgently needed. The availability of comprehensive germline gene databases and further applications of AIRR-seq studies to individuals of non-European ancestry will substantially enhance our understanding of human adaptive immune responses, promote the development of effective diagnostics and treatments, and eventually advance precision medicine., 22 pages,1 table

An exemplar outcome of an immunology-based intervention is vaccine development; the current COVID-19 pandemic is a case in point. Can we build an immunology research ecosystem in Africa that nurtures discovery and enables translation? We see African immunologists as key agents of change and discuss obstacles and opportunities.

HLA-DQB1*05:272 has a single transversion compared to the most similar variant, HLA-DQB1*05:01:01 in IPD-IMGT/HLA database. This article is protected by copyright. All rights reserved.

Developing an efficacious vaccine to SARS-CoV-2 infection is critical to stem COVID-19 fatalities and providing the global community with immune protection. We have used a bioinformatic approach to aid in the design of an epitope peptide-based vaccine against the spike protein of the virus. Five antigenic B cell epitopes with viable antigenicity and a total of 27 discontinuous B cell epitopes were mapped out structurally in the spike protein for antibody recognition. We identified eight CD8+T cell 9-mers along with 12 CD4+T cell 14-15-mer as promising candidate epitopes putatively restricted by a large number of MHC-I and II alleles respectively. We used this information to construct anin silicochimeric peptide vaccine whose translational rate was highly expressed when cloned in pET28a (+) vector. The vaccine construct was predicted to elicit high antigenicity and cell-mediated immunity when given as a homologous prime-boost, with triggering of toll-like receptor 5 by the adjuvant linker. The vaccine was characterized by an increase in IgM and IgG and an array of Th1 and Th2 cytokines. Uponin silicochallenge with SARS-CoV-2, there was a decrease in antigen levels using our immune simulations. We therefore propose that potential vaccine designs consider this approach.

BackgroundAntiretroviral therapy (ART) is universally recommended for all HIV-infected pregnant women to improve survival and to reduce mother-to-child HIV transmission. With widespread use of ART in areas of high HIV prevalence, there is concern that prolonged in-utero ART exposure may result in adverse birth outcomes, such as preterm delivery and low birthweight infants. Underlying drivers of these effects may be found in the placenta.ObjectiveWe examined whole placentas from live births to seek an association between timing of ART initiation and pregnancy outcome.Study DesignThis was a nested sub-study in a larger cohort of HIV-infected women recruited in a large primary care antenatal clinic in Cape Town, South Africa. Whole placentas (n=130) were collected at delivery and examined for histopathology from two ART groups. The stable group (n=53) initiated ART prior to pregnancy and the initiating group (n=77) started ART at a median of 15 weeks gestation. Adverse birth outcomes were defined by preterm delivery (PTD; n=9), small-for-gestational age (SGA; n=12) and low birthweight (LBW; n=11) in the two groups. Wilcoxon rank-sum and t-tests were used to measure differences in placental histopathology by ART group. Binomial and univariate linear regression models, chi-squared or Fisher’s exact test were used to quantify associations between placenta histopathology and maternal factors including ART timing and the association with pregnancy outcome.ResultsWomen in the stable group were significantly older (median [IQR] 33 years [28 - 37] vs 28 [25 - 32]; p=0.003), had higher CD4 cell counts 455 cells/ml [381 - 602] vs 369.5 [251 - 534.5], p=0.04) and were less likely to be prehypertensive or hypertensive at first antenatal care visit (p=0.03) than women in the initiating group. Overall, 119 (91%), women were on a fixed dose regimen of Tenofovir (TDF) + Lamivudine (3TC) + Efavirenz (EFV) and only 3 (2%; all in the stable group) were on a protease inhibitor (PI)-based regimen with no difference between the groups. Overall, nearly a third of placentas were small, although the fetal-placenta weight ratio was in the normal range for most women. Meconium exposure and chorioamnionitis was seen in 19% and 15% of placentas, respectively. Apart from maternal vascular malperfusion (MVM) and decidual arteriopathy, histopathology obervations did not differ significantly between stable and initiating groups. Placentas from the stable group showed increased MVM (39.6% vs 19.4%, p=0.01) and decidual arteriopathy (11.3% vs 1.3%, p=0.02), with a trend of decreased placental weight (392g vs 422g, p=0.09). MVM, in turn, was significantly associated with PTD and LBW (p=0.002 and pConclusionART initiation prior to pregnancy was associated with an increased risk of maternal vascular malperfusion and decidual arteriopathy, suggestive of placental dysfunction. The association between MVM with PTD and LBW suggests that a placenta-mediated mechanism may link the putative association between ART and adverse birth outcomes.

PurposePIMS, is a prospective cohort study in South Africa investigating the association between antiretroviral therapy (ART) use, preterm delivery (PTD)and small-for gestational age (SGA) live births. PIMS main hypotheses are that ART initiation in pregnancy and ART-induced hypertension are associated with PTD and SGA respectively and that reconstitution of cellular immune responses in women on ART from before pregnancy results in increases in PTD of appropriate-for-gestational age (AGA) infants.ParticipantsPregnant women (n=3972) aged ≥18 years regardless of HIV status recruited from 2015 to 2016 into the overall PIMS cohort (2517 HIV-uninfected, 1455 HIV-infected). A nested cohort contained 551 HIV-infected women who were ≤24 weeks’ GA on ultrasound: 261 initiated ART before pregnancy, 290 initiated during pregnancy.Findings to dateWomen in the overall cohort were followed antenatally through to delivery using routine clinical records; further women in the nested cohort were actively followed up until 12 months postpartum, with data were collected on maternal health (HIV care and ART use, clinical care and inter-current clinical history). Other procedures conducted on the nested cohort included physical examinations (anthropometry, blood pressure measurement), assessment of fetal growth (ultrasound), maternal and infant phlebotomy for storage of plasma, RNA and peripheral blood mononuclear cells, collection of delivery specimens (placenta and cord blood), and infant 12 month developmental assessment. Preliminary findings have contributed to our understanding of risk factors for adverse birth outcomes, and the relationship between pregnancy immunology, HIV/ART and adverse birth outcomes.Future plansUsing specimens collected from HIV-infected study participants throughout pregnancy and first year of life, the PIMS provides a valuable platform for answering a variety of research questions focused on temporal changes of immunology markers in women whose immune status is altered by HIV infection, and how ART initiated during pregnancy affects immune responses. The relationship between these immunological changes with adverse birth outcomes as well as possible longer-term impact of exposure to ART in fetal and early life will be explored. Additionally, further active and passive follow-up of mothers and their infants is planned at school-going age and beyond to chart growth, morbidity and development, as well as changes in family circumstances.

Supplemental Digital Content is available in the text, A subgroup of women who are co-infected with human immunodeficiency virus type 1 (HIV-1) and human papillomavirus (HPV), progress rapidly to cervical disease. We characterized HPV genotypes within cervical tumor biopsies, assessed the relationships of cervical disease stage with age, HIV-1 status, absolute CD4 count, and CD4 percentage, and identified the predictive power of these variables for cervical disease stage in a cohort of South African women. We recruited 181 women who were histologically diagnosed with cervical disease; 87 were HIV-1-positive and 94 were HIV-1-seronegative. Colposcopy-directed tumor biopsies were confirmed by histology and used for genomic DNA extraction. The Roche Linear Array HPV genotyping test was used for HPV genotyping. Peripheral whole blood was used for HIV-1 rapid testing. Fully automated FC500MPL/CellMek with PanLeucogate (PLG) was used to determine absolute CD4 count, CD4 percentage, and CD45 count. Chi-squared test, a logistic regression model, parametric Pearson correlation, and ROC curves were used for statistical analyses. We used the Benjamini-Horchberg test to control for false discovery rate (FDR, q-value). All tests were significant when both P and q were 28% CD4 cells (both P 350 compared to 30% (12/40) who possessed CD4 count ≤ 350 (both P

OBJECTIVE The effects of in-utero HIV-exposure on infectious morbidity and mortality in settings with universal maternal treatment and high breastfeeding rates are unclear. Further, the benefits of exclusive feeding options have not been assessed in the Option B+ era. We investigated these in two African settings with high breastfeeding uptake and good HIV treatment infrastructure during the first year of life. METHODS Cox regression with time-changing variables in a birth cohort of 749 HIV-exposed uninfected and HIV-unexposed uninfected infants from Cape Town, South Africa and Jos, Nigeria. RESULTS There was no difference in infectious morbidity incidence between HIV-exposed uninfected and HIV-unexposed uninfected infants (hazard ratio 1.01; 95% CI 0.78-1.32) after adjusting for confounding variables. Formula-fed infants had significantly higher infectious morbidity incidence when compared with exclusively breastfed infants (hazard ratio 1.64; 95% CI 1.03-2.63) and mixed-breastfed infants (hazard ratio 1.42; 95% CI 1.00-2.02) after adjusting for potential confounding variables. There was no significant difference in mortality among HIV-exposed infants and HIV-unexposed infants during the first year of life in this cohort (2.04 versus 0.94%, P = 0.38). Notably, exclusive breastfeeding for only 4 months had protective effects on morbidity up to 1 year. CONCLUSION In settings with universal antiretroviral coverage and high breastfeeding rates, breastfeeding mitigates the effects of in-utero HIV exposure among infants during the first year of life. These findings support previous recommendations for exclusive breastfeeding among HIV-infected women and highlight the role that breastfeeding plays on the health of infants in settings where exclusive breastfeeding is not always feasible or where replacement feeding is recommended.

Adolescents in Africa are at high risk for HIV infection, other sexually transmitted infections (STIs) and bacterial vaginosis (BV). Since behavior and burden of STIs/BV may influence HIV risk, behavioral risk factors and prevalence of STIs/BV were compared in HIV-seronegative adolescent females (n = 298; 16–22 years) from two South African communities (Soweto and Cape Town). STIs ( Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Mycoplasma genitalium, herpes simplex virus (HSV)-1, HSV-2, Treponema pallidum, and Haemophilus ducreyi) were detected by multiplex polymerase chain reaction, human papillomavirus (HPV) by Roche Linear Array, and BV by Nugent scoring. Rates of BV (Nugent ≥7; 46.6%) and HPV (66.8%) were high in both communities. Prevalence of C. trachomatis and N. gonorrhoeae were >2-fold higher in Cape Town than Soweto (Chlamydia: 42% [62/149] versus 18% [26/148], p 70% of young women with treatable conditions that could enhance HIV risk would have been missed because they lacked symptoms associated with syndromic management.

Successful future HIV vaccines are expected to generate an effective cellular and humoral response against the virus in both the peripheral blood and mucosal compartments. We previously reported the development of DNA-C and MVA-C vaccines based on HIV-1 subtype C and demonstrated their immunogenicity when given in a DNA prime-MVA boost combination in a nonhuman primate model. In the current study, rhesus macaques previously vaccinated with a DNA-C and MVA-C vaccine regimen were re-vaccinated 3.5 years later with MVA-C followed by a protein vaccine based on HIV-1 subtype C envelope formulated with MF59 adjuvant (gp140Env/MF59), and finally a concurrent boost with both vaccines. A single MVA-C re-vaccination elicited T cell responses in all animals similar to previous peak responses, with 4/7 demonstrating responses >1000 SFU/106 PBMC. In contrast to an Env/MF59-only vaccine, concurrent boosting with MVA-C and Env/MF59 induced HIV-specific cellular responses in multiple mucosal associated lymph nodes in 6/7 animals, with high magnitude responses in some animals. Both vaccine regimens induced high titer Env-specific antibodies with ADCC activity, as well as neutralization of Tier 1 viruses and modest Tier 2 neutralization. These data demonstrate the feasibility of inducing HIV-specific immunity in the blood and mucosal sites of viral entry by means of DNA and poxvirus-vectored vaccines, in combination with a HIV envelope-based protein vaccine.

At least one-third of infants born in sub-Saharan Africa have been exposed to the effects of maternal HIV infection and antiretroviral treatment. Intrauterine HIV exposure is associated with increased rates of morbidity and mortality in children. Although the mechanisms responsible for poor infant health with HIV-1 exposure are likely to be multifactorial, we posit that the maternal environment during gestation and in the perinatal period results in altered infant immunity and is possibly the strongest contributing factor responsible for the disproportionally high infectious events among HIV-exposed infants who remain HIV uninfected. This review provides a synthesis of studies reporting the impact of intrauterine HIV exposure, feeding practices, and microbiota on immune ontogeny in the first year of life in HIV-exposed uninfected infants. Review on the impact of HIV exposure, feeding practices and microbiota on immune ontogeny in HIV exposed uninfected infants.

crAssphages are a broad group of diverse bacteriophages in the order Caudovirales that have been found to be highly abundant in the human gastrointestinal tract. Despite their high prevalence, we have an incomplete understanding of how crAssphages shape and respond to ecological and evolutionary dynamics in the gut. Here, we report genomes of crAssphages from feces of one South African woman and three infants. Across the complete genome sequences of the South African crAssphages described here, we identify particularly elevated positive selection in RNA polymerase and phage tail protein encoding genes, contrasted against purifying selection, genome-wide. We further validate these findings against a crAssphage genome from previous studies. Together, our results suggest hotspots of selection within crAssphage RNA polymerase and phage tail protein encoding genes are potentially mediated by interactions between crAssphages and their bacterial partners.

The potential role for serological tests in the current COVID-19 pandemic has generated very considerable recent interest across many sectors worldwide, inter alia pathologists seeking additional weapons for their armoury of diagnostic tests; epidemiologists seeking tools to gain seroprevalence data that will inform improved models of the spread of disease; research scientists seeking tools to study the natural history of COVID-19 disease; vaccine developers seeking tools to assess vaccine efficacy in clinical trials; and companies and governments seeking tools to aid return-to-work decision-making. However, much of the local debate to date has centred on questions surrounding whether regulatory approval processes are limiting access to serological tests, and has not paused to consider the intrinsically limiting impact of underlying fundamental biology and immunology on where and how different COVID-19 serological tests can usefully be deployed in the response to the current pandemic. We review, from an immunological perspective, recent experimental evidence on the time-dependency of adaptive immune responses following SARS-CoV-2 infection and the impact of this on the sensitivity and specificity of COVID-19 antibody tests made at different time points post infection. We interpret this scientific evidence in terms of mooted clinical applications for current COVID-19 antibody tests in identifying acute infections, in confirming recent or past infections at the individual and population level, and in detecting re-infection and protective immunity. We conclude with guidance on where current COVID-19 antibody tests can make a genuine impact in the pandemic.

Background: A subset of women who are co-infected with Human Immunodeficiency Virus type 1 (HIV) and Human papillomavirus (HPV), progress rapidly to invasive cervical cancer regardless of antiretroviral therapy (ART) or immune status. We posit that HIV/HPV co-infection along with specific host HLA II -DRB1 and -DQB1 alleles play a major role in cervical cancer development. Methodology: We conducted a hospital-based genetic susceptibility case-control study in Cape Town, South Africa. We recruited 256 women of the same race, from which a total of 624 HLA-DRB1 and -DQB1 class II genotypes were studied. We characterized HLA II candidate genes using PCR based, Luminex intermediate resolution genotyping and confirmed significant associated genotypes at four-digit resolution by high resolution gel typing. We analyzed 160 alleles from cancer, 64 alleles from pre-cancer and 400 alleles from healthy control women. Whole blood was used for HIV antibody test and HLA II typing. Cervical tumor tissue biopsies were used for HPV genotyping. Tests were statistically significant if p

Purpose Heterogeneous findings exist on antiretroviral therapy (ART) use in pregnancy and preterm delivery (PTD) or infants born small-for-gestational age (SGA). Whether reported differences may be explained by methods used to ascertain gestational age (GA) has not been explored. Methods We enrolled consecutive pregnant women attending a large primary care antenatal clinic in South Africa. Public-sector midwives assessed GA by last menstrual period (LMP) and symphysis-fundal height (SFH). Separately, if clinical GA was less than 24 weeks, ultrasound (US) was performed by a research sonographer blinded to midwife assessments. In analysis, the impact of measurement error on the association between HIV/ART status and birth outcome by GA method was assessed, and factors associated with clinical GA underestimation or overestimation identified. Results In 1787 women included overall, estimated PTD incidence was 36% by LMP, 17% by SFH, and 11% by US. PTD risk was higher for HIV-infected than HIV-uninfected women using US-GA (adjusted odds ratio [aOR] 1.95; 95% CI 1.10-3.46); for LMP/SFH-GA, the associations were smaller and not significant. These findings persisted after adjustment for age, parity, height, and previous PTD. PTD risk did not vary by timing of ART initiation (before or during pregnancy) for any method. Elevated BMI and older age were associated with decreased risk of underestimation by both LMP and SFH; HIV status and obesity were associated with increased risk of overestimation by SFH. There were no differences in SGA incidence across GA methods. Conclusions Findings for an association between HIV/ART and birth outcomes are substantially influenced by GA assessment method. With growing public health interest in this association, future research efforts should seek to standardize optimal measures of gestation.