Neonatal HIV Infection Research Articles

Increased Expression on Innate Immune Factors in Placentas From HIV-Infected Mothers Concurs With Dampened Systemic Immune Activation.

Innate immunity is one of the main protection mechanisms against viral infections, but how this system works at the maternal-fetal interface, especially during HIV infection, is still poorly known. In this study, we investigated the relationship between pregnancy and innate mechanisms associated with HIV immunity by evaluating the expression of DAMPs, inflammasome components and type I/III IFNs in placenta and serum samples from HIV-infected mothers and exposed newborns. Our results showed that most of these factors, including HMGB1, IL-1, and IFN, were increased in placental villi from HIV-infected mothers. Curiously, however, these factors were simultaneously repressed in serum from HIV-infected mothers and their exposed newborns, suggesting that pregnancy could restrict HIV immune activation systemically but preserve the immune response at the placental level. An effective local antiviral status associated with a suppressed inflammatory environment can balance the maternal immune response, promoting homeostasis for fetal development and protection against HIV infection in neonates.

Early to treat, early to thrive

HIV Timing of antiretroviral therapy (ART) initiation for HIV can influence viral-reservoir seeding and also the immune response. However, this has not been well characterized in neonatal HIV infection. To discern how ART affects neonates, Garcia-Broncano et al. studied infants from Botswana who were placed on ART hours or months after birth. Early initiation of therapy reduced seeding of the viral reservoir and also modulated natural killer cell and T cell responses to HIV. Thus, immediate ART initiation—earlier than the current guidelines of a few weeks—could provide real benefit to infants with HIV. Sci. Transl. Med. 11 , eaax7350 (2019).

619: Mechanical dilation in HIV positive subjects does not increase risk of histologic chorioamnionitis

Chorioamnionitis is a risk factor for perinatal HIV transmission and early-onset neonatal sepsis. Placental inflammation increases risk of HIV transmission. The objective of this study is to explore the risk of histologic chorioamnionitis in HIV-1 positive subjects undergoing induction of labor with and without mechanical dilation. This is a multi-center retrospective cohort study of HIV positive women who underwent induction/augmentation of labor from 11/2010 – 8/2017 at two major tertiary care centers in different states. Delivery outcomes including: histologic and clinical chorioamnionitis, postpartum endometritis, and neonatal HIV infection were included for analysis. A bivariate analysis of demographic, HIV specific, and delivery outcome measures between the cohorts was conducted. Multivariate logistical regression modeling was used to control for possible confounding variables. A total of 396 HIV+ women delivered during the study period. 135 women met inclusion criteria and 95 had placental pathology available for review. 83 women (61.5%) underwent mechanical dilation and 51 (38.5%) had no mechanical dilation. The cohorts were similar in terms of race/ethnicity, age, parity, HIV viral load, CD4 count, and GBS status. The mechanical dilation cohort had less cervical dilation on admission compared to the control. 20 subjects had histologic chorioamnionitis (21.05%). There was no difference in rates of histologic chorioamnionitis between the cohorts with 14 (22.22%) of the mechanical dilation cohort and 6 (18.75%) of the no mechanical dilation cohort having evidence of histologic chorioamnionitis (p = 0.6951, OR 1.24 [CI 0.43-3.60]). A multi-variate logistic regression model was developed to control for race, age, and dilation on admission and did not change the outcome or significance. Clinical chorioamnionitis, postpartum endometritis, and neonatal HIV infection were rare with 4, 3, and 0 cases respectively in this study population. The use of mechanical dilation was not shown to be associated with increased risk of histologic chorioamnionitis in term HIV positive patients undergoing induction or augmentation of labor.

Pharmacological Prevention and Treatment of Maternal and Neonatal HIV Infection

Pharmacological Prevention and Treatment of Maternal and Neonatal HIV Infection

Profound loss of intestinal Tregs in acutely SIV-infected neonatal macaques.

Impairment of the intestinal mucosal immune system is an early feature of HIV-infected children. Most infected children exhibit clinical gastrointestinal symptoms at some stage of infection, and persistent diarrhea is a marker for rapid disease progression. It is known that Tregs are especially important in mediating intestinal immune homeostasis and that loss of this subset may result in intestinal inflammation and associated clinical signs. Large numbers of FoxP3(+) T cells were found in all tissues in newborn macaques, which coexpressed high levels of CD25 and CD4, indicating that they were Tregs. Moreover, neonates had much greater percentages of Tregs in intestinal tissues compared with peripheral lymphoid tissues. After SIV infection, a significant loss of Tregs was detected in the intestine compared with age-matched normal infants. Finally, SIV-infected FoxP3(+) T cells were detected in tissues in neonates as early as 7 SIV dpi. These results demonstrate that Tregs constitute a significant fraction of CD4(+) T cells in neonatal intestinal tissues and that an early, profound loss of Tregs occurs in acute SIV infection, which may contribute to the intestinal disorders associated with neonatal HIV infection.

Advances in basic and clinical immunology in 2012

Basic and clinical immunology articles published in the Journal in 2012 were mostly related to the expanding area of primary immunodeficiencies (PIDs). Novel forms of PID were identified by using whole-exome sequencing or after careful examination of flow cytometric data, as in the reports of lymphocyte-specific protein tyrosine kinase, CD27, and CD21 deficiencies. Absent IgG and IgA memory B cells were described in patients with hyper-IgE syndrome, which is consistent with defective antibody response and suggests a potential benefit of immunoglobulin replacement. Impaired production of antibodies to polysaccharide antigens by the human B-cell subset analog to murine B-1 cells was reported in a child with selective polysaccharide antibody deficiency. Increased production of inflammatory cytokines by monocyte-derived cells on Toll-like receptor activation was reported in patients with X-linked agammaglobulinemia, underscoring the important role of Bruton tyrosine kinase in modulation of inflammation. The mechanisms explaining susceptibility to yeast infections and development of chronic mucocutaneous candidiasis were extensively studied. Universal newborn screening for T-cell deficiencies is being implemented in several states, resulting in the diagnosis of a higher number of immunodeficient newborns than previously estimated. The use of laboratory testing to distinguish PIDs from HIV infection was clarified. In the management of PIDs, refinement of indication and strategies to hematopoietic stem cell transplantation resulted in improved outcomes. The use of anti-IL-6 mAbs showed promise as an alternative treatment in patients with Schnitzler syndrome.

The Need and Plan for Global Elimination of Congenital Syphilis

In every society, congenital syphilis (CS) has significant medical, economic, societal and emotional burdens; these are poorly characterized but high. Inexplicably, the elimination of CS has failed to attract international attention. Yet, the cornerstones of programs to do this universally are in place, the recent development of new diagnostic tools offers the now-practical possibility of testing every pregnant woman, testing is cost-effective, and programs for the elimination of CS can be joined with other programs to enhance efficiency. The magnitude of the CS burden, globally, rivals that of HIV infection in neonates yet receives little attention. The newly proposed World Health Organization Strategy for the Global Elimination of Congenital Syphilis aims to mobilize resources and provide a plan to address this under-recognized health problem.

Intestinal double positive CD4+CD8+ T cells of neonates are highly activated memory cells with higher proliferative capacity compared to single positive CD4+/CD8+ T cells (B115)

Abstract Peripheral blood and thymic double positive CD4+CD8+ (DP) T cells from neonates have been described in humans and a number of animals, but the function and immunophenotypic characteristics of other tissue-derived DP T cells are not clearly understood. Here we demonstrate the phenotypic characteristics of DP cells in 6 different tissues including thymus from normal neonatal rhesus macaques (Macaca mulatta) between 0–21 days of age. In general, DP T cells of neonates have higher percentages of memory markers (CD28+CD95+, CD45RA−) compared to single positive (SP) CD4+ and CD8+ T cells. In addition, intestinal DP T cells increase as the animals’ age and levels of CD62L decrease with age suggesting that DP cells proliferate and are activated with maturity and/or antigen exposure. Consistent with this, intestinal DP T cells in neonates express higher levels of activation markers and CCR5 expression. Furthermore, DP T cells have higher rates of proliferation compared to SP CD4+ and SP CD8+ T cells as determined by BrdU labelling techniques. Finally, DP T cells produce higher levels of cytokine production in response to mitogen stimulation compared to SP CD4+ or SP CD8+ T cells. Collectively, these findings demonstrate that intestinal DP T cells of neonates are proliferating, effector cells and are likely involved in regulating immune as compared to the immature DP T cells in the thymus. As in adults, these intestinal DP T cells may be important target cells for early HIV infection in neonates due to their activation, high expression of CCR5, and memory phenotype.

What Are the Roles and Responsibilities of the Media in Disseminating Health Information?

Background to the debate: In December 2004 three news stories in the popular press suggested that the side effects of single-dose nevirapine, which has been proven to prevent mother-to-child transmission of HIV, had been covered up. Many HIV experts believed that the stories were unwarranted and that they would undermine use of the drug, leading to a rise in neonatal HIV infection. The controversy surrounding these stories prompted the PLoS Medicine editors to ask health journalists, and others with an interest in media reporting of health, to share their views on the roles and responsibilities of the media in disseminating health information.

Elective Cesarean Delivery to Prevent Neonatal HIV Infection

More than two thirds of mother-child HIV-1 transmission occurs during labor and delivery. Studies have suggested that cesarean delivery reduces such

Productive infection of neonatal CD8+ T lymphocytes by HIV-1.

CD8+ T lymphocytes confer significant but ultimately insufficient protection against HIV infection. Here we report that activated neonatal CD8+ T cells can be productively infected in vitro by macrophage-tropic (M-tropic) HIV-1 isolates, which are responsible for disease transmission, whereas they are resistant to T cell-tropic (T-tropic) HIV strains. Physiological activation of CD8-alpha/beta+ CD4- T cell receptor-alpha/beta+ neonatal T cells, including activation by allogeneic dendritic cells, induces the accumulation of CD4 messenger RNA and the expression of CD4 Ag on the cell surface. The large majority of anti-CD3/B7.1-activated cord blood CD8+ T cells coexpress CD4, the primary HIV receptor, as well as CCR5 and CXCR4, the coreceptors used by M- and T-tropic HIV-1 strains, respectively, to enter target cells. These findings are relevant to the rapid progression of neonatal HIV infection. Infection of primary HIV-specific CD8+ T cells may compromise their survival and thus significantly contribute to the failure of the immune system to control the infection. Furthermore, these results indicate a previously unsuspected level of plasticity in the neonatal immune system in the regulation of CD4 expression by costimulation.

Tuberculosis in the newborn: an emerging disease.

In spite of the global increase in tuberculosis, which is in part fueled by the HIV pandemic, tuberculosis in the perinatal period is rare, and to date it has not been directly associated with maternal or neonatal HIV infection. To detect tuberculosis in newborns from a province with epidemics of both tuberculosis and HIV infection and to analyze the profile of tuberculosis in their mothers. At King Edward VIII Hospital, in KwaZulu Natal, South Africa, during a 1-year period all neonates at the neonatal unit in whom a differential diagnosis of tuberculosis was considered were investigated. The clinical profiles, short term outcome and relationship to maternal tuberculosis and HIV infection were determined for those neonates in whom the diagnosis of tuberculosis was confirmed. From the investigation of 77 neonates 11 with culture confirmed perinatal tuberculosis were identified. Six of these infants were born to mothers who had HIV and tuberculosis coinfection. Six of the 11 neonates could be classified as congenital tuberculosis. The predominant clinical findings were progressive pneumonia (9 of 11), pyrexia (9 of 11), growth retardation (7 of 11), hepatomegaly (6 of 11), splenomegaly (4 of 11) and meningitis (2 of 11). Seven of their mothers had evidence of current or past tuberculosis or had close contact with a tuberculosis case. One neonate and two mothers died within the first 3 months. This is the first report of perinatal tuberculosis in association with maternal HIV and tuberculosis coinfection.

Umbilical Cord Blood Mononuclear Cell HIV-1 LTR Binding Activities.

Vertically transmitted HIV disease constitutes a significant problem in pediatrics. In order to characterize some of the possible host factors involved in HIV replication in fetuses and newborns, we surveyed the HIV-1 LTR binding factors present in nuclear extracts from cord blood mononuclear cells. A series of electrophoretic mobility shift assays (EMSAs) showed that protein extracts from cord blood interacted with several regions of the HIV LTR. The most prominent binding activities involved the NF-kB sites, but other regions of the LTR also showed factor binding with the cord blood extracts. Some of these cord blood extract binding activities displayed qualitative differences when compared to adult peripheral blood mononuclear cell extracts in EMSA and UV cross-linking studies. Transient transfection experiments indicated that the NF-kB and Sp1 sequences were important for wild type levels of expression in cord blood cells, but that additional sequences 5' to the NF-kB sites also contributed activity. Thus, factors that interact with many of the well-known HIV LTR regulatory sites are present in cord blood cells. However, certain qualitative differences distinguished cord blood and adult peripheral blood binding activities and these may contribute to pathogenesis of HIV infection in neonates.

Vertical transmission of HIV in New York State: a basis for statewide testing of newborns.

Infants (n = 313) of HIV-infected mothers were enrolled (mean age 1.9 weeks, range 0-8 weeks) in a 3-year prospective study of vertical transmission. Fifty-six infants (17.9%) had laboratory and clinical evidence of HIV infection. Polymerase chain reaction (PCR) provided early and reliable identification of infected infants. Thirty-one of the 56 infected infants had specimens submitted when the infants were 4 weeks of age or less and 30 (97%) tested PCR positive. This percentage increased to 100% by 8 weeks of age when 51 of the 56 infected infants had specimens tested for that time period. Immune complex dissociation (ICD) antigen testing was a sensitive method for diagnosis of infection but only in infants older than 1 month. p24 antigen testing, although free of false positives, is less sensitive than either of the other methods. Among surrogate markers of HIV infection, elevation of soluble CD8 levels precedes an increase in immunoglobulin levels or a decline in CD4 T lymphocytes. Vertical transmission is significantly lower in Central and Western New York State than other regions. Transmission is significantly higher in low birthweight babies and in infants whose mothers have CD4 counts < 500. This study provided the basis for establishing a Pediatric HIV PCR Testing Service for the early diagnosis of HIV infection in neonates.

Reappraisal of the early diagnostic value of serial analyses of western blot patterns for HIV infection in neonates

Objective: Serial Western Blot (WB) testing was utilized for the early diagnosis of neonatal HIV infection. Methods: Serum samples included five anti-HIV positive mother/child pairs and 57 newborns who received hepatitis B immunoglobulin and hepatitis B vaccine. Enzyme-linked immunosorbent assay (ELISA) and serial WB were supplemented by polymerase chain reaction (PCR) and gag sequencing studies. Results: Serial WB patterns between the five mothers and their newborns were initially identical. Reaction lines, however, declined progressively and proportionately in the three infants not HIV infected. Two newborns were diagnosed early to be HIV-positive by evaluating the intensifying and increasing WB reaction lines. For the group of newborns who underwent the hepatitis B control program, all WB reaction lines declined progressively with time and none of these infants were truly HIV infected. Conclusion: Serial WB is simple and reliable and may be used for the early diagnosis of HIV infection in infants.

RAPID SEROLOGIC TESTING WITH IMMUNE-COMPLEX-DISSOCIATED HIV p24 ANTIGEN FOR EARLY DETECTION OF HIV INFECTION IN NEONATES

The ICD p24 antigen assay is a rapid, relatively simple serologic test that is likely to be of value in the early diagnosis of HIV infection in neonates.

6 Vertical transmission

Since AIDS was first described in children, much has been learnt about the epidemiology, clinical presentations and natural history of perinatally acquired HIV disease. As yet, several questions remain unanswered about the pathogenesis of vertical transmission, the relative risk associated with each mode of transmission, the rate of transmission from mother to child, and the factors that might contribute to the efficiency of transmission. Data presented thus far suggest that intrauterine exposure poses the greatest risk, but more recent reports have reopened speculation that infection could occur at or around the time of delivery. The prospects for intervention, to stop transmission from mother to child, rest on the ability to identify HIV-infected women; the knowledge of how and when the virus infects the fetus; and how to identify, as early as possible, those truly infected infants. Resources should therefore be set aside for routine screening for HIV in antenatal women. There is also a need to quantify the contribution made by intrauterine versus intrapartum events. Lastly, promising new techniques designed to detect neonatal HIV infection must be properly evaluated against standard methods, and correlated with clinical outcome. Only then can the efficacy of antiretroviral therapy be tried, to prevent vertical transmission.

DETECTING HIV IN NEONATES.

The standard assay for detecting HIV infection in neonates has not been reliable because its results are often confounded by maternal IgG antibodies, which can persist in uninfected infants for more than a year. Two studies now demonstrate the potential value of a …