Erika Ono

Strong HIV-1-specific T cell responses in HIV-1-exposed uninfected infants and neonates revealed after regulatory T cell removal.

Background In utero transmission of HIV-1 occurs on average in only 3%–15% of HIV-1-exposed neonates born to mothers not on antiretroviral drug therapy. Thus, despite potential exposure, the majority of infants remain uninfected. Weak HIV-1-specific T-cell responses have been detected in children exposed to HIV-1, and potentially contribute to protection against infection. We, and others, have recently shown that the removal of CD4+CD25+ T-regulatory (Treg) cells can reveal strong HIV-1 specific T-cell responses in some HIV-1 infected adults. Here, we hypothesized that Treg cells could suppress HIV-1-specific immune responses in young children. Methodology/Principal Findings We studied two cohorts of children. The first group included HIV-1-exposed-uninfected (EU) as well as unexposed (UNEX) neonates. The second group comprised HIV-1-infected and HIV-1-EU children. We quantified the frequency of Treg cells, T-cell activation, and cell-mediated immune responses. We detected high levels of CD4+CD25+CD127− Treg cells and low levels of CD4+ and CD8+ T cell activation in the cord blood of the EU neonates. We observed HIV-1-specific T cell immune responses in all of the children exposed to the virus. These T-cell responses were not seen in the cord blood of control HIV-1 unexposed neonates. Moreover, the depletion of CD4+CD25+ Treg cells from the cord blood of EU newborns strikingly augmented both CD4+ and CD8+ HIV-1-specific immune responses. Conclusions/Significance This study provides new evidence that EU infants can mount strong HIV-1-specific T cell responses, and that in utero CD4+CD25+ T-regulatory cells may be contributing to the lack of vertical transmission by reducing T cell activation.

Imbalance of naive and memory T lymphocytes with sustained high cellular activation during the first year of life from uninfected children born to HIV-1-infected mothers on HAART

The immune consequences of in utero HIV exposure to uninfected children whose mothers were submitted to highly active antiretroviral therapy (HAART) during gestation are not well defined. We evaluated 45 HIV-exposed uninfected (ENI) neonates and 45 healthy unexposed control (CT) neonates. All HIV-infected mothers received HAART during pregnancy, and the viral load at delivery was <50 copies/mL for 56.8%. Twenty-three ENI neonates were further evaluated after 12 months and compared to 23 unexposed healthy age-matched infants. Immunophenotyping was performed by flow cytometry in cord and peripheral blood. Cord blood lymphocyte numbers did not differ between groups. However, ENI neonates had a lower percentage of naive T cells than CT neonates (CD4+, 76.6 vs 83.1%, P < 0.001; CD8+, 70.9 vs 79.6%, P = 0.003) and higher percentages of central memory T cells than CT neonates (CD4+, 13.9 vs 8.7%, P < 0.001; CD8+, 8.6 vs 4.8%, P = 0.001). CD38 mean fluorescence intensity of T cells was higher in ENI neonates (CD4+, 62.2 vs 52.1, P = 0.007; CD8+, 47.7 vs 35.3, P < 0.001). At 12 months, ENI infants still had higher mean fluorescence intensity of CD38 on T cells (CD4+, 34.2 vs 23.3, P < 0.001; CD8+, 26.8 vs 19.4, P = 0.035). Despite effective maternal virologic control at delivery, HIV-exposed uninfected children were born with lower levels of naive T cells. Immune activation was present at birth and remained until at least 12 months of age, suggesting that in utero exposure to HIV causes subtle immune abnormalities.

Low CD4+ T-Cell Levels and B-Cell Apoptosis in Vertically HIV-exposed Noninfected Children and Adolescents

Lymphocyte subsets, activation markers and apoptosis were assessed in 20 HIV-exposed noninfected (ENI) children born to HIV-infected women who were or not exposed to antiretroviral (ARV) drugs during pregnancy and early infancy. ENI children and adolescents were aged 6-18 years and they were compared to 25 age-matched healthy non-HIV-exposed children and adolescents (Control). ENI individuals presented lower CD4(+) T cells/mm(3) than Control group (control: 1120.3 vs. ENI: 876.3; t-test, p = 0.030). ENI individuals had higher B-cell apoptosis than Control group (Control: 36.6%, ARV exposed: 82.3%, ARV nonexposed: 68.5%; Kruskal-Wallis, p < 0.05), but no statistical difference was noticed between those exposed and not exposed to ARV. Immune activation in CD4(+) T, CD8(+) T and in B cells was comparable in ENI and in Control children and adolescents. Subtle long-term immune alterations might persist among ENI individuals, but the clinical consequences if any are unknown, and these children require continued monitoring.

Immunogenicity and Tolerability of Hepatitis A Vaccine in HIV-Infected Children

The immunogenicity and tolerability of hepatitis A virus vaccine was evaluated in a group of 32 children with human immunodeficiency virus (HIV) infection and 27 children with seroreversion. After 2 doses of vaccine, 100% of children experienced seroconversion with good toleration of the vaccine. There were no differences in variation of virus load between immunized HIV-positive children and a group of 31 nonimmunized HIV-positive children with similar characteristics.

HIV-1-Infected Children on HAART: Immunologic Features of Three Different Levels of Viral Suppression

HIV‐1‐infected children show changes of blood lymphocyte subpopulations. We have, therefore, investigated how highly active anti‐retroviral therapy (ART) alter these subsets. Blood samples were taken from 41 HIV‐1‐infected children on ART who were divided into groups showing good, partial and poor responses to ART on the basis of viral load (VL) measurement in blood. The observations were compared to those seen in 20 uninfected children.

Humoral and Cellular Immune Responses to Measles and Tetanus: The Importance of Elapsed Time Since Last Exposure and the Nature of the Antigen

ObjectiveThis study aims to assess the cellular and humoral immune response pre- and post-vaccine rechallenge in healthy adults with previous exposure to measles (virus or vaccine) and different time intervals since last tetanus vaccine.MethodsHumoral immunity was tested by ELISA, and cellular immunity was tested by intracellular interferon gamma detection after in vitro stimulation with antigens.ResultsWhile cellular immunity was comparable among vaccinated individuals and those who had measles, higher antibody levels were found in those who had the disease in the past. Both antibodies and CD4+ T cell tetanus immune responses depended on elapsed time since last immunization. Following a vaccine booster, an increase in cellular immunity and antibodies was observed to both tetanus and measles. Measles humoral response was much more intense among individuals previously exposed to a wild virus.ConclusionsIn an era when natural boosters are less frequent, an immune surveillance might be necessary to investigate waning immunity as occurs for tetanus.

Vaccine antibodies and T- and B-cell interaction in juvenile systemic lupus erythematosus

Both systemic lupus erythematosus (SLE) and its treatment can cause immunosuppression and a decreased response to vaccination. We evaluated 30 children and adolescents with SLE, and 14 age-matched healthy subjects (control group) regarding immunophenotyping and lymphocyte apoptosis by flow cytometry, while measles and tetanus antibodies were measured by enzyme-linked immunosorbent assay (ELISA). The SLE group was divided according to disease activity into inactive SLE and active SLE. Individuals with active SLE had lower CD4+ T and natural killer (NK) cells/mm3 than the control group. Active and inactive SLE individuals had more CD38 molecules/CD8+ T cells and more CD4+ T, CD8+ T and B cells in apoptosis (as assessed by caspase-3 expression) than the control group. Patients with active SLE had a diminished CD28 expression on both CD4+ T and on CD8+ T cells and a higher CD86 expression on B cells than the control group. Measles antibody levels in the SLE groups were similar to the control group. In contrast, tetanus antibody levels were lower in the SLE groups than in the control group. The latter also directly correlated with the CD4+ T-cell and NK-cell counts from SLE patients (regression coefficient, 2.686 and 1.782; p = 0.010 and p = 0.039, respectively). We concluded that despite being up-to-date for tetanus vaccine, SLE patients presented with a poor immune response to tetanus vaccine.

Persistence of vaccine immunity against hepatitis B virus and response to revaccination in vertically HIV-infected adolescents on HAART

Humoral immune response to vaccine antigens is known to be reduced in perinatally HIV-infected children. Lymphocyte immunophenotyping, humoral immunity to hepatitis B after primary immunization and response to revaccination were evaluated in 40 HIV-infected adolescents on HAART and 23 healthy age-matched controls. Anti-HBs antibody levels >or=10 mIU/mL were found in 18/40 (40.5%) of the HIV-infected adolescents and 18/23 (78.3%) of the HIV-negative adolescents from Control group. Adolescents of HIV group with anti-HBs>or=1 0 mIU/mL presented a higher CD4+ T cell percentage, higher naïve and central memory CD8+ T cell percentages and lower immune activation markers. After revaccination, 12/18 (66.7%) adolescents of HIV group responded. Those adolescents who did not respond to revaccination presented a lower CD4+ T cell percentage, higher immune activation markers and more frequently detectable HIV viral load. We concluded that lower immune activation, higher CD4+ T cell percentage and better control of HIV replication may be associated with hepatitis B vaccine response.

A simple and cheaper in house varicella zoster virus antibody indirect ELISA

We have developed a cheaper an simple in house indirect ELISA that uses the live attenuated VZV vaccine as a coating antigen. The alternative ELISA had an agreement of 94% when compared with a commercial VZV ELISA kit. Moreover, our ELISA proved to be more reliable than the kit when assessing true negative samples. By adding a standard serum, we were able to produce results in international units per millilitre. Also, the addition of an extra step with 8M urea allowed the assessment of VZV IgG avidity without excessive costs. The cost per sample to test VZV IgG was 2.7 times cheaper with our ELISA, allowing the testing of many samples without the burden of production of VZV antigen in the laboratory.

Maternal obesity and inflammatory mediators: A controversial association

The link between maternal obesity and inflammatory mediators is still unclear. Our aim was to summarize the main findings of recently published studies on this topic. We performed a search in Medline for studies published in the last years on obesity, human pregnancy, and inflammatory mediators. We report the findings of 30 studies. The characteristics and number of participants, study design, gestational age at sample collection, and type of sample varied widely. Approximately two‐thirds of them investigated more than one mediator, and 50% included participants in only one trimester of pregnancy. The most frequently investigated mediators were leptin, tumour necrosis factor‐alpha (TNF‐α), and interleukin (IL)‐6. Almost all studies reported an association between maternal obesity, leptin, and C‐reactive protein (CRP) serum levels but not with IL‐1β and IL‐10. The association of IL‐6, TNF‐α, monocyte chemo‐attractant protein‐1 (MCP‐1), adiponectin, and resistin with maternal obesity is still controversial. To clarify the physiopathological link between maternal obesity and inflammation, more high‐quality studies are needed.