Edward D. Barker

Controlling HIV pathogenesis: the role of the noncytotoxic anti-HIV response of CD8+ T cells

Noncytotoxic CD8+ T cells may play a critical role in preventing progression to disease following human immunodeficiency virus (HIV) infection. This antiviral response, mediated by a novel CD8+ T-cell antiviral factor (CAF), occurs soon after infection and is maintained in asymptomatic individuals. Here, Jay Levy and colleagues propose that this antiviral activity represents a natural cellular immune reaction that controls HIV production and protects the host from potential harmful effects of cytotoxic T lymphocytes.

The joint development of physical and indirect aggression: Predictors of continuity and change during childhood

A person-oriented approach was adopted to examine joint developmental trajectories of physical and indirect aggression. Participants were 1183 children aged 2 years at the initial assessment and followed over 6 years. Most children followed either low or declining trajectories of physical aggression (PA), but 14.6% followed high stable trajectories. Approximately two-thirds of participants followed low indirect aggression (IA) trajectories (67.9%), and one-third (32.1%) followed high rising trajectories. The results combining both PA and IA group memberships indicate that most children (62.1%) exhibit desisting levels of PA and low levels of IA. A significant proportion followed a trajectory of moderately desisting PA and rising IA (14.2%), and 13.5% followed high level trajectories of both forms of aggression. Virtually no children were high on one type and low on the other. Multinomial regressions analyses were used to predict joint trajectory group membership from selected child and family variables measured at 2 years. Young motherhood and low income predicted membership in the high PA-high IA trajectory, but only hostile parenting remained significant after family processes variables were entered in the model. Being a boy, young motherhood, and hostile parenting were generally associated with higher levels of PA. Girls were more likely than boys to follow a trajectory of desisting PA and rising IA. The results suggest that some children, mostly girls, reduce their use of PA and tend to increase their use of IA, and that highly physically aggressive children also tend to be highly indirectly aggressive. Early family risk characteristics and hostile parenting interfere with the socialization of aggression.

Subtypes of aggressive behaviors: A developmental perspective

Aggressive behaviors in children and adolescents have undergone important conceptual and definitional modifications in the past two decades. In particular, subtypes of aggression have been proposed that separate the form and the function of the aggressive behaviors (i.e., social vs. physical aggression; reactive vs. proactive aggression). Moreover, new methodological tools have been developed to examine the developmental course of these subtypes, as well as their correlates. These conceptual and methodological innovations, in turn, have introduced new views of the development of aggressive behaviors. These “new views” contrast with more traditional perspectives about the evolution of aggressive behaviors from infancy to young adulthood, particularly with respect to the existence of individuals who begin to become aggressive by adolescence only. This article gives an overview of these definitional, conceptual, and methodological innovations. It also tries to reconcile different views about the development of aggressive behaviors from infancy through early adulthood. Theoretical and practical/clinical implications are also reviewed. The conclusion describes an integrative framework and identifies possible areas of research for the future.

Degranulation of Natural Killer Cells Following Interaction with HIV-1-Infected Cells Is Hindered by Downmodulation of NTB-A by Vpu

Natural killer (NK) cell degranulation in response to virus-infected cells is triggered by interactions between invariant NK cell surface receptors and their ligands on target cells. Although HIV-1 Vpr induces expression of ligands for NK cell activation receptor, NKG2D, on infected cells, this is not sufficient to promote lytic granule release. We show that triggering the NK cell coactivation receptor NK-T- and -B cell antigen (NTB-A) alongside NKG2D promotes NK cell degranulation. Normally, NK cell surface NTB-A binds to NTB-A on CD4+ T cells. However, HIV-1 Vpu downmodulates NTB-A on infected T cells. Vpu associates with NTB-A through its transmembrane region without promoting NTB-A degradation. Cells infected with HIV-1 Vpu mutant elicited at least 50% more NK cells to degranulate than wild-type virus. Moreover, NK cells have a higher capacity to lyse HIV-infected cells with a mutant Vpu. Thus, Vpu downmodulation of NTB-A protects the infected cell from lysis by NK cells.

Differentiating Early-Onset Persistent Versus Childhood-Limited Conduct Problem Youth

OBJECTIVE Among young children who demonstrate high levels of conduct problems, less than 50% will continue to exhibit these problems into adolescence. Such developmental heterogeneity presents a serious challenge for intervention and diagnostic screening in early childhood. The purpose of the present study was to inform diagnostic screening and preventive intervention efforts by identifying youths whose conduct problems persist. The authors examined 1) the extent to which early-onset persistent versus childhood-limited trajectories can be identified from repeated assessments of childhood and early-adolescent conduct problems and 2) how prenatal and early postnatal risks differentiate these two groups. METHOD To identify heterogeneity in early-onset conduct problems, the authors used data from a large longitudinal population-based cohort of children followed from the prenatal period to age 13. Predictive risk factors examined were prenatal and postnatal measures of maternal distress (anxiety, depression), emotional and practical support, and family and child characteristics (from birth to 4 years of age). RESULTS Findings revealed a distinction between early-onset persistent versus childhood-limited conduct problems in youths. Robust predictors of the early-onset persistent trajectory were maternal anxiety during pregnancy (32 weeks gestation), partner cruelty to the mother (from age 0 to 4 years), harsh parenting, and higher levels of child undercontrolled temperament. Sex differences in these risks were not identified. CONCLUSIONS Interventions aiming to reduce childhood conduct problems should address prenatal risks in mothers and early postnatal risks in both mothers and their young children.

The contribution of prenatal and postnatal maternal anxiety and depression to child maladjustment

Background: The adverse effect of both pre‐ and post‐natal maternal anxiety and depression on the development of offspring is shown by a large body of research. No published studies, however, have simultaneously: (i) controlled for co‐occurring prenatal risks that may influence maternal prenatal anxiety and depression; (ii) compared the relative contributions of prenatal and postnatal maternal anxiety and depression on child functioning; and (iii) assessed a full range of child psychopathology and functioning to determine the relative effects of prenatal and postnatal anxiety and depression in the mother. Method: Using 3,298 mother–offspring pairs, the authors examined these factors in a single‐path analytic model. Measurements of maternal anxiety and depression were collected at two time points: 32 weeks prenatal and 1.5 years postnatal. Other prenatal risks were assessed between 8 and 32 weeks of gestation. Child outcomes included (a) ordered‐categorical measures of DSM‐IV externalizing and internalizing disorders, and (b) an assessment of verbal IQ. Results: In both the prenatal and postnatal periods, maternal depression had a wider impact on different types of child maladjustment than maternal anxiety, which appeared more specific to internalizing difficulties in the child. Of note, prenatal risks were prospectively associated with child externalizing difficulties and verbal IQ, beyond the effects of prenatal and postnatal maternal anxiety and depression. Conclusion: The present results suggest that addressing both maternal anxiety and depression, in the prenatal and postnatal periods—as well as associated risk factors—may be the most effective approach to prevent adverse outcomes in the offspring. Depression and Anxiety, 2011.  © 2011 Wiley‐Liss, Inc.

Lysis of endogenously infected CD4+ T cell blasts by rIL-2 activated autologous natural killer cells from HIV-infected viremic individuals.

Understanding the cellular mechanisms that ensure an appropriate innate immune response against viral pathogens is an important challenge of biomedical research. In vitro studies have shown that natural killer (NK) cells purified from healthy donors can kill heterologous cell lines or autologous CD4+ T cell blasts exogenously infected with several strains of HIV-1. However, it is not known whether the deleterious effects of high HIV-1 viremia interferes with the NK cell-mediated cytolysis of autologous, endogenously HIV-1-infected CD4+ T cells. Here, we stimulate primary CD4+ T cells, purified ex vivo from HIV-1-infected viremic patients, with PHA and rIL2 (with or without rIL-7). This experimental procedure allows for the significant expansion and isolation of endogenously infected CD4+ T cell blasts detected by intracellular staining of p24 HIV-1 core antigen. We show that, subsequent to the selective down-modulation of MHC class-I (MHC-I) molecules, HIV-1-infected p24pos blasts become partially susceptible to lysis by rIL-2-activated NK cells, while uninfected p24neg blasts are spared from killing. This NK cell-mediated killing occurs mainly through the NKG2D activation pathway. However, the degree of NK cell cytolytic activity against autologous, endogenously HIV-1-infected CD4+ T cell blasts that down-modulate HLA-A and –B alleles and against heterologous MHC-Ineg cell lines is particularly low. This phenomenon is associated with the defective surface expression and engagement of natural cytotoxicity receptors (NCRs) and with the high frequency of the anergic CD56neg/CD16pos subsets of highly dysfunctional NK cells from HIV-1-infected viremic patients. Collectively, our data demonstrate that the chronic viral replication of HIV-1 in infected individuals results in several phenotypic and functional aberrancies that interfere with the NK cell-mediated killing of autologous p24pos blasts derived from primary T cells.

Research review: a critical review of studies on the developmental trajectories of antisocial behavior in females.

BACKGROUND Knowledge on the onset and the development of antisocial behavior in females is limited, because most of the research in this domain is based on males. METHODS We critically reviewed 46 empirical studies that examined developmental trajectories of antisocial behavior in females, notably to help determine whether or not an early-onset/life-course-persistent trajectory exists in females. RESULTS The review suggested that antisocial behavior in females can follow different developmental trajectories (e.g., early-onset/life-course-persistent, childhood-limited, adolescence-limited, adolescence-delayed-onset, adulthood-onset). However, many of the studies reviewed were limited by factors such as the use of global measures of antisocial behavior, the identification of the trajectories based on threshold criteria, and the small sample sizes. CONCLUSIONS Future studies should take into account the shortcomings highlighted in this review. Such studies are needed to improve the understanding and prevention of the development of antisocial behavior in females.

HIV-1 Vpr triggers natural killer cell-mediated lysis of infected cells through activation of the ATR-mediated DNA damage response.

Natural killer (NK) cells are stimulated by ligands on virus-infected cells. We have recently demonstrated that NK cells respond to human immunodeficiency virus type-1 (HIV-1)-infected autologous T-cells, in part, through the recognition of ligands for the NK cell activating receptor NKG2D on the surface of the infected cells. Uninfected primary CD4pos T-cell blasts express little, if any, NKG2D ligands. In the present study we determined the mechanism through which ligands for NKG2D are induced on HIV-1-infected cells. Our studies reveal that expression of vpr is necessary and sufficient to elicit the expression of NKG2D ligands in the context of HIV-1 infection. Vpr specifically induces surface expression of the unique-long 16 binding proteins (ULBP)-1 and ULBP-2, but not ULBP-3, MHC class I-related chain molecules (MIC)-A or MIC-B. In these studies we also demonstrated that Vpr increases the level of ULBP-1 and ULBP-2 mRNA in primary CD4pos T-cell blasts. The presence of ULBP-1 and ULBP-2 on HIV-1 infected cells is dependent on the ability of Vpr to associate with a protein complex know as Cullin 4a (Cul4a)/damaged DNA binding protein 1 (DDB1) and Cul4a-associated factor-1(DCAF-1) E3 ubiquitin ligase (Cul4aDCAF-1). ULBP-1 and -2 expression by Vpr is also dependent on activation of the DNA damage sensor, ataxia telangiectasia and rad-3-related kinase (ATR). When T-cell blasts are infected with a vpr-deficient HIV-1, NK cells are impaired in killing the infected cells. Thus, HIV-1 Vpr actively triggers the expression of the ligands to the NK cell activation receptor.

The persisting effect of maternal mood in pregnancy on childhood psychopathology

Developmental or fetal programming has emerged as a major model for understanding the early and persisting effects of prenatal exposures on the health and development of the child and adult. We leverage the power of a 14-year prospective study to examine the persisting effects of prenatal anxiety, a key candidate in the developmental programming model, on symptoms of behavioral and emotional problems across five occasions of measurement from age 4 to 13 years. The study is based on the Avon Longitudinal Study of Parents and Children cohort, a prospective, longitudinal study of a large community sample in the west of England (n = 7,944). Potential confounders included psychosocial and obstetric risk, postnatal maternal mood, paternal pre- and postnatal mood, and parenting. Results indicated that maternal prenatal anxiety predicted persistently higher behavioral and emotional symptoms across childhood with no diminishment of effect into adolescence. Elevated prenatal anxiety (top 15%) was associated with a twofold increase in risk of a probable child mental disorder, 12.31% compared with 6.83%, after allowing for confounders. Results were similar with prenatal depression. These analyses provide some of the strongest evidence to date that prenatal maternal mood has a direct and persisting effect on her childs psychiatric symptoms and support an in utero programming hypothesis.