GCN2 phosphorylates HIV-1 integrase and decreases HIV-1 replication by limiting viral integration.

GCN2 is a serine/threonine kinase involved in cellular stress response related to amino acid starvation. Previously, we showed that GCN2 interacts with HIV-1 integrase and is activated during HIV-1 infection. Herein, we identified HIV-1 integrase as a previously unknown substrate of GCN2 in vitro with a major site of phosphorylation at residue S255 located in the C-terminal domain of HIV-1 integrase. The underlying mechanism was investigated and it appeared that the integrase active site was required in order for GCN2 to target the integrase residue S255. Moreover, various integrases from other retroviruses (e.g. MLV, ASV) were also recognized as a substrate by GCN2. In cells, HIV-1 lentiviral particles harboring mutation at integrase position 255 were affected in their replication. Preventing phosphorylation resulted in an increase in infectivity that correlated with an increase in viral DNA integration. Infectivity of MLV was also higher in cells knocked-out for GCN2 suggesting a conserved mechanism to control viral replication. Altogether, our data suggest that GCN2 may constitute a general guardian of genome stability by regulating foreign DNA integration and as such be part of the antiviral armamentarium of the cell.

Evolution of perinatal depressive symptoms from pregnancy to two years postpartum in a low-risk sample: the MATQUID cohort.

BACKGROUND: Few studies have explored the evolution of perinatal depressive symptoms (PNDS) throughout the perinatal period. AIMS: To evaluate in a low-risk sample, whether different evolutive profiles of PNDS exist from pregnancy to 2-years postpartum, and whether the subgroups differ regarding psychopathological and demographic characteristics. METHODS: In a prospective, longitudinal study from 8 months pregnancy to 2 years postpartum, repeated measures of PNDS using the CES-D were performed on a sample of 579 women at low-risk for PNDS. First, semiparametric mixture models were used to identify groups of women with distinct trajectories of PNDS. Second, multinomial logistic regressions were used to identify risk factors for each group. RESULTS: Four distinct trajectories of PNDS evolution were found: (i) 72% of the women never presented with clinically significant depressive symptoms; (ii) 4% presented with depressive symptoms only during the postnatal period; (iii) 21% presented with depressive symptoms throughout the follow-up period, with a higher intensity during pregnancy; (iv) 3% presented with stable highly intense symptoms throughout the follow-up period. Psychosocial risk factors for PNDS were mainly identified in the patients of the third group, with an influence of socio-economical variables and anxiety traits. LIMITATIONS: The main limitations of the present study are the small size of the sample and the low level of risk for PNDS, so the results cannot be extrapolated to all types of populations. CONCLUSION: Different subtypes of evolutionary profiles of PNDS are found in a low-risk sample, and are associated with different profiles of risk factors.

Stimulation of the human RAD51 nucleofilament restricts HIV-1 integration in vitro and in infected cells.

Stable HIV-1 replication requires the DNA repair of the integration locus catalyzed by cellular factors. The human RAD51 (hRAD51) protein plays a major role in homologous recombination (HR) DNA repair and was previously shown to interact with HIV-1 integrase (IN) and inhibit its activity. Here we determined the molecular mechanism of inhibition of IN. Our standard in vitro integration assays performed under various conditions promoting or inhibiting hRAD51 activity demonstrated that the formation of an active hRAD51 nucleofilament is required for optimal inhibition involving an IN-DNA complex dissociation mechanism. Furthermore we show that this inhibition mechanism can be promoted in HIV-1-infected cells by chemical stimulation of the endogenous hRAD51 protein. This hRAD51 stimulation induced both an enhancement of the endogenous DNA repair process and the inhibition of the integration step. Elucidation of this molecular mechanism leading to the restriction of viral proliferation paves the way to a new concept of antiretroviral therapy based on the enhancement of endogenous hRAD51 recombination activity and highlights the functional interaction between HIV-1 IN and hRAD51.

[Psychometric properties of the French adaptation of the Family Relationship Index (FRI)]. / Qualités psychométriques de l'adaptation française du Family Relationship Index (FRI).

OBJECTIVE: The aim of the present study was to investigate the psychometric properties of the French adaptation of the Family Relationship Index (FRI) from Moos and Moos. The FRI is a self-report inventory which consists of 27 items assessing family relations. It is composed of three dimensions: family cohesion, family expressiveness (of feelings and emotions) and family conflict. METHOD: The FRI was translated and adapted into French according to published recommendations. After appropriate cultural adaptations, the scale was administered to a sample of 976 students with a mean age of 21.9 years and 43.5% of men. The participants completed the FRI and three other questionnaires: the Family Adaptability and Cohesion Scale (FACES), the Satisfaction with Life Scale and the General Health Questionnaire. Confirmatory factor analyses were used to test different models with one and three factors. The psychometric properties of the short version of the FRI, proposed by Kissane and Bloch (2002) and composed of 12 items, were also studied. RESULTS: Confirmatory factor analyses showed that the three factors solution was more relevant that the one factor solution (for Khi(2)/ddl, Root mean square error of approximation [RMSEA], Root mean square residual [RMR], Goodness of fit index [GFI], Adjusted goodness of fit [AGFI] and Comparative fit index [CFI]). However, three items belonging to family expression explained a small variance. Therefore, a version consisting of 24 items seemed more appropriate than the 27 items version proposed by Moos and Moos. Cultural differences may explain these results. Internal consistency was satisfactory for cohesion (0.79) and conflict (0.71) but weak for expression (0.55 for 27 items version and 0.62 for 24 items version). One month test-retest reliability showed high correlations for the three dimensions (from 0.77 to 0.85). Correlation between the cohesion subscale of the FRI and the cohesion subscale of the FACES was high (0.77), showing a good convergent validity. The correlations between the three FRI dimensions and the Satisfaction with Life Scale and the General Health Questionnaire were quite low (from -0.31 to 0.41). High family cohesion and high family expression were associated with high life satisfaction and good mental health. Conversely, high family conflict was associated with low life satisfaction and weak mental health. These results support the criterion validity of the FRI. Concerning the 12 items version of the FRI, the factor analysis results showed very good psychometric qualities. However, this short version had lower internal consistency (which ranged between 0.50 and 0.71), test-retest reliability (which ranged 0.68 and 0.81), convergent (0.69 for cohesion) and criterion validity (from -0.21 to 0.37 for the Satisfaction with Life Scale and from -0.28 to 0.19 for the General Health Questionnaire) than the longer versions. CONCLUSION: The results of the present study show that the FRI's 24 items version seems to be the more relevant. Nevertheless, the 12 items version shows interesting qualities. Further studies should confirm these results on other samples. Given the lack of French-language surveys assessing family relations, the FRI will be a useful tool for research and clinical practice.