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Background: Early antiretroviral therapy (ART) during pregnancy has dramatically reduced the risk of perinatal HIV transmission. However, studies have shown an association between premature delivery and the use of ART during pregnancy (particularly protease inhibitor (PI)-based therapies), which could be explained by placental dysfunction. The objective of this study was to evaluate the association of ART (class, duration of exposure and time of initiation) with placental function by using angiogenic factors placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) as biomarkers. Methods: Clinical and biological data from 159 pregnant women living with HIV were analyzed. Levels of each biomarker were measured in the first and second trimester of pregnancy. After logarithmic transformation, we compared these using generalized estimating equations according to (a) the type of ART; (b) the duration of exposure to ART; and (c) the time of initiation of ART. Results: After adjusting for variables such as ethnicity, maternal age, gestational age, body mass index, parity, smoking status, and sex of the fetus, we found no significant association between the class of ART (PI-based or not) and serum concentrations of PlGF or sFlt-1. Furthermore, no significant association was found between biomarker levels and the duration of ART exposure or the timing of ART initiation (pre- or post-conception). Conclusions: This study suggests that first and second trimester angiogenic factor levels are not significantly associated with ART, regardless of the duration or type (with or without PI). These observations seem reassuring when considering the use of ART during early pregnancy.

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Umbilical cord blood transplantation (UCBT) is commonly used to treat a variety of hematologic or neoplastic disorders in children. Compared to bone marrow transplantation (BMT), UCBT is associated with slow engraftment and a higher incidence of graft failure and opportunistic infections. The aim of the present study was to identify immunologic biomarkers expressed by CD8+ T cells during the post-transplant period that predispose patients to develop complications following UCBT or BMT. Pediatric patients who underwent UCBT (n=16) or BMT (n=7) were enrolled at CHU Sainte-Justine. Samples were obtained from graft inoculums and from transplanted subjects during 24 months of follow-up. Expression of inhibitory receptors associated with CD8+ T cell exhaustion (PD-1, CTLA-4, 2B4, TIM-3, BTLA-4, LAG-3) was studied ex vivo using multiparameter flow cytometry. Results showed that inhibitory receptors were expressed at very low levels in UCB graft inoculums. However, in the first 100 days after UCBT or BMT, a notable increase in the frequency PD-1+ CD8+ T cells and 2B4+ CD8+ T cells was observed, and frequencies of PD-1+ and 2B4+ T cells were inversely correlated with absolute CD8+ T cell counts. A low number of CD8+ T cells also co-expressed two or more inhibitory receptors. These results suggest that expression of exhaustion markers by CD8+ T cells in graft recipients during the early post-transplant period may modulate their activity and lead to functional impairment.

The majority of acute hepatitis C virus (HCV) infection (75%) leads to chronicity and liver diseases. While 25% of infected individuals can naturally clear the infection, long-term protection is elusive and reinfection can occur. We have previously showed that protection from viral persistence upon HCV reinfection correlates with expansion of HCV specific T cells with increased breadth. Viral persistence was associated with limited expansion of virus specific T cells. CD8 T cell receptor (TCR) repertoire analysis showed that clonotypes associated with protection upon reinfection are recruited from the memory population, with focusing of the repertoire. We hypothesized that protective immune memory response is associated with selection of T cell clonotypes with the highest TCR avidity and a polyfunctional profile. We FACS sorted HCV-specific CD8 T cells to generate individual clones representative of clonotypes of high, medium or low frequency in the TCR repertoire. Tetramer titration assay showed that the TCR avidity correlated with the clonotype expansion in vivo upon reinfection. All clones showed a polyfunctional profile but the main function varied between clones. In conclusion, our results suggest that the main determinant for the expansion of memory HCV specific CD8+ T cells during HCV reinfection was the TCR avidity. The results of this study have implications for the development of vaccination regimens to boost generation and selection of such clonotypes.

Background: Early antiretroviral therapy (ART) during pregnancy has dramatically reduced the risk of perinatal HIV transmission. However, studies have shown an association between premature delivery and the use of ART during pregnancy (particularly protease inhibitor (PI)-based therapies), which could be explained by placental dysfunction. The objective of this study was to evaluate the association of ART (class, duration of exposure and time of initiation) with placental function by using angiogenic factors placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) as biomarkers. Methods: Clinical and biological data from 159 pregnant women living with HIV were analyzed. Levels of each biomarker were measured in the first and second trimester of pregnancy. After logarithmic transformation, we compared these using generalized estimating equations according to (a) the type of ART; (b) the duration of exposure to ART; and (c) the time of initiation of ART. Results: After adjusting for variables such as ethnicity, maternal age, gestational age, body mass index, parity, smoking status, and sex of the fetus, we found no significant association between the class of ART (PI-based or not) and serum concentrations of PlGF or sFlt-1. Furthermore, no significant association was found between biomarker levels and the duration of ART exposure or the timing of ART initiation (pre- or post-conception). Conclusions: This study suggests that first and second trimester angiogenic factor levels are not significantly associated with ART, regardless of the duration or type (with or without PI). These observations seem reassuring when considering the use of ART during early pregnancy.

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