Antiretroviral therapy-associated modulation of Th1 and Th2 immune responses in HIV-infected pregnant women

Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, University College London (UCL), London, UK.
Journal of Reproductive Immunology (Impact Factor: 2.82). 07/2006; 70(1-2):143-50. DOI: 10.1016/j.jri.2005.12.001
Source: PubMed


A successful pregnancy is characterised by an increase in Th2 cytokines and suppression of Th1 cytokine production. A Th1 to Th2 cytokine shift is also observed in the disease progression of HIV infection. Highly active antiretroviral therapy (HAART) suppresses HIV viremia, increases CD4+ cell counts and counteracts the Th1 to Th2 shift. We hypothesised that the increased risk of premature delivery reported in HIV-infected, HAART-treated pregnant women is mediated through changes in the cytokine environment in pregnancy. Here, we present results relating to levels of interleukin (IL)-2 (Th1) and IL-10 (Th2) in peripheral blood mononuclear cells (PBMCs) measured three times during pregnancy in 49 HIV-infected women. Slope values representing the trend of repeated cytokine (IL-2-PHA, IL-2-Env, IL-10-PHA and IL-10-Env) measurements within women during pregnancy were estimated and median values compared by prematurity and HAART use. Multiple regression adjusted for HAART and cytokine slope clarified the additional and independent effect of HAART on prematurity risk. Results showed favourable immunomodulation induced by HAART with increased IL-2 and decreased IL-10. HAART use and IL-10-Env slopes were not significantly associated with prematurity risk, but each unit increase in IL-2-PHA slope was associated with an 8% increased risk of premature delivery (AOR, 1.08; 95% CI, 1.0-1.17; p=0.005). HAART use in pregnancy provides significant benefits in delaying HIV disease progression and reducing the risk of mother-to-child-transmission, but may be counterproductive in terms of successful pregnancy outcome.

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    • "Several studies in Europe and the USA have reported an increased risk of preterm delivery with antenatal highly active antiretroviral therapy (HAART), with associations of between 1.5- and 3.5-fold increased risk (Thorne et al., 2004; Cotter et al., 2006; Townsend et al., 2010a,b) and there are also preliminary indications from studies in sub-Saharan Africa (SSA) of the same association (Powis et al., 2011; van der Merwe et al., 2011). This has been hypothesized to be due to an immunological mechanism, with HAART in pregnancy associated with a reversal of the Th1 to Th2 switch that is an immunological feature of normal pregnancy (Fiore et al., 2006) rather than being caused by infant or placental factors. Given the enormous benefits of HAART for maternal health and PMTCT, and the fact that most of these preterm infants are born from gestations associated with relatively low morbidity and mortality risk, the benefits are considered to outweigh the risks in resource-rich settings (de Ruiter et al., 2008). "
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    ABSTRACT: BACKGROUND Human immunodeficiency virus (HIV) is prevalent in many countries where small-for-gestational age (SGA) and premature delivery are also common. However, the associations between maternal HIV, preterm delivery and SGA infants remain unclear. We estimate the prevalence of SGA and preterm (<37 weeks) births, their associations with antenatal maternal HIV infection and their contribution to infant mortality, in a high HIV prevalent, rural area in South Africa. METHODS Data were collected, in a non-randomized intervention cohort study, on all women attending antenatal clinics (2001–2004), before the availability of antiretroviral treatment. Newborns were weighed and gestational age was determined (based on last menstrual period plus midwife assessment antenatally). Poisson regression with robust variance assessed risk factors for preterm and SGA birth, while Cox regression assessed infant mortality and associated factors. RESULTS Of 2368 live born singletons, 16.6% were SGA and 21.4% were preterm. HIV-infected women (n= 1189) more commonly had SGA infants than uninfected women (18.1 versus 15.1%; P = 0.051), but percentages preterm were similar (21.8 versus 20.9%; P = 0.621). After adjustment for water source, delivery place, parity and maternal height, the SGA risk in HIV-infected women was higher [adjusted relative risk (aRR) 1.28, 95% confidence interval (CI): 1.06–1.53], but the association between maternal HIV infection and preterm delivery remained weak and not significant (aRR: 1.07, 95% CI: 0.91–1.26). In multivariable analyses, mortality under 1 year of age was significantly higher in SGA and severely SGA than in appropriate-for-gestational-age infants [adjusted hazard ratio (aHR): 2.12, 95% CI: 1.18–3.81 and 2.77, 95% CI: 1.56–4.91], but no difference in infant mortality was observed between the preterm and term infants (aHR: 1.18 95% CI: 0.79–1.79 for 34–36 weeks and 1.31, 95% CI: 0.58–2.94 for <34 weeks). CONCLUSIONS Maternal HIV infection increases the risk of SGA, but not preterm births, in this cohort.
    Full-text · Article · Mar 2012 · Human Reproduction
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    • "Cytokines were quantified by enzyme-linked immunosorbent assay (ELISA) in cell-free supernatants using commercial kits for human IL-2, IL-4, IL-7, IL-10, IL-12, TNF-α and IFN-γ (Duo Set®, R&D Systems Inc, Minneapolis, MN, USA). These cytokines were chosen as they are able to analyze Th1 and Th2 status [15]. "
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    ABSTRACT: Children born to HIV+ mothers are exposed intra-utero to several drugs and cytokines that can modify the developing immune system, and influence the newborn's immune response to infections and vaccines. We analyzed the relation between the distribution of cord blood lymphocyte subsets and cytokine profile in term newborns of HIV+ mothers using HAART during pregnancy and compared them to normal newborns. In a prospective, controlled study, 36 mother-child pairs from HIV+ mothers and 15 HIV-uninfected mothers were studied. Hematological features and cytokine profiles of mothers at 35 weeks of pregnancy were examined. Maternal and cord lymphocyte subsets as well as B-cell maturation in cord blood were analyzed by flow cytometry. The non-stimulated, as well as BCG- and PHA-stimulated production of IL2, IL4, IL7, IL10, IL12, IFN-γ and TNF-alpha in mononuclear cell cultures from mothers and infants were quantified using ELISA. After one year follow-up none of the exposed infants became seropositive for HIV. An increase in B lymphocytes, especially the CD19/CD5+ ones, was observed in cord blood of HIV-exposed newborns. Children of HIV+ hard drug using mothers had also an increase of immature B-cells. Cord blood mononuclear cells of HIV-exposed newborns produced less IL-4 and IL-7 and more IL-10 and IFN-γ in culture than those of uninfected mothers. Cytokine values in supernatants were similar in infants and their mothers except for IFN-γ and TNF-alpha that were higher in HIV+ mothers, especially in drug abusing ones. Cord blood CD19/CD5+ lymphocytes showed a positive correlation with cord IL-7 and IL-10. A higher maternal age and smoking was associated with a decrease of cord blood CD4+ cells. in uninfected infants born to HIV+ women, several immunological abnormalities were found, related to the residual maternal immune changes induced by the HIV infection and those associated with antiretroviral treatment. Maternal smoking was associated to changes in cord CD3/CD4 lymphocytes and maternal hard drug abuse was associated with more pronounced changes in the cord B cell line.
    Full-text · Article · Feb 2011 · BMC Infectious Diseases
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    ABSTRACT: Antiretroviral drugs have been used routinely to reduce the risk of mother-to-child transmission of HIV infection since 1994, following the AIDS Clinical Trials Group 076 trial, which demonstrated the efficacy of zidovudine in reducing the risk of in utero and intrapartum transmission. The use of antiretroviral drugs in pregnancy varies geographically, with widespread use of highly active antiretroviral therapy (HAART) in resource-rich settings for delaying maternal HIV disease progression as well as the prevention of mother-to-child transmission; however, in low- and middle-income settings, abbreviated prophylactic regimens focus on the perinatal period, with very limited access to HAART to date. The potential risks associated with antiretroviral exposure for pregnant women, fetuses and infants depend on the duration of this exposure as well as the number and type of drugs. As the benefits of HAART regimens in reducing the risk of mother-to-child transmission and in delaying disease progression are so great, their widespread use has been accepted, despite the relative lack of safety data from human pregnancies. Animal studies have suggested an increased risk of malformations associated with exposure to specific antiretroviral drugs, although evidence to support this from human studies is limited. Trials, cohorts and surveillance studies have shown no evidence of an increased risk of congenital malformations associated with in utero exposure to zidovudine, or other commonly used antiretroviral drugs, with an estimated 2-3% prevalence of birth defects (i.e. similar to that seen in the general population). Exposure to prophylactic zidovudine for prevention of mother-to-child transmission is associated with a usually mild and reversible, but rarely severe, anaemia in infants. However, a medium-term impact on haematological parameters of antiretroviral-exposed infants has been reported, with small but persistent reductions in levels of neutrophils, platelets and lymphocytes in children up to 8 years of age; the clinical significance of this remains uncertain. To date, there is no evidence to suggest that exposure to antiretroviral drugs in utero or neonatally is associated with an increased risk of childhood cancer, but the potential for mutagenic and carcinogenic effects at older ages cannot be excluded. Nucleoside analogue-related mitochondrial toxicity is well recognised from studies in non-pregnant individuals, whilst animal studies have provided evidence of mitochondrial toxicity resulting from in utero antiretroviral exposure. Clinically evident mitochondrial disease in children with antiretroviral exposure has only been described in Europe, with an estimated 18-month incidence of 'established' mitochondrial dysfunction of 0.26% among exposed children. Regarding pregnancy-related adverse effects, increased risks of prematurity, pre-eclampsia and gestational diabetes mellitus have been reported by a variety of observational studies with varying strengths of evidence and with conflicting results. Based on current knowledge, the immense benefits of antiretroviral prophylaxis in prevention of mother-to-child transmission far outweigh the potential for adverse effects. However, these potential adverse effects require further and longer term monitoring because they are likely to be rare and to occur later in childhood.
    Full-text · Article · Feb 2007 · Drug Safety
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