Dataset Information

Regulation of CCR5 expression in human placenta: insights from a study of mother-to-child transmission of HIV in Malawi.

ABSTRACT:

Background

Human promoter polymorphisms in the chemokine co-receptor 5 gene (CCR5) have been noted for association with mother-to-child transmission of HIV (HIV MTCT) as well as reduced receptor expression in vitro, but have not been clearly associated with CCR5 expression in vivo. Placental expression of CCR5 may be influenced by such polymorphisms as well as other in vivo regulatory factors.

Methodology/principal findings

We evaluated the associations between infant CCR5 polymorphisms, measures of maternal infection, and placental expression of CCR5 among mother-infant pairs in Blantyre, Malawi. RNA was extracted from placental tissue and used in multiplex real-time PCR to quantify gene expression. Through linear regression, we observed that CCR5-2554T (beta = -0.67, 95% CI = -1.23, -0.11) and -2132T (beta = -0.75, 95% CI = -0.131, -0.18) were significantly associated with reduced placental expression of CCR5. An incremental increase in CCR5 expression was observed for incremental increases in expression of two heparan sulfate genes involved in viral infection, HS3ST3A1 (beta = 0.27, 95% CI = 0.18, 0.35) and HS3ST3B1 (beta = 0.11, 95% CI = 0.06, 0.18). Among HIV infected mothers, an incremental increase in maternal HIV viral load was also associated with higher CCR5 expression (beta = 0.76, 95% CI = 0.12, 1.39). Maternal HIV status had no overall effect (beta = 0.072, 95% CI = -0.57, -0.72). Higher CCR5 expression was observed for mothers with malaria but was not statistically significant (beta = 0.37, 95% CI = -0.43, 1.18).

Conclusions/significance

These results provide in vivo evidence for genetic and environmental factors involved in the regulation of CCR5 expression in the placenta. Our findings also suggest that the measurement of placental expression of CCR5 alone is not an adequate indicator of the risk of mother-to-child transmission of HIV.

SUBMITTER: Joubert BR

PROVIDER: S-EPMC2821402 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Publications

Regulation of CCR5 expression in human placenta: insights from a study of mother-to-child transmission of HIV in Malawi.

Joubert Bonnie R BR Franceschini Nora N Mwapasa Victor V North Kari E KE Meshnick Steven R SR

PloS one 20100215 2

<h4>Background</h4>Human promoter polymorphisms in the chemokine co-receptor 5 gene (CCR5) have been noted for association with mother-to-child transmission of HIV (HIV MTCT) as well as reduced receptor expression in vitro, but have not been clearly associated with CCR5 expression in vivo. Placental expression of CCR5 may be influenced by such polymorphisms as well as other in vivo regulatory factors.<h4>Methodology/principal findings</h4>We evaluated the associations between infant CCR5 polymor ...[more]

PMID: 20169157

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Project description:BACKGROUND: More than 300,000 children are newly infected with HIV each year, predominantly through mother-to-child transmission (HIV MTCT). Identification of host genetic traits associated with transmission may more clearly explain the mechanisms of HIV MTCT and further the development of a vaccine to protect infants from infection. Associations between transmission and a selection of genes or single nucleotide polymorphisms (SNP)s may give an incomplete picture of HIV MTCT etiology. Thus, this study employed a genome-wide association approach to identify novel variants associated with HIV MTCT. METHODS: We conducted a nested case-control study of HIV MTCT using infants of HIV(+) mothers, drawn from a cohort study of malaria and HIV in pregnancy in Blantyre, Malawi. Whole genome scans (650,000 SNPs genotyped using Illumina genotyping assays) were obtained for each infant. Logistic regression was used to evaluate the association between each SNP and HIV MTCT. RESULTS: Genotype results were available for 100 HIV(+) infants (at birth, 6, or 12 weeks) and 126 HIV(-) infants (at birth, 6, and 12 weeks). We identified 9 SNPs within 6 genes with a P-value < 5 × 10(-5) associated with the risk of transmission, in either unadjusted or adjusted by maternal HIV viral load analyses. Carriers of the rs8069770 variant allele were associated with a lower risk of HIV MTCT (odds ratio = 0.27, 95% confidence interval = 0.14, 0.51), where rs8069770 is located within HS3ST3A1, a gene involved in heparan sulfate biosynthesis. Interesting associations for SNPs located within or near genes involved in pregnancy and development, innate immunological response, or HIV protein interactions were also observed. CONCLUSIONS: This study used a genome-wide approach to identify novel variants associated with the risk of HIV MTCT in order to gain new insights into HIV MTCT etiology. Replication of this work using a larger sample size will help us to differentiate true positive findings.

Project description:Male Involvement (MI) in the Prevention of Mother to Child Transmission (PMTCT) of Human Immunodeficiency Virus (HIV) services is essential in a patriarchal society where men are decision makers of the household. Male partners have a role in the woman's risk of acquiring HIV, uptake of HIV testing and participation in Mother to Child Transmission (MTCT) prevention programmes. Although MI is important for uptake of PMTCT interventions, it remains low in Africa. The purpose of this study was to identify factors that promote and hinder MI in PMTCT services in antenatal care (ANC) services in Blantyre, Malawi. Understanding of the factors that influence MI will assist in developing strategies that will involve men more in the programme thereby improving the uptake of PMTCT and HIV testing and counselling services by women and men respectively.An exploratory qualitative study was conducted from December 2012 to January 2013 at South Lunzu Health Centre (SLHC) in Blantyre, Malawi. It consisted of six face to face Key Informant Interviews (KIIs) with health care workers and four Focus Group discussions (FGDs) with 18 men and 17 pregnant women attending antenatal care at the clinic. The FGDs were divided according to sex and age. All FGDs and KIIs were digitally recorded and simultaneously transcribed and translated verbatim into English. Data were analysed using thematic content analysis.Participants in both FGDs and KIIs identified the following barriers: lack of knowledge of MI in PMTCT, socioeconomic factors, relationship issues, timidity to be seen in a woman's domain, unplanned and or extramarital pregnancies, fear of knowing one's HIV status, unwillingness to be associated with the service, health facility based factors, peer influence and cultural factors. The factors that would potentially promote male involvement were categorized into community, health facility and personal or family level factors.The factors that may hinder or promote MI arise from different sources. The success of MI lies on recognizing sources of barriers and averting them. Factors that promote MI need to be implemented at different levels of health care.

Project description:BackgroundStrategies to reduce the risk of mother-to-child transmission of the human immunodeficiency virus (HIV) include lifelong antiretroviral therapy (ART) for HIV-positive women, exclusive breastfeeding from birth for six weeks plus nevirapine or replacement feeding plus nevirapine from birth for four to six weeks, elective Caesarean section delivery, and avoiding giving children chewed food. In some settings, these interventions may not be practical, feasible, or affordable. Simple, inexpensive, and effective interventions (that could potentially be implemented even in the absence of prenatal HIV testing programmes) would be valuable. Vitamin A, which plays a role in immune function, is one low-cost intervention that has been suggested in such settings.ObjectivesTo summarize the effects of giving vitamin A supplements to HIV-positive women during pregnancy and after delivery.Search methodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) up to 25 August 2017, and checked the reference lists of relevant articles for eligible studies.Selection criteriaWe included randomized controlled trials conducted in any setting that compared vitamin A supplements to placebo or no intervention among HIV-positive women during pregnancy or after delivery, or both.Data collection and analysisAt least two review authors independently assessed study eligibility and extracted data. We expressed study results as risk ratios (RR) or mean differences (MD) as appropriate, with their 95% confidence intervals (CI), and conducted random-effects meta-analyses. This is an update of a review last published in 2011.Main resultsFive trials met the inclusion criteria. These were conducted in Malawi, South Africa, Tanzania, and Zimbabwe between 1995 and 2005 and none of the participants received ART. Women allocated to intervention arms received vitamin A supplements at a variety of doses (daily during pregnancy; a single dose immediately after delivery, or daily doses during pregnancy plus a single dose after delivery). Women allocated to comparison arms received identical placebo (6601 women, 4 trials) or no intervention (697 women, 1 trial). Four trials (with 6995 women) had low risk of bias and one trial (with 303 women) had high risk of attrition bias.The trials show that giving vitamin A supplements to HIV-positive women during pregnancy, the immediate postpartum period, or both, probably has little or no effect on mother-to-child transmission of HIV (RR 1.07, 95% CI 0.91 to 1.26; 4428 women, 5 trials, moderate certainty evidence) and may have little or no effect on child death by two years of age (RR 1.06, 95% CI 0.92 to 1.22; 3883 women, 3 trials, low certainty evidence). However, giving vitamin A supplements during pregnancy may increase the mean birthweight (MD 34.12 g, 95% CI -12.79 to 81.02; 2181 women, 3 trials, low certainty evidence) and probably reduces the incidence of low birthweight (RR 0.78, 95% CI 0.63 to 0.97; 1819 women, 3 trials, moderate certainty evidence); but we do not know whether vitamin A supplements affect the risk of preterm delivery (1577 women, 2 trials), stillbirth (2335 women, 3 trials), or maternal death (1267 women, 2 trials).Authors' conclusionsAntepartum or postpartum vitamin A supplementation, or both, probably has little or no effect on mother-to-child transmission of HIV in women living with HIV infection and not on antiretroviral drugs. The intervention has largely been superseded by ART which is widely available and effective in preventing vertical transmission.

Dataset Information

Regulation of CCR5 expression in human placenta: insights from a study of mother-to-child transmission of HIV in Malawi.

Background

Methodology/principal findings

Conclusions/significance

Publications

Regulation of CCR5 expression in human placenta: insights from a study of mother-to-child transmission of HIV in Malawi.

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