Maternal‐Fetal DNA Admixture Is Associated with Intrapartum Mother‐to‐Child Transmission of HIV‐1 in Blantyre, Malawi

Kwiek, Jesse J.; Arney, Leslie; Harawa, Visopo; Pedersen, Bonnie R.; Mwapasa, Victor; Rogerson, Stephen J.; Meshnick, Steven R.

doi:10.1086/587646

Cited by 22 publications

(18 citation statements)

References 12 publications

(17 reference statements)

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“…The observed contrast in cytokine levels between in utero and intrapartum MTCT provides additional data to support the hypothesis that IU and IP MTCT have different molecular mechanisms. Consistent with this hypothesis, we (and others) have previously observed no association between maternal-fetal blood admixture (also called placental microtransfusions) and IU MTCT [52-54]; in contrast, using two different assays, we have observed an association between placental microtransfusions and IP MTCT [52, 53]. Whether or not the prevalent edema that was associated with intrapartum MTCT is related to placental microtransfusions cannot be determined from this study.…”

Section: Discussionsupporting

confidence: 80%

Elevated cytokine and chemokine levels in the placenta are associated with in-utero HIV-1 mother-to-child transmission

Kumar

Exten

Milner

et al. 2012

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Objective To determine if there is an association between cytokine and chemokine levels in plasma isolated from the placenta and HIV-1 mother-to-child transmission (MTCT). Design We designed a case-control study of HIV-infected, pregnant women enrolled in the Malaria and HIV in Pregnancy cohort. Participants were recruited in Blantyre, Malawi from 2000-04. Cases were women whose children were HIV-1 DNA-positive at birth (in utero MTCT) or HIV-1 DNA-negative at birth and HIV-1 DNA-positive at 6-weeks post-partum (intrapartum MTCT); controls were women whose children were HIV-1 DNA-negative both at birth and 6-weeks post-partum. Methods After delivery, blood was isolated from an incision on the basal plate of the placenta. We used a Luminex assay to simultaneously quantify 27 cytokines, chemokines, and growth factors in placental plasma. HIV-1 RNA copies were quantified with the Roche Amplicor kit. Results Levels of IL-4, IL-5, IL-6, IL-7, IL-9, eotaxin, IL1Ra and IP-10 were significantly elevated in placental plasma isolated from cases of in utero HIV-1 MTCT. In contrast, only GCSF was elevated in placental plasma isolated from cases of intrapartum MTCT. After adjusting for maternal age, gestational age, and peripheral CD4+ T cell count, every log10 increase in placental IP-10 was associated with a three-fold increase in the prevalence of in utero HIV-1 MTCT. Conclusions Elevated cytokine and chemokine levels in placental plasma were associated with in utero and not intrapartum MTCT. IP-10, which is both a T-cell chemokine and potentiator of HIV-replication, was robustly and independently associated with prevalent, in utero MTCT.

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Section: Discussionsupporting

confidence: 80%

Elevated cytokine and chemokine levels in the placenta are associated with in-utero HIV-1 mother-to-child transmission

Kumar

Exten

Milner

et al. 2012

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“…Previous studies from the MHP cohort have reported an association between malaria and the HIV-1 load (53), an association between maternal syphilis seroreactivity and HIV-1 MTCT (52), an association between maternal-infant blood admixture during intrapartum HIV-1 MTCT (40,41), and a reduction in HIV-1 quasispecies diversity during HIV-1 MTCT (42). In order to better understand the relationship between the HIV-1 load in peripheral and placental plasmas, we stratified viral-load data from the MHP cohort by HIV-1 transmission status.…”

Section: Resultsmentioning

confidence: 99%

“…It is currently unknown if alterations in these Env positions allow HIV-1 to escape other antibody-directed immune reactions, such as antibody-dependent cellular cytotoxicity (ADCC). In addition to selective pressure from the immune system, the differences in env associated with either placental localization or in utero MTCT could also be a result of viral adaptation to the tissues of the placenta, which has a unique repertoire of (40,41,46). Thus, our working assumption is that HIV-1 must cross an intact maternal-fetal barrier during in utero MTCT.…”

Section: Discussionmentioning

confidence: 99%

Different Regions of HIV-1 Subtype CenvAre Associated with Placental Localization andIn UteroMother-to-Child Transmission

Kumar

Handelman

Voronkin

et al. 2011

J Virol

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HIV infections are initiated by a limited number of variants that diverge into a diverse quasispecies swarm. During in utero mother-to-child transmission (IU MTCT), transmitted viral variants must pass through multiple unique environments, and our previously published data suggest a nonstochastic model of transmission. As an alternative to a stochastic model of viral transmission, we hypothesize that viral selection in the placental environment influences the character of the viral quasispecies when HIV-1 is transmitted in utero. To test this hypothesis, we used single-template amplification to isolate HIV-1 envelope gene (env) sequences from both peripheral plasma and the placentas of eight nontransmitting (NT) and nine IU-transmitting participants. Statistically significant compartmentalization between peripheral and placental HIV-1 env was detected in one of the eight NT cases and six of the nine IU MTCT cases. In addition, viral sequences isolated from IU MTCT placental tissue showed variation in env V1 loop lengths compared to matched maternal sequences, while NT placental env sequences did not. Finally, comparison of env sequences from NT and IU MTCT participants indicated statistically significant differences in Kyte-Doolittle hydropathy in the signal peptide, C2, V3, and C3 regions. Our working hypothesis is that the hydropathy differences in Env associated with IU MTCT alter viral cellular tropism or affinity, allowing HIV-1 to efficiently infect placentally localized cells.

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“…Our study failed to support this hypothesis despite finding a high frequency of detectible maternal DNA in cord blood. However, Kwiek et al 21 , working independently in Malawi, recently reported a correlation between maternal DNA in cord blood and perinatal HIV transmission risk. Their report was based on data from 9 infected and 69 uninfected infants, but despite small numbers, they observed significant associations between levels of detected maternal DNA in umbilical cord blood and intrapartum HIV transmission (p=0.02), as well as a surprising possible association with in utero transmission (13 infected infants, p=0.06).…”

Section: Discussionmentioning

confidence: 99%

The role of transplacental microtransfusions of maternal lymphocytes in HIV transmission to newborns

Biggar

Lee

Wen

et al. 2008

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Background Perinatal HIV transmission could occur via microtransfused maternal blood during delivery. If so, detecting maternal cells in umbilical cord blood should correlate with infection risk. Objective To develop sensitive assays for maternal DNA in infant's blood stored as dried blood spots (DBS) and examine the correlation between microtransfusion and perinatal HIV infection risk. Methods Blood-in-blood serial dilutions were prepared as DBS. Extracted DNA was amplified for unique minor-population sequences using 24 allele-specific polymerase-chain-reaction (AS-PCR) assays. Using newborns born to HIV+ mothers, paired mother-infant samples were similarly examined to identify unique maternal sequences targeted by AS-PCR of DNA extracted from cord blood DBS. Cord-blood PCR-negative infants were categorized as uninfected or perinatally infected by HIV PCR on samples collected 4–8 weeks after birth. Results Sequences from added cells were detected at ≤1:1000 dilutions in 19 of 20 aliquots, and ≤1:10,000 dilutions in 7 of 20 aliquots; the median limit of detection (probit analysis) was 1 added genomic sequence in 9500 background sequences of amplifiable DNA. Maternal sequences were detected in cord-blood DBS of 50% of infected infants (N=18) and 44% of uninfected infants (N=43). Infection did not correlate with more frequent detection of maternal sequences. Conclusion This semi-quantitative assay reliably detected maternal DNA sequences in DBS at levels of less than 1:1000 cells. Maternal sequences were frequently detected but did not correlate infection risk with detection or level of maternal DNA in umbilical cord blood. Therefore we could not demonstrate that microtransfusions at parturition were responsible for perinatal HIV transmission.

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Maternal‐Fetal DNA Admixture Is Associated with Intrapartum Mother‐to‐Child Transmission of HIV‐1 in Blantyre, Malawi

Abstract: Intrapartum MTCT was associated with placental microtransfusions. The associations among placental microtransfusion, in-utero MTCT, maternal immunosuppression, and poor birth outcome should be further investigated.

Cited by 22 publications

References 12 publications

Elevated cytokine and chemokine levels in the placenta are associated with in-utero HIV-1 mother-to-child transmission

Elevated cytokine and chemokine levels in the placenta are associated with in-utero HIV-1 mother-to-child transmission

Different Regions of HIV-1 Subtype CenvAre Associated with Placental Localization andIn UteroMother-to-Child Transmission

The role of transplacental microtransfusions of maternal lymphocytes in HIV transmission to newborns

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