Longitudinal Analysis of Human Immunodeficiency Virus Type 1 RNA in Breast Milk and of Its Relationship to Infant Infection and Maternal Disease

University of Washington Seattle, Seattle, Washington, United States
The Journal of Infectious Diseases (Impact Factor: 6). 04/2003; 187(5):741-7. DOI: 10.1086/374273
Source: PubMed


Transmission of human immunodeficiency virus type 1 (HIV-1) via breast-feeding can occur throughout lactation. Defining both
fluctuation in breast-milk virus level over time and how breast-milk virus correlates with mother-to-child transmission is
important for establishing effective interventions. We quantified breast-milk HIV-1 RNA levels in serial samples collected
from 275 women for up to 2 years after delivery. Higher maternal plasma virus load, lower maternal CD4 T cell count, and detection
of HIV-1 DNA in maternal genital secretions were significantly associated with elevated breast-milk HIV-1 RNA. Within women
who breast-fed, median virus load in colostrum/early milk was significantly higher than that in mature breast milk collected
14 days after delivery (P⩽.004). Breast-feeding mothers who transmitted HIV-1 to their infants had both significantly higher
breast-milk viral RNA throughout lactation and more-consistent viral shedding, compared with mothers who did not transmit
HIV-1. In breast-feeding women, a 2-fold–increased risk of transmission was associated with every 10-fold increase in breast-milk
virus load (95% confidence interval, 1.3–3.0; P<.001). These results indicate that the risk of infant infection from breast-feeding
is influenced by breast-milk virus load, which is highest early after delivery

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    • "RNA was isolated from the CD8+ T cells using the QIAAMP Viral RNA kit (QIAGEN). HIV-1 copies were quantified using quantitative RT-PCR using previously described methods [111,112]. The CD4+ T cells were incubated at 37°C 5% C02, and the infectious virus concentration in the culture supernatants was measured after 3 days as detailed above. "
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    ABSTRACT: Previous studies suggest that active selection limits the number of HIV-1 variants acquired by a newly infected individual from the diverse variants circulating in the transmitting partner. We compared HIV-1 envelopes from 9 newly infected subjects and their linked transmitting partner to explore potential mechanisms for selection. Recipient virus envelopes had significant genotypic differences compared to those present in the transmitting partner. Recombinant viruses incorporating pools of recipient and transmitter envelopes showed no significant difference in their sensitivity to receptor and fusion inhibitors, suggesting they had relatively similar entry capacity in the presence of low CD4 and CCR5 levels. Aggregate results in primary cells from up to 4 different blood or skin donors showed that viruses with envelopes from the transmitting partner as compared to recipient envelopes replicated more efficiently in CD4+ T cells, monocyte derived dendritic cell (MDDC) - CD4+ T cell co-cultures, Langerhans cells (LCs) - CD4+ T cell co-cultures and CD4+ T cells expressing high levels of the gut homing receptor, alpha4beta7, and demonstrated greater binding to alpha4beta7 high / CD8+ T cells. These transmitter versus recipient envelope virus phenotypic differences, however, were not always consistent among the primary cells from all the different blood or skin donation volunteers. Although genotypically unique variants are present in newly infected individuals compared to the diverse swarm circulating in the chronically infected transmitting partner, replication in potential early target cells and receptor utilization either do not completely dictate this genetic selection, or these potential transmission phenotypes are lost very soon after HIV-1 acquisition.
    Full-text · Article · Dec 2013 · Retrovirology
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    • "The majority of children who become infected with HIV-1 acquire the virus from their infected mothers during pregnancy, labour, delivery or breast-feeding. Although approximately 42% of mother-to-child transmission (MTCT) is due to prolonged breast-feeding [2-4], for many HIV-1-positive mothers formula feeding is not an option for social, practical and health reasons; breast-feeding reduces infant mortality due to nutrition and protection against other common childhood diseases [5]. Although antiretroviral therapy (ART) can significantly reduce the risk of MTCT, ARTs reach approximately 57% of HIV-1-infected mothers in low- and middle-income countries [6], and residual MTCT can occur despite ART [7]. "
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    ABSTRACT: A vaccine to decrease transmission of human immunodeficiency virus type 1 (HIV-1) during breast-feeding would complement efforts to eliminate infant HIV-1 infection by antiretroviral therapy. Relative to adults, infants have distinct immune development, potentially high-risk of transmission when exposed to HIV-1 and rapid progression to AIDS when infected. To date, there have been only three published HIV-1 vaccine trials in infants. We conducted a randomized phase I clinical trial PedVacc 001 assessing the feasibility, safety and immunogenicity of a single dose of candidate vaccine MVA.HIVA administered intramuscularly to 20-week-old infants born to HIV-1-negative mothers in The Gambia. Infants were followed to 9 months of age with assessment of safety, immunogenicity and interference with Expanded Program on Immunization (EPI) vaccines. The trial is the first stage of developing more complex prime-boost vaccination strategies against breast milk transmission of HIV-1. From March to October 2010, 48 infants (24 vaccine and 24 no-treatment) were enrolled with 100% retention. The MVA.HIVA vaccine was safe with no difference in adverse events between vaccinees and untreated infants. Two vaccine recipients (9%) and no controls had positive ex vivo interferon-γ ELISPOT assay responses. Antibody levels elicited to the EPI vaccines, which included diphtheria, tetanus, whole-cell pertussis, hepatitis B virus, Haemophilus influenzae type b and oral poliovirus, reached protective levels for the vast majority and were similar between the two arms. A single low-dose of MVA.HIVA administered to 20-week-old infants in The Gambia was found to be safe and without interference with the induction of protective antibody levels by EPI vaccines, but did not alone induce sufficient HIV-1-specific responses. These data support the use of MVA carrying other transgenes as a boosting vector within more complex prime-boost vaccine strategies against transmission of HIV-1 and/or other infections in this age group. NCT00982579 The Pan African Clinical Trials Registry PACTR2008120000904116.
    Full-text · Article · Oct 2013 · PLoS ONE
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    • "Further, we previously showed significantly increased TLR2 expression in peripheral blood mononuclear cells of Kenyan commercial sex workers with AIDS, which is reduced with HAART treatment [29]. Our data is timely given a recent publication confirming increased levels of HIV-1 RNA in BM positively correlate with vertical transmission [51], [52]. "
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    ABSTRACT: The majority of infants who breastfeed from their HIV-positive mothers remain uninfected despite constant and repeated exposure to virus over weeks to years. This phenomenon is not fully understood but has been closely linked to innate factors in breast milk (BM). Most recently we have focused on one such innate factor, soluble Toll-like receptor 2 (sTLR2) for its significant contribution as an inhibitor of inflammation triggered by bacterial and viral antigens. We hypothesized that sTLR2 in BM inhibits immune activation/inflammation and HIV-1 infection. sTLR2 protein profiles were analyzed in HIV-uninfected BM and showed dramatic variability in expression concentration and predominant sTLR2 forms between women. sTLR2 immunodepleted BM, versus mock-depleted BM, incubated with Pam(3)CSK(4) lead to significant increases in IL-8 production in a TLR2-dependant fashion in U937, HEK293-TLR2, and Caco-2. Importantly, TLR2-specific polyclonal and monoclonal antibody addition to BM prior to cell-free R5 HIV-1 addition led to significantly (P<0.01, P<0.001, respectively) increased HIV-1 infection in TZM-bl reporter cells. To confirm these findings, sTLR2-depletion in BM led to significantly (P<0.001) increased HIV-1 infection in TZM-bl cells. Notably, immunodepletion does not allow for the complete removal of sTLR2 from BM, thus functional testing shown here may underestimate the total effect elicited by sTLR2 against HIV-1 and synthetic bacterial ligand. This study provides evidence for the first time that sTLR2 in BM may provide a dual protective role for infants breastfeeding from their HIV-infected mothers by; (1) immunomodulating pro-inflammatory responses to bacterial ligands, and (2) directly inhibiting cell-free HIV-1 infection. Thus, sTLR2 in BM may be critical to infant health and prove beneficial in decreasing vertical HIV-1 transmission to infants.
    Full-text · Article · Jul 2012 · PLoS ONE
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