The Journal of Pediatrics
Volume 149, Issue 5 , Pages 591-593, November 2006

Maternal milk IgA and mother-to-child transmission of human immunodeficiency virus: Not a silver spoon

  • Rupert Kaul, MD, PhD

      Affiliations

    • Corresponding Author InformationReprint requests: Rupert Kaul, Clinical Science Division, Medical Sciences Building #6356, University of Toronto, Toronto, Ontario, Canada, M5S1A8.

Clinical Science Division, University of Toronto, Toronto, Ontario, Canada, M5S1A8

Article Outline

Abbreviations: HIV, Human immunodeficiency virus

 

Breast-feeding in the context of maternal human immunodeficiency virus (HIV)-1 infection is the subject of considerable controversy. Observational data have shown a consistent association between breast-feeding and postpartum HIV transmission to the newborn infant,1, 2 and the risk of transmission has been quantified by a randomized, clinical trial as 16%, accounting for almost half of the HIV transmission in breast-feeding mothers.3 Indeed, the risk of consuming 1 L of breast milk from an infected mother may be similar to that of HIV transmission during an episode of unprotected heterosexual sex.4 However, breast milk also is a vital source of both nutrition and immune protection for a newborn child. As a result, in settings where infant mortality exceeds 40 per 1000, the survival benefit of breast-feeding may exceed the mortality attributable to breast milk–associated HIV transmission.5

See related article, p 611

It also has been hypothesized that HIV transmission may be reduced by the practice of exclusive breast-feeding, rather than mixing breast milk with water or formula feeding.6 It is within a trial examining the utility of exclusive breast-feeding that the study by Kuhn et al7 in this issue of The Journal explores the immune correlates of breast milk transmission of HIV.

Why most infants can breast-feed from an HIV-infected mother for prolonged periods without acquiring HIV infection is poorly understood. Breast milk contains both cell-free and cell-associated HIV, both of which have been associated with an increased risk of transmission.8 Viral transmission is thought to occur across the infant’s gastrointestinal mucosa, aided by low gastric acidity, although the process is poorly understood.9 Breast milk, particularly colostrum, is rich in both innate and acquired immune factors, many of which have been shown to influence HIV infectivity and transmission in vitro and in vivo.9 Potential protective innate factors include α defensins,10 Lewis X component,11 natural antibodies to CCR512 and lactoferrin;13 acquired immune factors present in breast milk include maternal HIV-specific IgA, IgG, and cytotoxic T lymphocytes.9

Kuhn et al7 examined the potential protective role of HIV-specific IgA in human milk from HIV-infected mothers. Although HIV-specific IgG antibodies predominate over IgA in human milk, secretory IgA is found in the human milk of roughly 50% of infected women, has been shown to prevent epithelial HIV transcytosis, and is felt to be more mucosally active than IgG.9 Mucosal HIV-specific IgA has been found in the genital tract of exposed uninfected individuals, implying a potential role in protective mucosal immunity,14 although there are no data linking IgA to improved outcome in HIV-infected individuals. In effect, the authors hoped that the provision of maternal IgA in the milk of infected mothers might act as a form of passive infant immunization to protect against HIV acquisition.

The investigators collected milk from mothers soon after delivery and measured blood CD4 count, HIV RNA viral load in blood and breast milk, and HIV-specific IgA levels in breast milk. Mothers who transmitted HIV to their infants during the postpartum period (cases; n = 26) were compared with a random sample of mothers who did not (controls; n = 64). All of the mothers practiced breast-feeding exclusively. As expected, transmission was associated with a higher HIV RNA viral load in milk, which in turn correlated with increased blood HIV viral load and decreased blood CD4 T-lymphocyte count. There was no association between breast milk IgA and any of these parameters, but, unexpectedly, IgA was more common in the milk of transmitting mothers compared with nontransmitting controls. Although a previous smaller case-control study showed no association between IgA and protection,15 there has been no previous suggestion that IgA might enhance transmission.

What are the practical implications of these finding? Within the limitations of the case-control format, this was a well-done study, and the demonstration that maternal IgA does not protect against milk transmission of HIV is definitive. There are a few potential confounding factors, although these do not change the overall conclusion. It is notoriously difficult to measure mucosal IgA, with poor interlaboratory agreement,16 and the overall rates of IgA detection were high compared with previous studies (50/64; 78%). However, this is an experienced laboratory, with personnel appropriately blinded to case-control status. Without measurement of the secretory component, whether the IgA represented true secretory (ie, locally produced) IgA or may have been derived from blood is unclear. This may have some significance, because the secretory component may be important, particularly in immune exclusion at mucosal surfaces.17 None of these concerns should detract from the conclusion that maternal IgA was not protective—although this conclusion is not completely unexpected. In general, both virus-specific IgA and IgG from an HIV-infected individual poorly neutralize autologous virus. In the case of blood IgG, this is known to be the result of rapid virus mutation to escape from host antibody responses.18 Certainly, the lack of protection offered by autologous antibodies (IgA or IgG) in an HIV-infected person should not be taken to mean that HIV-specific antibodies could not be protective if induced before exposure in an uninfected person, such as in the context of active or passive vaccination.

Why does IgA appear to enhance HIV transmission? Kuhn et al note that IgA levels in breast milk could reflect higher local HIV replication or diversity. It is also possible that higher IgA levels in transmitting mothers could represent a host’s attempt to control virus that has undergone more extensive immune escape. IgA levels in maternal milk are higher after premature delivery, as the authors discuss, and prematurity enhances HIV transmission. HIV-specific IgA levels were associated with lower birth weight, and although the association with transmission remained after controlling for birth weight, data on gestational age at delivery were not presented. Total immunoglobin levels, including IgA, increase in blood with progression of HIV disease, and so increased HIV-specific IgA may reflect a generalized increase in total IgA in both the plasma and milk of women with more advanced disease. Finally, the frequency of other protective innate immune factors in breast milk was not examined. Overall, the data on potential enhancement of transmission by maternal HIV-specific IgA are less robust, and more detailed studies of the virology and immunology of human milk are needed to confirm this.

In summary, this well-performed study shows that IgA antibodies in the milk of an HIV-infected mother will not protect her child from acquiring HIV if she continues to breast-feed. Where local circumstances allow the infant to receive nutrition safely by alternate means, this should be encouraged. Whether exclusive breast-feeding is safer than intermittent breast-feeding in settings where there is no safer alternative remains to be seen; the results of the larger trial in which this substudy was nested may provide some guidance on this issue. The findings do not provide evidence one way or the other as to the potential protective efficacy of HIV-specific IgA induced by active or passive vaccination.

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References 

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PII: S0022-3476(06)00787-6

doi:10.1016/j.jpeds.2006.08.024

Refers to article:

  • Hiv-specific secretory IgA in breast milk of HIV-positive mothers is not associated with protection against HIV transmission among breast-fed infants

    Louise Kuhn, Daria Trabattoni, Chipepo Kankasa, Moses Sinkala, Francesca Lissoni, Mrinal Ghosh, Grace Aldrovandi, Don Thea, Mario Clerici
    The Journal of Pediatrics November 2006 (Vol. 149, Issue 5, Pages 611-616)

The Journal of Pediatrics
Volume 149, Issue 5 , Pages 591-593, November 2006

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