Abstract
The majority of infants’ breastfeeding from their HIV-infected mothers do not acquire HIV-1 infection despite exposure to cell-free virus and cell-associated virus in HIV-infected breast milk. Paradoxically, exclusive breastfeeding regardless of the HIV status of the mother has led to a significant decrease in mother-to-child transmission (MTCT) compared with non-exclusive breastfeeding. Although it remains unclear how these HIV-exposed infants remain uninfected despite repeated and prolonged exposure to HIV-1, the low rate of transmission is suggestive of a multitude of protective, short-lived bioactive innate immune factors in breast milk. Indeed, recent studies of soluble factors in breast milk shed new light on mechanisms of neonatal HIV-1 protection. This review highlights the role and significance of innate immune factors in HIV-1 susceptibility and infection. Prevention of MTCT of HIV-1 is likely due to multiple factors, including innate immune factors such as lactoferrin and elafin among many others. In pursuing this field, our lab was the first to show that soluble toll-like receptor 2 (sTLR2) directly inhibits HIV infection, integration, and inflammation. More recently, we demonstrated that sTLR2 directly binds to selective HIV-1 proteins, including p17, gp41, and p24, leading to significantly reduced NFκB activation, interleukin-8 production, CCR5 expression, and HIV infection in a dose-dependent manner. Thus, a clearer understanding of soluble milk-derived innate factors with known antiviral functions may provide new therapeutic insights to reduce vertical HIV-1 transmission and will have important implications for protection against HIV-1 infection at other mucosal sites. Furthermore, innate bioactive factors identified in human milk may serve not only in protecting infants against infections and inflammation but also the elderly; thus, opening the door for novel innate immune therapeutics to protect newborns, infants, adults, and the elderly.
Highlights
It had been recognized for centuries that breastfeeding and infant health were associated, one of the earliest systematic studies to demonstrate this was conducted by Grulee et al in 1935 [1]
Given that HIV-infected breast milk can contain high levels of cell-free virus (CFV) and cell-associated virus (CAV), it seems paradoxical that with prolonged and repeated exposure to HIV during EBF can significantly decrease postnatal mother-to-child transmission (MTCT) of HIV compared with mixed feeding or non-exclusive breastfeeding [21,22,23,24]
We showed a positive correlation of soluble toll-like receptor 2 (sTLR2) and IL-15 levels in breast milk [55], indicating that these protective factors can function in concert to reduce MTCT of HIV
Summary
It had been recognized for centuries that breastfeeding and infant health were associated, one of the earliest systematic studies to demonstrate this was conducted by Grulee et al in 1935 [1]. Given that HIV-infected breast milk can contain high levels of cell-free virus (CFV) and cell-associated virus (CAV), it seems paradoxical that with prolonged and repeated exposure to HIV during EBF can significantly decrease postnatal MTCT of HIV compared with mixed feeding or non-exclusive breastfeeding (nEBF) [21,22,23,24]. There were no significant differences in viral load, CD4+ T cell levels or co-infections between the women who EBF and those that nEBF their infants that could account for the difference in transmission rates [22, 23] This preventative method is so effective in the PMTCT of HIV and in protection against enteric infections that the WHO recommends EBF despite the HIV status of the mother when safe and sustainable alternative feeding is unavailable [30].
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