Abstract
BackgroundBreast milk transmission of HIV-1 remains a major route of pediatric infection. Defining the characteristics of viral variants to which breastfeeding infants are exposed is important for understanding the genetic bottleneck that occurs in the majority of mother-to-child transmissions. The blood-milk epithelial barrier markedly restricts the quantity of HIV-1 in breast milk, even in the absence of antiretroviral drugs. The basis of this restriction and the genetic relationship between breast milk and blood variants are not well established.Methodology/Principal FindingsWe compared 356 HIV-1 subtype C gp160 envelope (env) gene sequences from the plasma and breast milk of 13 breastfeeding women. A trend towards lower viral population diversity and divergence in breast milk was observed, potentially indicative of clonal expansion within the breast. No differences in potential N-linked glycosylation site numbers or in gp160 variable loop amino acid lengths were identified. Genetic compartmentalization was evident in only one out of six subjects in whom contemporaneously obtained samples were studied. However, in samples that were collected 10 or more days apart, six of seven subjects were classified as having compartmentalized viral populations, highlighting the necessity of contemporaneous sampling for genetic compartmentalization studies. We found evidence of CXCR4 co-receptor using viruses in breast milk and blood in nine out of the thirteen subjects, but no evidence of preferential localization of these variants in either tissue.Conclusions/SignificanceDespite marked restriction of HIV-1 quantities in milk, our data indicate intermixing of virus between blood and breast milk. Thus, we found no evidence that a restriction in viral genotype diversity in breast milk accounts for the genetic bottleneck observed following transmission. In addition, our results highlight the rapidity of HIV-1 env evolution and the importance of sample timing in analyses of gene flow.
Highlights
Studies of HIV-1 variants in blood indicate that regardless of transmission route, descendents of a single virion establish infection in the new host [1,2,3,4,5,6,7,8]
Levels of HIV-1 in breast milk (BM) compared to PL To define the degree to which the breast epithelium restricted the amount of HIV-1 in milk, we compared the amount of viral RNA in PL and BM in over 600 lactating women (Figure 1)
Likewise, when we looked for signature motifs by calculating the frequency of amino acid (AA) at each site using Viral Epidemiology Signature Pattern Analysis (VESPA), we identified intraindividual signature sites distinguishing PL and BM but no interhost signature pattern was found
Summary
Studies of HIV-1 variants in blood indicate that regardless of transmission route, descendents of a single virion establish infection in the new host [1,2,3,4,5,6,7,8]. Levels of HIV-1 in these transmitting compartments (e.g., genital fluids and breast milk) are usually much lower than those in blood [14,15,16], but few studies have addressed how mucosal restriction contributes to the apparent transmission genetic bottleneck. Elucidating the relationship between HIV-1 strains circulating in blood and those in mucosal transmitting compartments is important for understanding the dynamics of transmission as well as for the design of vaccines and other prevention strategies [17]. The blood-milk epithelial barrier markedly restricts the quantity of HIV-1 in breast milk, even in the absence of antiretroviral drugs. The basis of this restriction and the genetic relationship between breast milk and blood variants are not well established
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