Abstract
BackgroundBreastfeeding is a leading cause of infant HIV-1 infection in the developing world, yet only a minority of infants exposed to HIV-1 via breastfeeding become infected. As a genetic bottleneck severely restricts the number of postnatally-transmitted variants, genetic or phenotypic properties of the virus Envelope (Env) could be important for the establishment of infant infection. We examined the efficiency of virologic functions required for initiation of infection in the gastrointestinal tract and the neutralization sensitivity of HIV-1 Env variants isolated from milk of three postnatally-transmitting mothers (n=13 viruses), five clinically-matched nontransmitting mothers (n=16 viruses), and seven postnatally-infected infants (n = 7 postnatally-transmitted/founder (T/F) viruses).ResultsThere was no difference in the efficiency of epithelial cell interactions between Env virus variants from the breast milk of transmitting and nontransmitting mothers. Moreover, there was similar efficiency of DC-mediated trans-infection, CCR5-usage, target cell fusion, and infectivity between HIV-1 Env-pseudoviruses from nontransmitting mothers and postnatal T/F viruses. Milk Env-pseudoviruses were generally sensitive to neutralization by autologous maternal plasma and resistant to breast milk neutralization. Infant T/F Env-pseudoviruses were equally sensitive to neutralization by broadly-neutralizing monoclonal and polyclonal antibodies as compared to nontransmitted breast milk Env variants.ConclusionPostnatally-T/F Env variants do not appear to possess a superior ability to interact with and cross a mucosal barrier or an exceptional resistance to neutralization that define their capability to initiate infection across the infant gastrointestinal tract in the setting of preexisting maternal antibodies.
Highlights
Breastfeeding is a leading cause of infant HIV-1 infection in the developing world, yet only a minority of infants exposed to HIV-1 via breastfeeding become infected
Selection of env variants from breast milk of postnatallytransmitting and nontransmitting mothers and from plasma of postnatally-infected infants From a cohort of HIV-1-infected lactating women (CHAVI 009) [33], HIV-1 env gene sequences were amplified by single genome amplification (SGA) from milk collected at 4 to 6 weeks after delivery from mothers who were confirmed to postnatally-transmit HIV-1 to their infant (n = 3)
As previous studies have reported a bias toward CCR5 usage in T/F viruses [19,48], we investigated the coreceptor tropism of breast milk variants and infant T/F variants
Summary
Breastfeeding is a leading cause of infant HIV-1 infection in the developing world, yet only a minority of infants exposed to HIV-1 via breastfeeding become infected. As a genetic bottleneck severely restricts the number of postnatally-transmitted variants, genetic or phenotypic properties of the virus Envelope (Env) could be important for the establishment of infant infection. Mother to child transmission (MTCT) of HIV-1 via breastfeeding is responsible for over a third of pediatric HIV-1 infections in the developing world [1]. These postnatal infections occur throughout the duration of breastfeeding [2,3]. A comparative analysis of the genotypic and phenotypic characteristics of postnatally-transmitted and nontransmitted HIV-1 variants is critical for understanding the biologic mechanisms of postnatal HIV-1 transmission and designing targeted prophylactic strategies
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