Association of HIV-1 Envelope-Specific Breast Milk IgA Responses with Reduced Risk of Postnatal Mother-to-Child Transmission of HIV-1

Abstract

Infants born to HIV-1-infected mothers in resource-limited areas where replacement feeding is unsafe and impractical are repeatedly exposed to HIV-1 throughout breastfeeding. Despite this, the majority of infants do not contract HIV-1 postnatally, even in the absence of maternal antiretroviral therapy. This suggests that immune factors in breast milk of HIV-1-infected mothers help to limit vertical transmission. We compared the HIV-1 envelope-specific breast milk and plasma antibody responses of clade C HIV-1-infected postnatally transmitting and nontransmitting mothers in the control arm of the Malawi-based Breastfeeding Antiretrovirals and Nutrition Study using multivariable logistic regression modeling. We found no association between milk or plasma neutralization activity, antibody-dependent cell-mediated cytotoxicity, or HIV-1 envelope-specific IgG responses and postnatal transmission risk. While the envelope-specific breast milk and plasma IgA responses also did not reach significance in predicting postnatal transmission risk in the primary model after correction for multiple comparisons, subsequent exploratory analysis using two distinct assay methodologies demonstrated that the magnitudes of breast milk total and secretory IgA responses against a consensus HIV-1 envelope gp140 (B.con env03) were associated with reduced postnatal transmission risk. These results suggest a protective role for mucosal HIV-1 envelope-specific IgA responses in the context of postnatal virus transmission. This finding supports further investigations into the mechanisms by which mucosal IgA reduces risk of HIV-1 transmission via breast milk and into immune interventions aimed at enhancing this response. IMPORTANCEInfants born to HIV-1-infected mothers are repeatedly exposed to the virus in breast milk. Remarkably, the transmission rate is low, suggesting that immune factors in the breast milk of HIV-1-infected mothers help to limit transmission. We compared the antibody responses in plasma and breast milk of HIV-1-transmitting and -nontransmitting mothers to identify responses that correlated with reduced risk of postnatal HIV-1 transmission. We found that neither plasma nor breast milk IgG antibody responses were associated with risk of HIV-1 transmission. In contrast, the magnitudes of the breast milk IgA and secretory IgA responses against HIV-1 envelope proteins were associated with reduced risk of postnatal HIV-1 transmission. The results of this study support further investigations of the mechanisms by which mucosal IgA may reduce the risk of HIV-1 transmission via breastfeeding and the development of strategies to enhance milk envelope-specific IgA responses to reduce mother-to-child HIV transmission and promote an HIV-free generation.

Combined HIV-1 Envelope Systemic and Mucosal Immunization of Lactating Rhesus Monkeys Induces a Robust Immunoglobulin A Isotype B Cell Response in Breast Milk

“…Breast milk from HIV-infected women contains protective Env-specific antibodies (6,8,17,42), the presence of which makes development of a maternal HIV vaccine to enhance these preexisting responses an attractive strategy to prevent breastfeeding transmission of HIV. In this study, we gained further understanding of the isotypes, specificities, and functions of HIV-specific breast milk antibody responses induced by i.n./i.m.…”

“…Although breast milk from both HIV-infected humans and SIV-infected rhesus monkeys contains higher-magnitude Envspecific IgG than IgA, in our recent analysis of breast milk antibody responses of women from the Breastfeeding Antiretrovirals and Nutrition (BAN) study, only breast milk HIV envelope gp140-specific IgA was associated with reduced risk of postnatal HIV-1 acquisition (6,7,17). These results suggest that a maternal vaccine with the ability to elicit robust IgA responses in milk could potentially be protective.…”

“…In a recent study, vaccine-elicited mucosal IgA responses were associated with protection against vaginal simian-human immunodeficiency virus (SHIV) challenge (14), and multiple investigations have demonstrated that passive rectal immunization with neutralizing dimeric IgA can protect from subsequent SHIV exposure (15,16). Similarly, we recently reported an association between a high magnitude of Env-specific IgA and low rates of breast milk HIV transmission (17). Thus, Env-specific IgA responses in the systemic and mucosal compartments seem to play dramatically different physiologic roles.…”

Vaccine-Elicited Mucosal and Systemic Antibody Responses Are Associated with Reduced Simian Immunodeficiency Viremia in Infant Rhesus Macaques

“…Importantly, recent human studies demonstrated that HIVspecific breast milk IgA levels could reduce the risk of HIV acquisition in human infants (63). A subsequent study by the same group showed that strong HIV Env-specific IgA responses could be induced in lactating macaques by vaccination (64).…”

Fc Receptor-Mediated Activities of Env-Specific Human Monoclonal Antibodies Generated from Volunteers Receiving the DNA Prime-Protein Boost HIV Vaccine DP6-001

“…(20) was measured using a Luc-based ADCC assay according to a previously described procedure (21,22). Cryopreserved PBMCs were used as a source of effector cells (effector-to-target cell ratio, 30:1).…”