title: 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.
  
  
  OBJECTIVE
  Infants 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.
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Pollara
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: McGuire
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Genevieve G
authors.initials: GG
authors.lastname: Fouda
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Wes
authors.initials: W
authors.lastname: Rountree
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Josh
authors.initials: J
authors.lastname: Eudailey
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: R Glenn
authors.initials: RG
authors.lastname: Overman
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Seaton
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Deal
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: R Whitney
authors.initials: RW
authors.lastname: Edwards
authors.affiliation: The University of North Carolina Project, Lilongwe, Malawi.
authors.forename: Gerald
authors.initials: G
authors.lastname: Tegha
authors.affiliation: The University of North Carolina Project, Lilongwe, Malawi.
authors.forename: Deborah
authors.initials: D
authors.lastname: Kamwendo
authors.affiliation: The University of North Carolina Project, Lilongwe, Malawi.
authors.forename: Jacob
authors.initials: J
authors.lastname: Kumwenda
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Julie A E
authors.initials: JA
authors.lastname: Nelson
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Christie
authors.initials: C
authors.lastname: Brinkley
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Denny
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Ochsenbauer
authors.affiliation: Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Sascha
authors.initials: S
authors.lastname: Ellington
authors.affiliation: Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Caroline C
authors.initials: CC
authors.lastname: King
authors.affiliation: Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Denise J
authors.initials: DJ
authors.lastname: Jamieson
authors.affiliation: Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: van der Horst
authors.affiliation: Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Athena P
authors.initials: AP
authors.lastname: Kourtis
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Georgia D
authors.initials: GD
authors.lastname: Tomaras
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Ferrari
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA sallie.permar@dm.duke.edu.
authors.forename: Sallie R
authors.initials: SR
authors.lastname: Permar
mesh_terms: D000328:Adult; D057134:Antibodies, Neutralizing / Q000378:metabolism; D000918:Antibody Specificity; D000920:Antibody-Dependent Cell Cytotoxicity; D001942:Breast Feeding / Q000009:adverse effects; D005260:Female; D015483:HIV Antibodies / Q000097:blood / Q000378:metabolism*; D015658:HIV Infections / Q000150:complications / Q000276:immunology* / Q000635:transmission*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D018928:Immunity, Mucosal; D007070:Immunoglobulin A / Q000097:blood / Q000378:metabolism*; D007071:Immunoglobulin A, Secretory / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D007223:Infant; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D008295:Malawi; D008895:Milk, Human / Q000276:immunology* / Q000821:virology*; D018448:Models, Immunological; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology / Q000821:virology; D012307:Risk Factors; D055815:Young Adult; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D007070:Immunoglobulin A; D007071:Immunoglobulin A, Secretory; D007074:Immunoglobulin G; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1