title: Maternal Binding and Neutralizing IgG Responses Targeting the C-Terminal Region of the V3 Loop Are Predictive of Reduced Peripartum HIV-1 Transmission Risk.
abstract: The development of an effective maternal HIV-1 vaccine that could synergize with antiretroviral therapy (ART) to eliminate pediatric HIV-1 infection will require the characterization of maternal immune responses capable of blocking transmission of autologous HIV to the infant. We previously determined that maternal plasma antibody binding to linear epitopes within the variable loop 3 (V3) region of HIV envelope (Env) and neutralizing responses against easy-to-neutralize tier 1 viruses were associated with reduced risk of peripartum HIV infection in the historic U.S. Woman and Infant Transmission Study (WITS) cohort. Here, we defined the fine specificity and function of the potentially protective maternal V3-specific IgG antibodies associated with reduced peripartum HIV transmission risk in this cohort. The V3-specific IgG binding that predicted low risk of mother-to-child-transmission (MTCT) was dependent on the C-terminal flank of the V3 crown and particularly on amino acid position 317, a residue that has also been associated with breakthrough transmission in the RV144 vaccine trial. Remarkably, the fine specificity of potentially protective maternal plasma V3-specific tier 1 virus-neutralizing responses was dependent on the same region in the V3 loop. Our findings suggest that MTCT risk is associated with neutralizing maternal IgG that targets amino acid residues in the C-terminal region of the V3 loop crown, suggesting the importance of the region in immunogen design for maternal vaccines to prevent MTCT.IMPORTANCEEfforts to curb HIV-1 transmission in pediatric populations by antiretroviral therapy (ART) have been highly successful in both developed and developing countries. However, more than 150,000 infants continue to be infected each year, likely due to a combination of late maternal HIV diagnosis, lack of ART access or adherence, and drug-resistant viral strains. Defining the fine specificity of maternal humoral responses that partially protect against MTCT of HIV is required to inform the development of a maternal HIV vaccine that will enhance these responses during pregnancy. In this study, we identified amino acid residues targeted by potentially protective maternal V3-specific IgG binding and neutralizing responses, localizing the potentially protective response in the C-terminal region of the V3 loop crown. Our findings have important implications for the design of maternal vaccination strategies that could synergize with ART during pregnancy to achieve the elimination of pediatric HIV infections.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA.|Duke Human Vaccine Institute, Durham, North Carolina, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Martinez
authors.affiliation: Duke Human Vaccine Institute, Durham, North Carolina, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Vandergrift
authors.affiliation: Duke Human Vaccine Institute, Durham, North Carolina, USA.
authors.forename: Ayooluwa O
authors.initials: AO
authors.lastname: Douglas
authors.affiliation: Duke Human Vaccine Institute, Durham, North Carolina, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: McGuire
authors.affiliation: Duke Human Vaccine Institute, Durham, North Carolina, USA.
authors.forename: John
authors.initials: J
authors.lastname: Bainbridge
authors.affiliation: Duke Human Vaccine Institute, Durham, North Carolina, USA.
authors.forename: Nathan I
authors.initials: NI
authors.lastname: Nicely
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA.|Duke Human Vaccine Institute, Durham, North Carolina, USA.|Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Georgia D
authors.initials: GD
authors.lastname: Tomaras
authors.affiliation: Duke Human Vaccine Institute, Durham, North Carolina, USA.|Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Genevieve G
authors.initials: GG
authors.lastname: Fouda
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA sallie.permar@duke.edu.|Duke Human Vaccine Institute, Durham, North Carolina, USA.|Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Sallie R
authors.initials: SR
authors.lastname: Permar
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D019380:Anti-HIV Agents / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000097:blood* / Q000276:immunology; D015331:Cohort Studies; D000939:Epitopes / Q000276:immunology; D005260:Female; D015483:HIV Antibodies / Q000097:blood* / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control / Q000635:transmission* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000097:blood* / Q000276:immunology; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control*; D058725:Peripartum Period; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology / Q000821:virology
chemical_list: D016915:AIDS Vaccines; D019380:Anti-HIV Agents; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007074:Immunoglobulin G
keywords: HIV; V3; antibodies; mother-to-child transmission