HIV-specific antibodies are considered a critical component of a HIV vaccine response, yet there is a paucity of data demonstrating the potential of such antibodies to provide protection in HIV exposed populations. A protective antibody response to HIV must include antibodies that exhibit adequate breadth to recognize diverse circulating stains of HIV-1, which can differ by 30% in envelope sequence. Thus, while studies in macaque model systems demonstrate that antibodies can provide protection against a single variant, these models cannot address the potential of antibodies to protect against the overwhelming antigenic diversity of circulating HIV strains. In the setting of mother-to-child transmission (MTCT), including breastfeeding transmission, antibody pressure is present in both the mother and the infant and thus has the potential to impact transmission by multiple mechanisms. Therefore, infant HIV exposure provides a natural model of what might occur with a vaccine that induced HIV-specific antibodies, and a unique opportunity to define humoral immune correlates of protection against HIV infection. Both neutralizing antibodies and antibodies that act through antibody-dependent cell cytoxicity (ADCC) have now been implicated in protection in the setting of MTCT and both could play a role. However, variable results across studies of maternal and infant HIV antibodies in relation to transmission has hindered our ability to gain a clear picture f immune correlates in MTCT. These discrepancies most likely reflect the fact that many studies were small and/or used samples from suboptimal time points in relation to when transmission occurred. Here we will capitalize on a large clinical trial of MTCT - the Nairobi Breastfeeding Clinical Trial - that enrolled several hundred HIV positive pregnant women and followed them from the third trimester through 2 years of life in the infant. In this trial, there was regular folow-up of both mothers and infants and there is a wealth of data from this study as well as banked samples. Here we propose to utilize this unique large cohort with regular sample collection and detailed data on infant infection to examine the role of both maternal and infant ADCC in MTCT. We will also examine the relationship of antibody responses, including binding and neutralizing antibodies and their epitope specificity, with infant HIV acquisition. Together these studies will provide comprehensive data within one well-characterized cohort on antibody correlates of MTCT. Such information is critical to determining the function and specificity of antibodies that provide protection in the setting of MTCT, which in turn will inform developing effective vaccine strategies.
HIV antibodies are considered a critical component of a protective response, but we know surprisingly little about the potential of antibodies to prevent HIV infection. The setting of mother-to-child transmission provides a situation where HIV antibodies are present in both the mother and the infant at times when the infant is exposed to HIV. The studies proposed here will address the potential of antibodies to afford protection of infants against HIV, and thus help define the immune responses that could contribute to protection from HIV infection.
|Milligan, Caitlin; Omenda, Maxwel M; Chohan, Vrasha et al. (2016) Maternal Neutralization-Resistant Virus Variants Do Not Predict Infant HIV Infection Risk. MBio 7:e02221-15|
|Simonich, Cassandra A; Williams, Katherine L; Verkerke, Hans P et al. (2016) HIV-1 Neutralizing Antibodies with Limited Hypermutation from an Infant. Cell 166:77-87|
|Verkerke, Hans P; Williams, James A; Guttman, Miklos et al. (2016) Epitope-Independent Purification of Native-Like Envelope Trimers from Diverse HIV-1 Isolates. J Virol 90:9471-82|
|Richardson, Barbra A; John-Stewart, Grace; Atkinson, Claire et al. (2016) Vertical Cytomegalovirus Transmission From HIV-Infected Women Randomized to Formula-Feed or Breastfeed Their Infants. J Infect Dis 213:992-8|
|Sanders, Rogier W; van Gils, Marit J; Derking, Ronald et al. (2015) HIV-1 VACCINES. HIV-1 neutralizing antibodies induced by native-like envelope trimers. Science 349:aac4223|
|Milligan, Caitlin; Richardson, Barbra A; John-Stewart, Grace et al. (2015) Passively acquired antibody-dependent cellular cytotoxicity (ADCC) activity in HIV-infected infants is associated with reduced mortality. Cell Host Microbe 17:500-6|
|Milligan, Caitlin; Richardson, Barbra A; John-Stewart, Grace et al. (2015) FCGR2A and FCGR3A Genotypes in Human Immunodeficiency Virus Mother-to-Child Transmission. Open Forum Infect Dis 2:ofv149|
|Slyker, Jennifer; Farquhar, Carey; Atkinson, Claire et al. (2014) Compartmentalized cytomegalovirus replication and transmission in the setting of maternal HIV-1 infection. Clin Infect Dis 58:564-72|
|Goo, Leslie; Chohan, Vrasha; Nduati, Ruth et al. (2014) Early development of broadly neutralizing antibodies in HIV-1-infected infants. Nat Med 20:655-8|
|Milligan, Caitlin; Overbaugh, Julie (2014) The role of cell-associated virus in mother-to-child HIV transmission. J Infect Dis 210 Suppl 3:S631-40|
Showing the most recent 10 out of 26 publications