One goal of an HIV vaccine is to elicit antibodies that protect against infection by either neutralizing virus or killing infected cells. At this time, dat from human vaccine trials on the immune correlates of protection are limited. Mother-to-child transmission (MTCT), however, provides another unique setting in which to study the role of pre-existing antibodies in protection. Infants receive passively transferred HIV-specific antibodies in utero that may protect against infection during breastfeeding. This proposal utilizes a unique cohort of HIV-positive mothers and their infants from Nairobi, Kenya conducted from 1992 to 1998. The infants to be studied were all uninfected at birth but continually exposed to the virus via breastfeeding, and thus at risk for infection. Using this cohort, we will focus on th role of Fc-mediated antibody responses in MTCT. One such response is antibody-dependent cellular cytotoxicity (ADCC), which has been shown to influence HIV-1 acquisition and disease progression in macaques and humans. This study will address the hypothesis that ADCC activity mediated by passively acquired antibodies is inversely correlated with risk of infection i infants born to HIV-positive mothers. As ADCC activity is mediated through the Fc portion of the antibody and Fc receptor (FcR) genotype correlates with differential antibody binding, we will also examine the role of FcR genotype on HIV acquisition and progression. Finally, the third part of this proposal will examine the role of autologous ADCC responses in MTCT. In these experiments, ADCC assays will be customized to test each infant's antibodies against maternal viral antigens to which they were exposed, while utilizing effector cells bearing the FcR genotype(s) of the infant. Overall, these studies will provide knowledge on the role of pre-existing ADCC antibodies and host genetics in MTCT. These data will help inform future vaccine studies and provide insight into host factors that may influence vaccine effectiveness.

Public Health Relevance

Using a cohort of HIV-infected mothers and their infants from Nairobi, Kenya, this study investigates the role of antibodies in preventing HIV transmission and the impact of host genotype on infection and disease progression. Information gained from the research in this proposal may be used to define immune responses important in preventing HIV acquisition and thus improve vaccine design and patient care.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Miller, Judith A
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University of Washington
Public Health & Prev Medicine
Schools of Medicine
United States
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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
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
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