Immune correlates of protection against Human Immunodeficiency Virus Type 1 (HIV-1) acquisition in humans remain unknown. The role of antibodies in providing protection, either through neutralization to prevent virions from infecting cells or Fragment crystallizable (Fc) effector functions to help clear already infected cells, are poorly understood. Previous work fails to support neutralizing antibodies (nAbs) as an in vivo protective correlate, therefore we sought to investigate whether the Fc effector function, antibody-dependent cellular cytotoxicity (ADCC), was protective. Mother-to-child-transmission (MTCT) cohorts provide a model of passive immunization and viral challenge, because infants acquire antibodies from their mother throughout gestation and breastfeeding and are consistently exposed to HIV. We hypothesized that infants of non-transmitting mothers would be protected due to higher ADCC responses compared to transmitting mother-infant pairs. To address our hypothesis, we developed a cell line susceptible to viruses incorporating HIV envelopes (Envs) isolated from maternal plasma for use in a luciferase-based ADCC assay. Serum samples came from the control arm of the Breastfeeding, Antiretroviral, and Nutrition (BAN) cohort in Malawi where HIV-infected mothers that transmitted (TM) infection to their infants were matched to two non-transmitting (NTM) mothers on parameters known to be important in MTCT, including maternal age, viral load, absolute CD4 count, and time to sample collection. All transmission events occurred during breastfeeding and the samples assessed in this study came from a timepoint prior to documented transmission. HIV-exposed but uninfected (HEU) infants had significantly higher levels of ADCC responses against their corresponding mother’s variants compared to HIV-exposed infected (HEI) infants. Additionally, higher ADCC was associated with reduced morbidity and mortality in infected infants up to 1 year after birth. Although nAbs were previously determined to not play a role in the prevention of MTCT in this cohort, our data suggests that neutralization and ADCC are independent antibody responses that may act in conjunction to prevent transmission. In order to utilize these protective antibodies in a preventative HIV-1 vaccine, the antibodies must recognize a range of Envs to be effective globally. ADCC breadth and potency (ADCCBP) was determined against a panel of heterologous globally diverse variants, unrelated to the infected mother’s Envs. No significant difference in ADCCBP was observed between TM and NTM mother-infant pairs. However, we identified samples with elite ADCCBP, specified as the top 5% of samples tested, and future HIV-1 vaccines may want to elicit the types of antibodies present in these samples. In summary, maternally acquired ADCC correlates with protection against HIV-1 transmission to exposed infants and is associated with lower infant morbidity up to 1 year after birth. Further characterization of antibodies with elite ADCCBP may be helpful in developing an effective vaccine.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/43795 |
| Date | 03 February 2022 |
| Creators | Thomas, Allison S. |
| Contributors | Sagar, Manish |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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