Examination Date

Fall 10-31-2025

Degree

Dissertation

Degree Program

Microbiology, Immunology and Parasitology

Examination Committee

Pam Kozlowski, PhD; Alison Quayle, PhD; Joy Sturtevant, PhD; Ben Kelly, PhD; Robert Siggins, PhD

Abstract

In human immunodeficiency virus (HIV) type 1 vaccine studies with rhesus macaques (RM), protection against mucosal infection by simian or simian-human immunodeficiency virus has been associated with induction of HIV envelope (Env)-specific IgA in secretions at the site of challenge. Determining how these antibodies may have prevented or controlled infection has been difficult because the volume of secretion is too small to perform in vitro assays. Here we used serum IgA as a surrogate to interrogate protective mechanisms of anti-Env mucosal IgA antibodies in RM HIV vaccine recipients and to determine if the full potential of RM IgA antibodies to mediate Fc-dependent reactions can be assessed with human cells which are traditionally used in HIV functional assays. IgA was purified from serum of RM vaccinated with a "moderately difficult to neutralize" tier 2 serum neutralizing antibody-inducing trimeric Env immunogen and shown to neutralize virus just as well or even more efficiently than anti-Env IgG purified from the same animal. Importantly, better neutralization by IgA was linked to the presence of polymeric antibodies, the primary form of IgA produced by mucosal plasma cells. It has been assumed that RM IgA can mediate Fc-dependent functions such as antibody-dependent phagocytosis (ADP), but this has not yet been confirmed using RM phagocytes. There is only 73% homology between the IgA binding domain of macaque and human FcaR, raising concerns as to whether binding of RM IgA to the human monocytes used in ADP in vitro assays is strong enough to trigger function and accurately depict IgA-mediated ADP. We confirmed that classical monocytes in RM express the FcaR (CD89) and can mediate ADP of HIV Env-labeled beads in the presence of RM anti-Env IgA. However, our data indicates that RM IgA-mediated ADP may be underestimated in current assays with human cells due to species-biased binding of RM IgA to the macaque FcaR. Overall, our results suggest that HIV vaccine-induced Env-specific IgA synthesized by plasma cells in systemic or mucosal tissues of RM could function in protection by neutralizing or enhancing phagocytosis of virus.

Additional Files
Smith, Justin - Dissertation Report Form.pdf (112 kB)
Dissertation Report Form
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