Degree

Master of Science (MS)

Semester of Graduation

Spring 2026

Department

Biology

Document Type

Thesis

Abstract

Despite over four decades of research, no safe and effective vaccine exists to prevent HIV acquisition or control established infection, with 39.9 million people living with the virus globally in 2023 and mucosal routes like vaginal exposure driving persistent transmission. This thesis investigates optimized intravaginal delivery strategies for pINV-SIVsc, a replication-deficient lentiviral vector (ΔTARΔnef) regulated by the keratinocyte-specific involucrin promoter, to maximize transduction of basal epithelial stem cells and sustain localized SIV antigen expression in the vaginal mucosa—the primary site of simian/HIV transmission. By transducing self- renewing stem cells, this platform mimics the persistent immune stimulation of live- attenuated vectors like RhCMV/SIV while eliminating replication risks, addressing key failures of prior clinical trials that yielded immunogenic but non-protective responses due to poor mucosal T cell control and bnAb induction. Preliminary data in female macaques validated the approach: a single post-menses dose elicited durable vaginal IgA/IgG, SIV gag/env-specific CD8+ T cells with effector memory bias, and partial protection against repeated SIVmac239 challenges, with some animals achieving long-term viremia control. Building on this, we directly compared dropwise liquid administration versus aerosol spray via Teleflex micro-sprayer in naïve young adult female macaques, administering prime/boost doses of pINV-SIVsc during the follicular phase for optimal basal access. Longitudinal monitoring employed immunoPET/CT for antigen kinetics through 18 weeks, 14-color flow cytometry on colorectal mononuclear cells/PBMCs/lymph node FNAs, and ELISA for SIV gp130-specific mucosal/plasma IgA/IgG. Dropwise delivery proved superior, yielding robust focal vaginal antigen uptake versus weaker diffuse signals in spray groups, alongside higher colorectal CD8+ skewed to polyfunctional Tem phenotypes. Plasma IgA peaked modestly but IgG remained low. These findings refute aerosol advantages seen in mRNA studies, highlighting liquid mechanics for deeper stem cell transduction in multilayered vaginal epithelium, and position pINV-SIVsc as a safe platform for durable mucosal CD8+ immunity.

Date

2-6-2026

First Committee Chair

Edward I. Patterson

First Committee Member

Ritwij Purushottam Kulkarni

Second Committee Member

Mirna Marinic

Third Committee Member

Francois Villinger

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Available for download on Friday, May 28, 2027

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