PhD Thesis Defense: Urjeet Khanwalkar

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"Advancing HIV Antibody Therapeutics Through Modeling Meaningful Antibody Mediated Protection Against HIV in Humanized Mice"

Abstract

Human immunodeficiency virus (HIV), and the associated acquired immunodeficiency syndrome (AIDS), continues to be an active pandemic across multiple geographical and demographic populations. Prophylactics, such as vaccines, are generally considered the most effective method of combating infectious diseases. Unfortunately, despite considerable effort there is still no vaccine available for HIV. Broadly neutralizing antibodies (bnAbs) have emerged as a promising modality for prevention and treatment of HIV, but studies have shown that neutralization alone is not sufficient to protect from and/or cure the infection. Antibodies with enhanced effector functions could be the key to developing effective anti-HIV therapies, but we need a better understanding of which antibody effector functions are important and necessary. Clinical trials for HIV prophylactics are limited by the lack of a clear correlate of protection. Traditional in-vitro assays for viral neutralization as well as other antibody-mediated effects do not recapitulate clinically relevant protection. Animal studies typically involve the use of non-human primates (NHP), but these studies are limited since HIV does not readily infect NHPs. Recently, more sophisticated humanized mouse models have emerged that more closely represent the human immune cell populations.

We propose an experimental model to leverage these humanized mice for investigating antibody-mediated functions in-vivo. We report the ability to distinguish antibody-mediated protection driven by the Fc-region of antibodies, for both monoclonal as well as polyclonal antibodies. This experimental model would streamline discovery and development of effective HIV therapeutics. Taken together, this body of work aims to advance development of improved antibody therapeutics.

Thesis Committee

• Margie Ackerman (Chair)
• Yina Huang
• Hung Nguyen
• Alejandro Balazs (External)

Contact

For more information, contact Thayer Registrar at thayer.registrar@dartmouth.edu.