PhD Thesis Proposal: Urjeet Khanwalkar

"Challenging mouse models for advancing HIV therapeutics" 

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. HIV is also a highly mutagenic virus and there are several strains circulating and evolving at any given time. We are developing a barcoded library of infectious molecular clones (IMCs) which would allow researchers to quantitatively and qualitatively assess HIV infection and progression and how these change with different therapeutic regiments. Separately, we have also developed a lipid nanoparticle-based method to engineer primary naïve human B cells. This platform could unlock new therapeutic modalities as well as enable a deeper understanding of B cell biology, specifically the processes of class switching as B cell maturation. Taken together, this body of work aims to advance development of improved antibody therapeutics.

Thesis Committee

• Margie Ackerman (Chair)
• Dr Hung
• Dr Nguyen

Contact

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