Therapeutic Uses of Broadly Neutralizing Anti-HIV-1 Antibodies in Humanized Mice

Author

Ariel Halper-Stromberg

Date of Award

2015

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Nussenzweig Laboratory

Abstract

Combination anti-retroviral drug therapy (ART) significantly suppresses HIV-1 viremia in most infected individuals, but is incapable of curing disease. The major barrier to HIV-1 cure is a population of long-lived cells that harbor replication-competent provirus and are refractory to current therapies—termed the latent reservoir. New therapeutic approaches to clear latent HIV-1-infected cells are necessary to achieve cure. In the first part of this thesis, I show that HIV-1 mutates and diversifies at the expected rate within humanized mice (humice) and that hu-mice can sustain HIV-1 viremia for up to 4 months, thus allowing hu-mice to be used as a small animal model to study HIV-1 therapeutics. Using hu-mice, I show that when administered as single agents, recently discovered broadly neutralizing monoclonal antibodies (bNAbs) induce selective pressure at restricted viral epitopes. This causes a transient drop in viremia and the rapid emergence of viral escape mutants. When bNAbs are administered in combinations that target at least three independent epitopes, the emergence of viral escape variants is prevented. In the second part of this thesis, I show that viremia returns in hu-mice when antibody concentrations drop beneath their therapeutic thresholds. But the rebounding viruses do not carry signature escape mutations and are still sensitive to antibody neutralization. This suggests silently infected cells persist in hu-mice. I use hu-mice to assess viral eradication regimens that combine antibody therapy with latency reversal agents (LRAs). I show that a combination of bNAbs plus a combination of LRAs prevent viral rebound in humanized mice. To determine if antibodies play a unique role in clearing latently infected cells, I compared antibodies to ART for their efficacy in preventing viral rebound. I found that antibodies were more effective than ART at preventing viral rebound, and that this effect depended on intact Fc-FcR interactions. Within the limitations of the model, these studies provide proof of principle that antibodies combined with LRAs can be used to clear the latent reservoir in humanized mice and should be explored in other models.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Recommended Citation

Halper-Stromberg, Ariel, "Therapeutic Uses of Broadly Neutralizing Anti-HIV-1 Antibodies in Humanized Mice" (2015). Student Theses and Dissertations. 408.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/408