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Dose-Response Models Reveal Critical Features of Inhibitor Activity and Viral Infection

  • Author(s): Webb, Nicholas Eugene
  • Advisor(s): Lee, Benhur
  • et al.
Abstract

Over the past 34 years astonishing global efforts have transformed HIV/AIDS from a clinical death sentence into a manageable long-term illness. With approximately 35 million people now living with HIV, our eyes move toward managing and containing HIV infection as a chronic condition on a global scale. Achieving this goal will require the advent of new treatment strategies that target a variety of highly conserved viral features and a more complex analytical framework to assess resistance and transmission potential during treatment as well as to evaluate the potential clinical pathologies of resistant variants.

Contributing to this goal, this dissertation focuses on evaluating novel treatment strategies from two complementary and important perspectives. First, we apply analytical frameworks adapted from biochemistry to more comprehensively asses the therapeutic expectations of emerging immunotherapeutics and novel inhibitor targets. These extensible methods provide a more accurate description of antiviral activity at levels that will be necessary to suppress viral replication and prevent resistance than more traditional potency-based comparisons. Additionally, the mathematical foundation of these methods connects high clinical expectation to more detailed biochemical mechanisms that present specific criteria to aid in the rational design of more effective therapies.

This analytical framework can, alternatively, be used to understand how a virus responds to the presence of a drug, which will be necessary for assessing how HIV and its pathology might evolve, on a global scale, in the face of widespread treatment. To this end, quantifying infection efficiency and understanding how HIV virion interact with their target cells through extensible mathematical models reveal the impacts that treatment can have on the most fundamental properties of HIV infection. Understanding treatment from the perspective of the virus can aid the design of more potent therapies that pose unsurmountable barriers to resistance and might specifically target transmissibility.

Our results present a unique analysis of the activity of broadly neutralizing HIV antibodies that provides a new dimension to evaluating the clinical expectations of novel immunotherapies in the context of long-term management. This analysis is also used to further distinguish the cytotoxic and antiviral activities of a novel HIV inhibitor class: the disulfide isomerase inhibitors, where we reveal the significant potential of this class as well as specific criteria for the development of stronger and less toxic analogs to boost the diversity of available HIV treatments. We then extend this analytical method to assess the inherent infectious properties of HIV in response to treatment, to evaluate resistance in the more clinical context of target-cell tropism, receptor usage and infectivity.

Managing HIV infection as a long-term condition on a global scale will require more sophisticated efforts in developing and assessing novel treatments in terms of both inhibitor activity and direct viral responses. The methods and experimental strategies presented here are an essential first step to describing the activity of inhibitors and the activity of HIV, itself. Our results illuminate novel mechanistic features that can aid the development of novel treatments specifically suited to contain and control HIV.

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