title: Conflicting Selection Pressures Will Constrain Viral Escape from Interfering Particles: Principles for Designing Resistance-Proof Antivirals.
abstract: The rapid evolution of RNA-encoded viruses such as HIV presents a major barrier to infectious disease control using conventional pharmaceuticals and vaccines. Previously, it was proposed that defective interfering particles could be developed to indefinitely control the HIV/AIDS pandemic; in individual patients, these engineered molecular parasites were further predicted to be refractory to HIV's mutational escape (i.e., be 'resistance-proof'). However, an outstanding question has been whether these engineered interfering particles-termed Therapeutic Interfering Particles (TIPs)-would remain resistance-proof at the population-scale, where TIP-resistant HIV mutants may transmit more efficiently by reaching higher viral loads in the TIP-treated subpopulation. Here, we develop a multi-scale model to test whether TIPs will maintain indefinite control of HIV at the population-scale, as HIV ('unilaterally') evolves toward TIP resistance by limiting the production of viral proteins available for TIPs to parasitize. Model results capture the existence of two intrinsic evolutionary tradeoffs that collectively prevent the spread of TIP-resistant HIV mutants in a population. First, despite their increased transmission rates in TIP-treated sub-populations, unilateral TIP-resistant mutants are shown to have reduced transmission rates in TIP-untreated sub-populations. Second, these TIP-resistant mutants are shown to have reduced growth rates (i.e., replicative fitness) in both TIP-treated and TIP-untreated individuals. As a result of these tradeoffs, the model finds that TIP-susceptible HIV strains continually outcompete TIP-resistant HIV mutants at both patient and population scales when TIPs are engineered to express >3-fold more genomic RNA than HIV expresses. Thus, the results provide design constraints for engineering population-scale therapies that may be refractory to the acquisition of antiviral resistance.
authors.affiliation: Gladstone Institutes (Virology and Immunology), San Francisco, California, United States of America.|Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, United States of America.
authors.forename: Luke I
authors.initials: LI
authors.lastname: Rast
authors.affiliation: Gladstone Institutes (Virology and Immunology), San Francisco, California, United States of America.
authors.forename: Igor M
authors.initials: IM
authors.lastname: Rouzine
authors.affiliation: Gladstone Institutes (Virology and Immunology), San Francisco, California, United States of America.
authors.forename: Ganna
authors.initials: G
authors.lastname: Rozhnova
authors.affiliation: Gladstone Institutes (Virology and Immunology), San Francisco, California, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bishop
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, United States of America.
authors.forename: Ariel D
authors.initials: AD
authors.lastname: Weinberger
authors.affiliation: Gladstone Institutes (Virology and Immunology), San Francisco, California, United States of America.|Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, United States of America.|QB3: California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Leor S
authors.initials: LS
authors.lastname: Weinberger
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D019295:Computational Biology; D003673:Defective Viruses / Q000187:drug effects* / Q000235:genetics*; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000235:genetics; D019143:Evolution, Molecular; D006678:HIV / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D015658:HIV Infections / Q000188:drug therapy / Q000635:transmission / Q000821:virology; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D012641:Selection, Genetic; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents