Evolutionary Analysis of Human Immunodeficiency Virus Type 1 Therapies Based on Conditionally Replicating Vectors

Abstract

Efforts to reduce the viral load of human immunodeficiency virus type 1 (HIV-1) during long-term treatment are challenged by the evolution of anti-viral resistance mutants. Recent studies have shown that gene therapy approaches based on conditionally replicating vectors (CRVs) could have many advantages over anti-viral drugs and other approaches to therapy, potentially including the ability to circumvent the problem of evolved resistance. However, research to date has not explored the evolutionary consequences of long-term treatment of HIV-1 infections with conditionally replicating vectors. In this study, we analyze a computational model of the within-host co-evolutionary dynamics of HIV-1 and conditionally replicating vectors, using the recently proposed ‘therapeutic interfering particle’ as an example. The model keeps track of the stochastic process of viral mutation, and the deterministic population dynamics of T cells as well as different strains of CRV and HIV-1 particles. We show that early in the co-infection, mutant HIV-1 genotypes that escape suppression by CRV therapy appear; this is similar to the dynamics observed in drug treatments and other gene therapies. In contrast to other treatments, however, the CRV population is able to evolve and catch up with the dominant HIV-1 escape mutant and persist long-term in most cases. On evolutionary grounds, gene therapies based on CRVs appear to be a promising tool for long-term treatment of HIV-1. Our model allows us to propose design principles to optimize the efficacy of this class of gene therapies. In addition, because of the analogy between CRVs and naturally-occurring defective interfering particles, our results also shed light on the co-evolutionary dynamics of wild-type viruses and their defective interfering particles during natural infections.

Design Requirements for Interfering Particles To Maintain Coadaptive Stability with HIV-1

“…Specifically, the analysis indicates that DIPs that suppress HIV replication via genome stealing will be unstable due to divergence between the HIV-1 DIS and the DIP DIS (i.e., interference and recombination via genome heterodimerization are minimized). This analytical finding raises doubts regarding the validity of a recent computational model that analyzes the evolutionary stability of conditionally replicating HIVs (i.e., DIPs) based exclusively on genome stealing (72). That DIS divergence is, in principle, possible is supported by the finding that different HIV-1 subtypes display diverse DIS sequences (73).…”

Reply to “Coadaptive Stability of Interfering Particles with HIV-1 When There Is an Evolutionary Conflict”

“…Ke and Lloyd-Smith for their letter (1) highlighting the critical discrepancies between the claims of their recent simulation study (2) and the results derived by evolutionary calculations in our analytic study (3). In contrast to our direct calculations, Ke and Lloyd-Smith argue that therapeutic interfering particles (TIPs)-generated by conditionally replicating vectors-would stably cross dimerize with HIV and indefinitely coevolve with the virus.…”

Coadaptive Stability of Interfering Particles with HIV-1 When There Is an Evolutionary Conflict

“…Their analyses are illuminating, particularly in highlighting the importance of multiple DIP infections of a cell and the possible role of "capsid stealing" by the DIPs. However, they state that the coevolution of HIV-1 and DIPs has not been explored previously while simultaneously raising "doubts regarding the validity" of our recent study of this problem (2). We wish to clarify two key issues and broaden the discussion.…”

“…Furthermore, in vitro studies have shown that mutated DIS sequences substantially decrease the efficiency of HIV-1 packaging and/or cellular infectivity (at least for the subset of mutations that have been studied) (5-8). Our recent work integrated these factors and showed that a genome-stealing strategy can be coevolutionarily stable, though we emphasized that experimental confirmation will be needed for particular DIP constructs (2).…”

“…We explored the coevolutionary dynamics arising from this conflict and identified a characteristic three-phase pattern (2). Initially, the DIP treatment is effective in suppressing HIV-1, but then HIV-1 evolves to escape DIPs by reducing P. Under some circumstances, DIPs then evolve to catch up with HIV-1 and establish a set point phase characterized by sustained suppression of HIV-1 viral load and "Red Queen" coevolutionary dynamics.…”