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

Ruian Ke,James O Lloyd-Smith

doi:10.1371/journal.pcbi.1002744

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.

Highlights

The human immunodeficiency virus type 1 (HIV-1) pandemic has been a major challenge in global public health for decades, and continues to impose crippling burdens of morbidity and mortality worldwide
Static fitness landscapes To gain insight into the competition between different strains of HIV-1 and therapeutic interfering particle (TIP), we started with the two simplest evolutionary scenarios: the ‘HIV-1 mutant’ model and the ‘TIP mutant’ model
We have used mathematical models to analyze the co-evolutionary dynamics of HIV-1 and a gene therapy delivered by a conditionally-replicating vector (CRV) in the peripheral blood within a host

Summary

Introduction

The HIV-1 pandemic has been a major challenge in global public health for decades, and continues to impose crippling burdens of morbidity and mortality worldwide. While recent years have brought major breakthroughs in identifying the protective effect of male circumcision [1,2,3] and the transmission-blocking potential of early antiretroviral (ARV) drug therapy [4], the scalability and sustainability of these strategies remains in doubt. ARV therapy can reduce viral loads to undetectable levels, but affected populations must be reached, continuous treatment (and investment) is required, long-term ARV use can result in side effects, and there is an ever-present risk that the virus will evolve drug resistance [5,6,7]. Gene therapies offer many advantages compared with pharmaceutical drugs, such as low economic cost, ease of administration, and potential to reduce HIV-1 viral loads by sustained interference with the viral life cycle (reviewed in [9,10])

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