Estimating HIV-1 fitness characteristics from cross-sectional genotype data.
Despite the success of highly active antiretroviral therapy (HAART) in the management of human immunodeficiency virus (HIV)-1 infection, virological failure due to drug resistance development remains a major challenge. Resistant mutants display reduced drug susceptibilities, but in the absence of drug, they generally have a lower fitness than the wild type, owing to a mutation-incurred cost. The interaction between these fitness costs and drug resistance dictates the appearance of mutants and influences viral suppression and therapeutic success. Assessing in vivo viral fitness is a challenging task and yet one that has significant clinical relevance. Here, we present a new computational modelling approach for estimating viral fitness that relies on common sparse cross-sectional clinical data by combining statistical approaches to learn drug-specific mutational pathways and resistance factors with viral dynamics models to represent the host-virus interaction and actions of drug mechanistically. We estimate in vivo fitness characteristics of mutant genotypes for two antiretroviral drugs, the reverse transcriptase inhibitor zidovudine (ZDV) and the protease inhibitor indinavir (IDV). Well-known features of HIV-1 fitness landscapes are recovered, both in the absence and presence of drugs. We quantify the complex interplay between fitness costs and resistance by computing selective advantages for different mutants. Our approach extends naturally to multiple drugs and we illustrate this by simulating a dual therapy with ZDV and IDV to assess therapy failure. The combined statistical and dynamical modelling approach may help in dissecting the effects of fitness costs and resistance with the ultimate aim of assisting the choice of salvage therapies after treatment failure.
Institute of Biochemistry and Biology, University of Potsdam, Potsdam, Germany; Graduate Research Training Program PharMetrX: Pharmacometrics & Computational Disease Modelling, Free University of Berlin and University of Potsdam, Berlin/Potsdam, Germany.
Sathej
S
Gopalakrishnan
Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland; SIB Swiss Institute of Bioinformatics, Basel, Switzerland.
Hesam
H
Montazeri
Institute of Mathematics, University of Potsdam, Potsdam, Germany.
Stephan
S
Menz
Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland; SIB Swiss Institute of Bioinformatics, Basel, Switzerland.
Niko
N
Beerenwinkel
Institute of Biochemistry and Biology, University of Potsdam, Potsdam, Germany; Institute of Mathematics, University of Potsdam, Potsdam, Germany.
Wilhelm
W
Huisinga
D019380:Anti-HIV Agents / Q000494:pharmacology; D003430:Cross-Sectional Studies; D024882:Drug Resistance, Viral / Q000235:genetics; D056084:Genetic Fitness; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D019469:Indinavir / Q000494:pharmacology; D008954:Models, Biological; D009154:Mutation; D016896:Treatment Outcome; D015215:Zidovudine / Q000494:pharmacology
D019380:Anti-HIV Agents; D015215:Zidovudine; D019469:Indinavir