A de novo approach to inferring within-host fitness effects during untreated HIV-1 infection

Autoři: Christopher J. R. Illingworth aff001;  Jayna Raghwani aff004;  David Serwadda aff006;  Nelson K. Sewankambo aff006;  Merlin L. Robb aff008;  Michael A. Eller aff008;  Andrew R. Redd aff009;  Thomas C. Quinn aff010;  Katrina A. Lythgoe aff004
Působiště autorů: Department of Genetics, University of Cambridge, Cambridge, United Kingdom aff001;  Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, United Kingdom aff002;  School of Chemical and Biological Sciences, Queen Mary University of London, London, United Kingdom aff003;  Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom aff004;  Department of Zoology, Peter Medawar Building, University of Oxford, Oxford, United Kingdom aff005;  Rakai Health Sciences Program, Kalisizo, Uganda, School of Public Health, Makerere University, Kampala, Uganda aff006;  School of Medicine, Makerere University, College of Health Sciences, Kampala, Uganda aff007;  U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America aff008;  Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, United States of America aff009;  Department of Medicine, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America aff010;  Laboratory of Immunoregulation, Division of Intramural Research, NIAID, NIH, Baltimore Maryland, United States of America aff011
Vyšlo v časopise: A de novo approach to inferring within-host fitness effects during untreated HIV-1 infection. PLoS Pathog 16(6): e32767. doi:10.1371/journal.ppat.1008171
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008171


In the absence of effective antiviral therapy, HIV-1 evolves in response to the within-host environment, of which the immune system is an important aspect. During the earliest stages of infection, this process of evolution is very rapid, driven by a small number of CTL escape mutations. As the infection progresses, immune escape variants evolve under reduced magnitudes of selection, while competition between an increasing number of polymorphic alleles (i.e., clonal interference) makes it difficult to quantify the magnitude of selection acting upon specific variant alleles. To tackle this complex problem, we developed a novel multi-locus inference method to evaluate the role of selection during the chronic stage of within-host infection. We applied this method to targeted sequence data from the p24 and gp41 regions of HIV-1 collected from 34 patients with long-term untreated HIV-1 infection. We identify a broad distribution of beneficial fitness effects during infection, with a small number of variants evolving under strong selection and very many variants evolving under weaker selection. The uniquely large number of infections analysed granted a previously unparalleled statistical power to identify loci at which selection could be inferred to act with statistical confidence. Our model makes no prior assumptions about the nature of alleles under selection, such that any synonymous or non-synonymous variant may be inferred to evolve under selection. However, the majority of variants inferred with confidence to be under selection were non-synonymous in nature, and in most cases were have previously been associated with either CTL escape in p24 or neutralising antibody escape in gp41. We also identified a putative new CTL escape site (residue 286 in gag), and a region of gp41 (including residues 644, 648, 655 in env) likely to be associated with immune escape. Sites inferred to be under selection in multiple hosts have high within-host and between-host diversity although not all sites with high between-host diversity were inferred to be under selection at the within-host level. Our identification of selection at sites associated with resistance to broadly neutralising antibodies (bNAbs) highlights the need to fully understand the role of selection in untreated individuals when designing bNAb based therapies.

Klíčová slova:

Alleles – Antibodies – Evolutionary immunology – Haplotypes – HIV-1 – Natural selection – Species diversity – Viral evolution


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