Recombination in HIV and the evolution of drug resistance: for better or for worse?

Bretscher, Michael T.; Althaus, Christian L.; Müller, Viktor; Bonhoeffer, Sebastian

doi:10.1002/bies.10386

Cited by 112 publications

(120 citation statements)

References 41 publications

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“…Recombination represents a complementary mechanism that has the potential to accelerate HIV-1 diversification and evolution greatly (30,31), although some models challenge this view (32,33). By introducing multiple simultaneous alterations in the genome, recombination can generate constellations of alleles that would be otherwise unlikely or unable to assemble by means of mutation alone (31,34).…”

Section: Discussionmentioning

confidence: 99%

Dynamics of HIV-1 recombination in its natural target cells

Levy

Aldrovandi

Kutsch

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

407

513

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Genetic recombination is believed to assist HIV-1 diversification and escape from host immunity and antiviral therapies, yet this process remains largely unexamined within the natural target-cell populations. We developed a method for measuring HIV-1 recombination directly that employs reporter viruses bearing functional enhanced yellow fluorescent protein (YFP) and enhanced cyan fluorescent protein (CFP) genes in which recombination produces a modified GFP gene and GFP fluorescence in the infected cells. These reporter viruses allow simultaneous quantification of the dynamics of HIV-1 infection, coinfection, and recombination in cell culture and in animal models by flow-cytometric analysis. Multiround infection assays revealed that productive cellular coinfection was subject to little functional inhibition. As a result, generation of recombinants proceeded according to the square of the infection rate during HIV-1 replication in T lymphocytes and within human thymic grafts in severe combined immunodeficient (SCID)-hu (Thy/Liv) mice. These results suggest that increases in viral load may confer a compounding risk of virus escape by means of recombinational diversification. A single round of replication in T lymphocytes in culture generated an average of nine recombination events per virus, and infection of macrophages led to ≈30 crossover events, making HIV-1 up to an order of magnitude more recombinogenic than recognized previously and demonstrating that the infected cell exerts a profound influence on the frequency of recombination

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Section: Discussionmentioning

confidence: 99%

Dynamics of HIV-1 recombination in its natural target cells

Levy

Aldrovandi

Kutsch

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

407

513

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“…Consequently, the effect of recombination on the evolution of drug resistance has attracted considerable attention from epidemiologists, in particular with respect to resistance in the human immunodeficiency virus (HIV) (Bretscher et al 2004;Fraser 2005;Carvajal-Rodríguez et al 2007;Kouyos et al 2009). However, most epidemiological models are deterministic and focus on the time to resistance rather than on the probability of resistance (Bretscher et al 2004;Fraser 2005). An exception is the simulation study by Kouyos et al (2009), which incorporates stochasticity and allows populations to go extinct.…”

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confidence: 99%

The Role of Recombination in Evolutionary Rescue

Uecker

Hermisson

2015

Genetics

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How likely is it that a population escapes extinction through adaptive evolution? The answer to this question is of great relevance in conservation biology, where we aim at species' rescue and the maintenance of biodiversity, and in agriculture and medicine, where we seek to hamper the emergence of pesticide or drug resistance. By reshuffling the genome, recombination has two antagonistic effects on the probability of evolutionary rescue: it generates and it breaks up favorable gene combinations. Which of the two effects prevails depends on the fitness effects of mutations and on the impact of stochasticity on the allele frequencies.In this article, we analyze a mathematical model for rescue after a sudden environmental change when adaptation is contingent on mutations at two loci. The analysis reveals a complex nonlinear dependence of population survival on recombination. We moreover find that, counterintuitively, a fast eradication of the wild type can promote rescue in the presence of recombination. The model also shows that two-step rescue is not unlikely to happen and can even be more likely than single-step rescue (where adaptation relies on a single mutation), depending on the circumstances.KEYWORDS rapid adaptation; epistasis; drift; population dynamics; ecology P OPULATIONS facing severe environmental change need to adapt rapidly to the new conditions, or they will go extinct. The most prominent examples for evolutionary rescue in natural populations are provided by failed eradication of pathogens or pests that develop resistance against drugs or pesticides. Understanding which factors drive the evolution of resistance has been a concern since the application of drugs and pesticides. In recent years, the topic of evolutionary rescue has attracted increasing interest of evolutionary biologists at a broader front. Both theoretical models and laboratory experiments have been used to investigate the influence of many genetic or environmental factors on the survival probability of an endangered population, e.g., the importance of standing genetic variation, sexual reproduction, the history of stress, the severity and speed of environmental deterioration, or population structure Unckless 2008, 2014; Gonzalez 2009, 2011;Agashe et al. 2011;Lachapelle and Bell 2012;Gonzalez and Bell 2013;; see also the reviews by Alexander et al. 2014 andCarlson et al. 2014). Despite significant progress, a largely open area in research on rescue concerns the influence of recombination on the probability of population survival.Recombination has two fundamental effects on adaptation that work against each other: it brings favorable gene combinations together but it also breaks them up. Recombination hence has the potential both to promote rescue and to impede it. In classical population genetics (assuming a constant population size), the interplay of the two opposing effects of recombination has been an intensively studied problem for decades (e.g., reviewed in Barton and Charlesworth 1998;Otto 2009;Hartfield and Keigh...

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“…In a recent study aimed at understanding the kinetics of HIV recombination, Bretscher et al (15) considered a framework where cells are either singly or doubly infected by HIV. This framework provides useful insights into HIV recombination, challenging the widespread notion that recombination facilitates the emergence of drug resistance.…”

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confidence: 99%

HIV dynamics with multiple infections of target cells

Dixit

Perelson²

2005

Proc. Natl. Acad. Sci. U.S.A.

116

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The high incidence of multiple infections of cells by HIV sets the stage for rapid HIV evolution by means of recombination. Yet how HIV dynamics proceeds with multiple infections remains poorly understood. Here, we present a mathematical model that describes the dynamics of viral, target cell, and multiply infected cell subpopulations during HIV infection. Model calculations reproduce several experimental observations and provide key insights into the influence of multiple infections on HIV dynamics. We find that the experimentally observed scaling law, that the number of cells coinfected with two distinctly labeled viruses is proportional to the square of the total number of infected cells, can be generalized so that the number of triply infected cells is proportional to the cube of the number of infected cells, etc. Despite the expectation from Poisson statistics, we find that this scaling relationship only holds under certain conditions, which we predict. We also find that multiple infections do not influence viral dynamics when the rate of viral production from infected cells is independent of the number of times the cells are infected, a regime expected when viral production is limited by cellular rather than viral factors. This result may explain why extant models, which ignore multiple infections, successfully describe viral dynamics in HIV patients. Inhibiting CD4 down-modulation increases the average number of infections per cell. Consequently, altering CD4 down-modulation may allow for an experimental determination of whether viral or cellular factors limit viral production.multiple infection ͉ recombination ͉ scaling ͉ CD4 down-modulation ͉ mathematical model

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Recombination in HIV and the evolution of drug resistance: for better or for worse?

Cited by 112 publications

References 41 publications

Dynamics of HIV-1 recombination in its natural target cells

Dynamics of HIV-1 recombination in its natural target cells

The Role of Recombination in Evolutionary Rescue

HIV dynamics with multiple infections of target cells

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