Abstract
HIV-1 accumulates changes in its genome through both recombination and mutation during the course of infection. For recombination to occur, a single cell must be infected by two HIV strains. These coinfection events were experimentally demonstrated to occur more frequently than would be expected for independent infection events and do not follow a random distribution. Previous mathematical modeling approaches demonstrated that differences in target cell susceptibility can explain the non-randomness, both in the context of direct cell-to-cell transmission, and in the context of free virus transmission (Q. Dang et al., Proc. Natl. Acad. Sci. USA 101:632-7, 2004: K. M. Law et al., Cell reports 15:2711-83, 2016). Here, we build on these notions and provide a more detailed and extensive quantitative framework. We developed a novel mathematical model explicitly considering the heterogeneity of target cells and analysed datasets of cell-free HIV-1 single and double infection experiments in cell culture. Particularly, in contrast to the previous studies, we took into account the different susceptibility of the target cells as a continuous distribution. Interestingly, we showed that the number of infection events per cell during cell-free HIV-1 infection follows a negative-binomial distribution, and our model reproduces these datasets.
Highlights
The Human Immunodeficiency Virus type-1 (HIV-1) population in an infected individual is characterized by high genetic diversity that allows rapid adaptation to the changing environment, such as the development of an immune response or the initiation of an antiretroviral therapy
The authors considered only either “susceptible” or “unsusceptible” cell populations, and using a mathematical model found that heterogeneity in target cell susceptibility could account for the observation that more double infections occur in vivo than predicted by random models[18]
We modelled the distribution of HIV infection events during cell-free infection in vitro, taking into account differences in susceptibility within the target cell population
Summary
The Human Immunodeficiency Virus type-1 (HIV-1) population in an infected individual is characterized by high genetic diversity that allows rapid adaptation to the changing environment, such as the development of an immune response or the initiation of an antiretroviral therapy. By mixing the viral genomes, in one step, recombination creates new variants whose adaptation to the environment may exceed those of the parental viruses[2, 3] This process could participate in the unfavourable prognosis of patients infected by two strains of HIV, known as double infection[4]. Previous work has established that cell-associated HIV-1 transmission leads to frequent multiple infection events, while the majority of cells infected by free virions carry a single genome[12]. Despite the difference in efficacy, both virus transmission pathways result in a higher frequency of double-infected cells than would be expected for independent transmission events, showing that these infections do not follow a random distribution[13,14,15,16,17]. Our results re-evaluate the potential impact of cell-free HIV-1 infection on HIV-1 genetic recombination
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