Biology subjects

Levy, D. N.

Publications and source records attributed to Levy, D. N..

3 recordsLinked to original sources

bioRxiv2020

Quantifying the dynamics of viral recombination during free virus and cell-to-cell transmission in HIV-1 infection

Recombination has been shown to contribute to HIV-1 evolution in vivo, but the underlying dynamics are extremely complex, depending on the nature of the fitness landscapes and of epistatic interactions. A less well-studied determinant of recombinant evolution is the mode of virus transmission in the cell population. HIV-1 can spread by free virus transmission, resulting largely in singly infected cells, and also by direct cell-to-cell transmission, resulting in the simultaneous infection of cells with multiple viruses. We investigate the contribution of these two transmission pathways to recombinant evolution, by applying mathematical models to in vitro experimental data on the growth of fluorescent reporter viruses under static conditions (where both transmission pathways operate), and under gentle shaking conditions, where cell-to-cell transmission is largely inhibited. The parameterized mathematical models are then used to extrapolate the viral evolutionary dynamics beyond the experimental settings. Assuming a fixed basic reproductive ratio of the virus (independent of transmission pathway), we find that recombinant evolution is fastest if virus spread is driven only by cell-to-cell transmission, and slows down if both transmission pathways operate. Recombinant evolution is slowest if all virus spread occurs through free virus transmission. This is due to cell-to-cell transmission (i) increasing infection multiplicity, (ii) promoting the co-transmission of different virus strains from cell to cell, and (iii) increasing the rate at which point mutations are generated as a result of more reverse transcription events. This work further resulted in the estimation of various parameters that characterize these evolutionary processes. For example, we estimate that during cell-to-cell transmission, an average of 3 viruses successfully integrated into the target cell, which can significantly raise the infection multiplicity compared to free virus transmission. In general, our study points towards the importance of infection multiplicity and cell-to-cell transmission for HIV-evolution.

evolutionary biology↗

bioRxiv2018

Multiple infection of cells changes the dynamics of basic viral evolutionary processes

The infection of cells by multiple copies of a given virus can impact virus evolution in a variety of ways, for example through recombination and reassortment, or through intra-cellular interactions among the viruses in a cell, such as complementation or interference. Surprisingly, multiple infection of cells can also influence some of the most basic evolutionary processes, which has not been studied so far. Here, we use computational models to explore how infection multiplicity affects the fixation probability of mutants, the rate of mutant generation, and the timing of mutant invasion. This is investigated for neutral, disadvantageous, and advantageous mutants. Among the results, we note surprising growth dynamics for neutral and disadvantageous mutants: Starting from a single mutant-infected cell, an initial growth phase is observed which is more characteristic of an advantageous mutant and is not observed in the absence of multiple infection. Therefore, in the short term, multiple infection increases the chances that neutral or dis-advantageous mutants are present. Following this initial growth phase, however, the mutant dynamics enter a second phase that is driven by neutral drift or negative selection, respectively, which determines the long-term fixation probability of the mutant. Contrary to the short-term dynamics, the probability of mutant fixation, and thus existence, is lower in the presence compared to the absence of multiple infection, and declines with infection multiplicity. Hence, while infection multiplicity promotes mutant existence in the short term, it makes it less likely in the longer term. Understanding of these dynamics is essential for the investigation of more complex viral evolutionary processes, for which the dynamics described here for the basis. We demonstrate relevance to the interpretation of experiments in the context of published data on phage {varphi}6 evolution at low and high multiplicities.

evolutionary biology↗

bioRxiv2018

Virus and CTL dynamics in the extra-follicular and follicular tissue compartments in SIV-infected macaques

Data from SIV-infected macaques indicate that virus-specific cytotoxic T lymphocytes (CTL) are mostly present in the extrafollicular (EF) compartment of the lymphoid tissue, with reduced homing to the follicular (F) site. This contributes to the majority of the virus being present in the follicle and represents a barrier to virus control. Using mathematical models, we investigate these dynamics. Two models are analyzed. The first assumes that CTL can only become stimulated and expand in the extra-follicular compartment, with migration accounting for the presence of CTL in the follicle. In the second model, follicular CTL can also undergo antigen-induced expansion. Consistent with experimental data, both models predict increased virus compartmentalization in the presence of stronger CTL responses and lower virus loads, and a more pronounced rise of extra-follicular compared to follicular virus during CD8 cell depletion experiments. The models, however, differ in other aspects. The follicular expansion model results in dynamics that promote the clearance of productive infection in the extrafollicular site, with any productively infected cells found being the result of immigration from the follicle. This is not observed in the model without follicular CTL expansion. The models further predict different consequences of introducing engineered, follicular-homing CTL, which has been proposed as a therapeutic means to improve virus control. Without follicular CTL expansion, this is predicted to result in a reduction of virus load in both compartments. The follicular CTL expansion model, however, makes the counter-intuitive prediction that addition of F-homing CTL not only results in a reduction of follicular virus load, but also in an increase in extrafollicular virus replication. These predictions remain to be experimentally tested, which will be relevant for distinguishing between models and for understanding how therapeutic introduction of F-homing CTL might impact the overall dynamics of the infection.

systems biology↗