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Virus wars: using one virus to block the spread of another.

Paff ML, Nuismer SL, Ellington A, Molineux IJ, Bull JJ - PeerJ (2016)

Bottom Line: The failure of traditional interventions to block and cure HIV infections has led to novel proposals that involve treating infections with therapeutic viruses-infectious viruses that specifically inhibit HIV propagation in the host.Early efforts in evaluating these proposals have been limited chiefly to mathematical models of dynamics, for lack of suitable empirical systems.Observed dynamics broadly agree with those predicted by a computer simulation model, although some differences are noted.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Integrative Biology, University of Texas, Austin, TX, United States; The Institute for Cellular and Molecular Biology, University of Texas, Austin, TX, United States.

ABSTRACT
The failure of traditional interventions to block and cure HIV infections has led to novel proposals that involve treating infections with therapeutic viruses-infectious viruses that specifically inhibit HIV propagation in the host. Early efforts in evaluating these proposals have been limited chiefly to mathematical models of dynamics, for lack of suitable empirical systems. Here we propose, develop and analyze an empirical system of a therapeutic virus that protects a host cell population against a lethal virus. The empirical system uses E. coli bacteria as the host cell population, an RNA phage as the lethal virus and a filamentous phage as the therapeutic virus. Basic dynamic properties are established for each virus alone and then together. Observed dynamics broadly agree with those predicted by a computer simulation model, although some differences are noted. Two cases of dynamics are contrasted, differing in whether the therapeutic virus is introduced before the lethal virus or after the lethal virus. The therapeutic virus increases in both cases but by different mechanisms. With the therapeutic virus introduced first, it spreads infectiously without any appreciable change in host dynamics. With the therapeutic virus introduced second, host abundance is depressed at the time therapy is applied; following an initial period of therapeutic virus spread by infection, the subsequent rise of protection is through reproduction by hosts already protected. This latter outcome is due to inheritance of the therapeutic virus state when the protected cell divides. Overall, the work establishes the feasibility and robustness to details of a viral interference using a therapeutic virus.

No MeSH data available.


Related in: MedlinePlus

Growth dynamics of lethal virus (Qβ) on an initially high density of susceptible hosts.(A) Three replicates of observed densities of host and phage over time (one replicate provides host density without phage density). Lethal virus was added to a culture of exponentially growing hosts (≈108 cells/mL) at an initial density of ≈8 × 104 phage/mL. Host density shows a far more shallow decline than expected from the numerical analyses (in B). 10× dilutions were made immediately after the indicated sampling. (B) Numerical analysis predicting densities of lethal virus and host shows a rapid loss of hosts—to orders of magnitude lower values than in empirical runs. Curves show the numerical output; for visual comparison, symbols are placed at the same times as in the empirical assays. 10× dilutions were imposed in the numerical analyses at the same times as in empirical assays. Results are broadly robust to phage parameter values. (See Table 2 for parameter values; initial values of variables were: lethal virus =105 phage/mL, host =108 cells/mL.)
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fig-3: Growth dynamics of lethal virus (Qβ) on an initially high density of susceptible hosts.(A) Three replicates of observed densities of host and phage over time (one replicate provides host density without phage density). Lethal virus was added to a culture of exponentially growing hosts (≈108 cells/mL) at an initial density of ≈8 × 104 phage/mL. Host density shows a far more shallow decline than expected from the numerical analyses (in B). 10× dilutions were made immediately after the indicated sampling. (B) Numerical analysis predicting densities of lethal virus and host shows a rapid loss of hosts—to orders of magnitude lower values than in empirical runs. Curves show the numerical output; for visual comparison, symbols are placed at the same times as in the empirical assays. 10× dilutions were imposed in the numerical analyses at the same times as in empirical assays. Results are broadly robust to phage parameter values. (See Table 2 for parameter values; initial values of variables were: lethal virus =105 phage/mL, host =108 cells/mL.)

Mentions: Cells infected with therapeutic virus (phage f1) are largely resistant to infection by Qβ, because their densities follow similar trajectories in the presence as in the absence of Qβ. There is nonetheless some growth of Qβ on these cells. A culture of cells infected with f1 carrying kanamycin resistance was grown overnight in LB with kanamycin (50 µg/mL). Cells were pelleted, and the pellet was re-suspended in 10 ml LB lacking drug and grown for 1 h before phage Qβ was added to a concentration of 104–105/mL. To maintain cells in a continual state of growth (which enhances infection), 10× dilutions were made immediately after some platings, as indicated (densities are not adjusted for dilutions). Curves with triangles give densities of f1-infected cells, curves with circles give densities of lethal virus Qβ. For comparison, the density of sensitive hosts in the presence of Qβ alone is shown from time 240 (A) and 300 (B) (blue stars, from Fig. 3).


Virus wars: using one virus to block the spread of another.

Paff ML, Nuismer SL, Ellington A, Molineux IJ, Bull JJ - PeerJ (2016)

Growth dynamics of lethal virus (Qβ) on an initially high density of susceptible hosts.(A) Three replicates of observed densities of host and phage over time (one replicate provides host density without phage density). Lethal virus was added to a culture of exponentially growing hosts (≈108 cells/mL) at an initial density of ≈8 × 104 phage/mL. Host density shows a far more shallow decline than expected from the numerical analyses (in B). 10× dilutions were made immediately after the indicated sampling. (B) Numerical analysis predicting densities of lethal virus and host shows a rapid loss of hosts—to orders of magnitude lower values than in empirical runs. Curves show the numerical output; for visual comparison, symbols are placed at the same times as in the empirical assays. 10× dilutions were imposed in the numerical analyses at the same times as in empirical assays. Results are broadly robust to phage parameter values. (See Table 2 for parameter values; initial values of variables were: lethal virus =105 phage/mL, host =108 cells/mL.)
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Show All Figures
getmorefigures.php?uid=PMC4933091&req=5

fig-3: Growth dynamics of lethal virus (Qβ) on an initially high density of susceptible hosts.(A) Three replicates of observed densities of host and phage over time (one replicate provides host density without phage density). Lethal virus was added to a culture of exponentially growing hosts (≈108 cells/mL) at an initial density of ≈8 × 104 phage/mL. Host density shows a far more shallow decline than expected from the numerical analyses (in B). 10× dilutions were made immediately after the indicated sampling. (B) Numerical analysis predicting densities of lethal virus and host shows a rapid loss of hosts—to orders of magnitude lower values than in empirical runs. Curves show the numerical output; for visual comparison, symbols are placed at the same times as in the empirical assays. 10× dilutions were imposed in the numerical analyses at the same times as in empirical assays. Results are broadly robust to phage parameter values. (See Table 2 for parameter values; initial values of variables were: lethal virus =105 phage/mL, host =108 cells/mL.)
Mentions: Cells infected with therapeutic virus (phage f1) are largely resistant to infection by Qβ, because their densities follow similar trajectories in the presence as in the absence of Qβ. There is nonetheless some growth of Qβ on these cells. A culture of cells infected with f1 carrying kanamycin resistance was grown overnight in LB with kanamycin (50 µg/mL). Cells were pelleted, and the pellet was re-suspended in 10 ml LB lacking drug and grown for 1 h before phage Qβ was added to a concentration of 104–105/mL. To maintain cells in a continual state of growth (which enhances infection), 10× dilutions were made immediately after some platings, as indicated (densities are not adjusted for dilutions). Curves with triangles give densities of f1-infected cells, curves with circles give densities of lethal virus Qβ. For comparison, the density of sensitive hosts in the presence of Qβ alone is shown from time 240 (A) and 300 (B) (blue stars, from Fig. 3).

Bottom Line: The failure of traditional interventions to block and cure HIV infections has led to novel proposals that involve treating infections with therapeutic viruses-infectious viruses that specifically inhibit HIV propagation in the host.Early efforts in evaluating these proposals have been limited chiefly to mathematical models of dynamics, for lack of suitable empirical systems.Observed dynamics broadly agree with those predicted by a computer simulation model, although some differences are noted.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Integrative Biology, University of Texas, Austin, TX, United States; The Institute for Cellular and Molecular Biology, University of Texas, Austin, TX, United States.

ABSTRACT
The failure of traditional interventions to block and cure HIV infections has led to novel proposals that involve treating infections with therapeutic viruses-infectious viruses that specifically inhibit HIV propagation in the host. Early efforts in evaluating these proposals have been limited chiefly to mathematical models of dynamics, for lack of suitable empirical systems. Here we propose, develop and analyze an empirical system of a therapeutic virus that protects a host cell population against a lethal virus. The empirical system uses E. coli bacteria as the host cell population, an RNA phage as the lethal virus and a filamentous phage as the therapeutic virus. Basic dynamic properties are established for each virus alone and then together. Observed dynamics broadly agree with those predicted by a computer simulation model, although some differences are noted. Two cases of dynamics are contrasted, differing in whether the therapeutic virus is introduced before the lethal virus or after the lethal virus. The therapeutic virus increases in both cases but by different mechanisms. With the therapeutic virus introduced first, it spreads infectiously without any appreciable change in host dynamics. With the therapeutic virus introduced second, host abundance is depressed at the time therapy is applied; following an initial period of therapeutic virus spread by infection, the subsequent rise of protection is through reproduction by hosts already protected. This latter outcome is due to inheritance of the therapeutic virus state when the protected cell divides. Overall, the work establishes the feasibility and robustness to details of a viral interference using a therapeutic virus.

No MeSH data available.


Related in: MedlinePlus