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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 when therapeutic virus is introduced before lethal virus.(A, B) Two replicates of observed experimental densities when therapeutic virus is introduced 60 min prior to lethal virus. Free therapeutic virus (≈105 phage/ml) was added to a culture of growing hosts (≈108 cells/ml). After 60 min of growth, lethal virus was added (at ≈4 × 103 phage/ml). The open black triangle is an upper limit of therapeutic-virus infected hosts under the assumption that all free therapeutic virus infects immediately. As such, the slope shown for the yellow line (triangles) during the first hour is lower, perhaps much lower than the true slope. 10 dilutions were made immediately after the times indicated. (C) Numerical dynamics. 10× dilutions are introduced at the same times as in the empirical assays, and symbols are placed on the curves at the same times as samples were assayed empirically. Parameter values are from Table 2. (D) Comparison of the surviving host dynamics in response to lethal virus for a population into which therapeutic virus was introduced (circles, red) versus a population in which therapeutic virus was not introduced (squares, blue). Replicates are indicated as dashed vs. solid lines. The blue curves are from Fig. 3; the red are from (A) and (B) but combine protected and uninfected host densities.
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fig-6: Growth dynamics when therapeutic virus is introduced before lethal virus.(A, B) Two replicates of observed experimental densities when therapeutic virus is introduced 60 min prior to lethal virus. Free therapeutic virus (≈105 phage/ml) was added to a culture of growing hosts (≈108 cells/ml). After 60 min of growth, lethal virus was added (at ≈4 × 103 phage/ml). The open black triangle is an upper limit of therapeutic-virus infected hosts under the assumption that all free therapeutic virus infects immediately. As such, the slope shown for the yellow line (triangles) during the first hour is lower, perhaps much lower than the true slope. 10 dilutions were made immediately after the times indicated. (C) Numerical dynamics. 10× dilutions are introduced at the same times as in the empirical assays, and symbols are placed on the curves at the same times as samples were assayed empirically. Parameter values are from Table 2. (D) Comparison of the surviving host dynamics in response to lethal virus for a population into which therapeutic virus was introduced (circles, red) versus a population in which therapeutic virus was not introduced (squares, blue). Replicates are indicated as dashed vs. solid lines. The blue curves are from Fig. 3; the red are from (A) and (B) but combine protected and uninfected host densities.

Mentions: Empirical results broadly agree with the numerical analyses (Fig. 6). Introduction of therapeutic virus first led to a rapid increase of hosts infected with the therapeutic virus. With a low initial ratio of therapeutic virus to cells (0.001) and the 1 h delay between therapeutic virus and lethal virus introductions, many uninfected hosts remained unprotected when the lethal virus was introduced; lethal virus density increased considerably (Figs. 6A and 6B). Nonetheless, the benefit of the therapeutic virus was evident from its huge effect on surviving host density (Fig. 6D).


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 when therapeutic virus is introduced before lethal virus.(A, B) Two replicates of observed experimental densities when therapeutic virus is introduced 60 min prior to lethal virus. Free therapeutic virus (≈105 phage/ml) was added to a culture of growing hosts (≈108 cells/ml). After 60 min of growth, lethal virus was added (at ≈4 × 103 phage/ml). The open black triangle is an upper limit of therapeutic-virus infected hosts under the assumption that all free therapeutic virus infects immediately. As such, the slope shown for the yellow line (triangles) during the first hour is lower, perhaps much lower than the true slope. 10 dilutions were made immediately after the times indicated. (C) Numerical dynamics. 10× dilutions are introduced at the same times as in the empirical assays, and symbols are placed on the curves at the same times as samples were assayed empirically. Parameter values are from Table 2. (D) Comparison of the surviving host dynamics in response to lethal virus for a population into which therapeutic virus was introduced (circles, red) versus a population in which therapeutic virus was not introduced (squares, blue). Replicates are indicated as dashed vs. solid lines. The blue curves are from Fig. 3; the red are from (A) and (B) but combine protected and uninfected host densities.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4933091&req=5

fig-6: Growth dynamics when therapeutic virus is introduced before lethal virus.(A, B) Two replicates of observed experimental densities when therapeutic virus is introduced 60 min prior to lethal virus. Free therapeutic virus (≈105 phage/ml) was added to a culture of growing hosts (≈108 cells/ml). After 60 min of growth, lethal virus was added (at ≈4 × 103 phage/ml). The open black triangle is an upper limit of therapeutic-virus infected hosts under the assumption that all free therapeutic virus infects immediately. As such, the slope shown for the yellow line (triangles) during the first hour is lower, perhaps much lower than the true slope. 10 dilutions were made immediately after the times indicated. (C) Numerical dynamics. 10× dilutions are introduced at the same times as in the empirical assays, and symbols are placed on the curves at the same times as samples were assayed empirically. Parameter values are from Table 2. (D) Comparison of the surviving host dynamics in response to lethal virus for a population into which therapeutic virus was introduced (circles, red) versus a population in which therapeutic virus was not introduced (squares, blue). Replicates are indicated as dashed vs. solid lines. The blue curves are from Fig. 3; the red are from (A) and (B) but combine protected and uninfected host densities.
Mentions: Empirical results broadly agree with the numerical analyses (Fig. 6). Introduction of therapeutic virus first led to a rapid increase of hosts infected with the therapeutic virus. With a low initial ratio of therapeutic virus to cells (0.001) and the 1 h delay between therapeutic virus and lethal virus introductions, many uninfected hosts remained unprotected when the lethal virus was introduced; lethal virus density increased considerably (Figs. 6A and 6B). Nonetheless, the benefit of the therapeutic virus was evident from its huge effect on surviving host density (Fig. 6D).

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