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. 2006 Aug;80(15):7590-9.
doi: 10.1128/JVI.01623-05.

Kinetics of influenza A virus infection in humans

Prasith Baccam  1 , Catherine Beauchemin, Catherine A Macken, Frederick G Hayden, Alan S Perelson
Affiliations

Kinetics of influenza A virus infection in humans

Prasith Baccam et al. J Virol. 2006 Aug.

Abstract

Currently, little is known about the viral kinetics of influenza A during infection within an individual. We utilize a series of mathematical models of increasing complexity, which incorporate target cell limitation and the innate interferon response, to examine influenza A virus kinetics in the upper respiratory tracts of experimentally infected adults. The models were fit to data from an experimental H1N1 influenza A/Hong Kong/123/77 infection and suggest that it is important to include the eclipse phase of the viral life cycle in viral dynamic models. Doing so, we estimate that after a delay of approximately 6 h, infected cells begin producing influenza virus and continue to do so for approximately 5 h. The average lifetime of infected cells is approximately 11 h, and the half-life of free infectious virus is approximately 3 h. We calculated the basic reproductive number, R(0), which indicated that a single infected cell could produce approximately 22 new productive infections. This suggests that antiviral treatments have a large hurdle to overcome in moderating symptoms and limiting infectiousness and that treatment has to be initiated as early as possible. For about 50% of patients, the curve of viral titer versus time has two peaks. This bimodal behavior can be explained by incorporating the antiviral effects of interferon into the model. Our model also compared well to an additional data set on viral titer after experimental infection and treatment with the neuraminidase inhibitor zanamivir, which suggests that such models may prove useful in estimating the efficacies of different antiviral therapies for influenza A infection.

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Figures

FIG. 1.
FIG. 1.
Fits of the target cell-limited model without delay (equations 1 to 3) (solid lines) and with delay (equations 5 to 8) (dashed lines) to experimental data (filled squares) from H1N1 experimental influenza virus infections (28). The graphs present viral titers in TCID50/ml of nasal wash (black) and fractions of target cells remaining (blue) over the courses of the infections. The horizontal dotted lines mark the limit of detection for viral titer.
FIG. 2.
FIG. 2.
Fits of the target cell-limited model with delay that incorporates interferon (equations 5 to 8 and 9 to 11) to experimental data (filled squares) from H1N1 experimental influenza virus infections (28). The graphs present the viral titers (black), the IFN concentrations (red), and the fractions of target cells remaining (blue) over the courses of the infections. The horizontal dotted lines mark the limit of detection for viral titer.
FIG. 3.
FIG. 3.
Course of influenza virus infections with and without the neuraminidase inhibitor zanamivir given intranasally. The average virus titers for 26 volunteers given placebo (solid triangles), 31 volunteers given an NI early (26 or 32 h) (filled circles), and 12 volunteers given an NI delayed (50 h) (filled squares) following experimental infection are shown. The predicted virus titers using the target cell-limited model with delay (solid line) are shown for the placebo group, the early-treatment group, and the delayed-treatment group. The horizontal dotted line marks the limit of detection for viral titer. The parameter values used to describe the infections before therapy (placebo group) are V0 = 0.25 TCID50/ml, β = 1.4 × 10−2 (TCID50/ml)−1 · d−1, k = 3.2 d−1, p = 2.7 × 10−5TCID50/ml · d−1, c = 3.2 d−1, and δ = 3.2 d−1. Those parameter values are held constant for the treatment groups, except for p, which was set to 0.03p from time of drug administration onwards, namely, from 1.2 d and 2.08 d for the early- and delayed-treatment groups, respectively. Prophylactic use of an NI was modeled as a reduction in viral production rate by 97% at time of infection (dashed line). Experimental data were taken from Hayden et al. (15).
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