Influenza Virus Infection Model With Density Dependence Supports Biphasic Viral Decay

Abstract

Mathematical models that describe infection kinetics help elucidate the time scales, effectiveness, and mechanisms underlying viral growth and infection resolution. For influenza A virus (IAV) infections, the standard viral kinetic model has been used to investigate the effect of different IAV proteins, immune mechanisms, antiviral actions, and bacterial coinfection, among others. We sought to further define the kinetics of IAV infections by infecting mice with influenza A/PR8 and measuring viral loads with high frequency and precision over the course of infection. The data highlighted dynamics that were not previously noted, including viral titers that remain elevated for several days during mid-infection and a sharp 4-5 log 10 decline in virus within one day as the infection resolves. The standard viral kinetic model, which has been widely used within the field, could not capture these dynamics. Thus, we developed a new model that could simultaneously quantify the different phases of viral growth and decay with high accuracy. The model suggests that the slow and fast phases of virus decay are due to the clearance rate changing as the density of infected cells changes. To characterize this model, we fit the model to the viral load data, examined the parameter behavior, and connected the results and parameters to linear regression estimates. The resulting parameters and model dynamics revealed that the rate of viral clearance during resolution occurs 25 times faster than the clearance during mid-infection and that small decreases to this rate can significantly prolong the infection. This likely reflects the high efficiency of the adaptive immune response. The new model provides a well-characterized representation of IAV infection dynamics, is useful for analyzing and interpreting viral load dynamics in the absence of immunological data, and further insight into the regulation of viral control.

Dynamically linking influenza virus infection kinetics, lung injury, inflammation, and disease severity

“…Animal weights generally drop slowly in the first several days during an IAV infection and more rapidly as the infection begins to resolve (Srivastava et al, 2009;Huang et al, 2017). This is unlike viral load dynamics in these animals, which increase rapidly during the first 0-3 d pi then remain relatively constant prior to resolution (Smith et al, 2018).…”

“…Following the peak, virus enters a biphasic decline. In the first phase (2-6 d pi), virus decays slowly and at a relatively constant rate (0.2 log 10 TCID 50 ∕d) (Smith et al, 2018). In the second phase (7-8 d pi), virus is cleared rapidly with a loss of 4 − 5 log 10 TCID 50 in 1-2 d (average of −3.8 log 10 TCID 50 ∕d) (Smith et al, 2018).…”

“…During IAV infection in both humans and animals, viral loads increase rapidly for the first 1-2 days of infection before reaching a peak (e.g., as in Smith et al (2018); Baccam et al (2006); Miao et al (2010); Toapanta and Ross (2009); Carrat et al (2008); Srivastava et al (2009); Gao et al (2013)). If the host is infected with a novel strain or has no prior immunity, viral loads in the lung then begin to decline, first slowly (sometimes < 1 log 10 TCID 50 ∕d) then rapidly (> 4 − 5 log 10 TCID 50 ∕d) (Smith et al, 2018;Gao et al, 2013). We previously quantified this biphasic viral decline with a mathematical model, which indicated that the rate of infected cell clearance increases as the density of infected cells decreases (Smith et al, 2018).…”

“…If the host is infected with a novel strain or has no prior immunity, viral loads in the lung then begin to decline, first slowly (sometimes < 1 log 10 TCID 50 ∕d) then rapidly (> 4 − 5 log 10 TCID 50 ∕d) (Smith et al, 2018;Gao et al, 2013). We previously quantified this biphasic viral decline with a mathematical model, which indicated that the rate of infected cell clearance increases as the density of infected cells decreases (Smith et al, 2018). The timing of the second, rapid viral decay phase coincides with the expansion of CD8 + T cells, which are the primary cell responsible for clearing infected cells and resolving the infection (Zhang and Bevan, 2011;Chen et al, 2018;McMichael et al, 1983; La Gruta and Turner, 2014;Kreijtz et al, 2011), and, to a lesser extent, neutralizing antibodies (Chen et al, 2018;Kreijtz et al, 2011;Fang and Sigal, 2005;Wang et al, 2015;McMichael et al, 1983) and cytotoxic CD4 + T cells (Wilkinson et al, 2012).…”

Report on the spatial spread of defective interfering particles and its role in suppressing infectious particles

“…The virions clearance rate c is another extensively studied parameter and widely accepted same as defined with 95% confidence interval for the acute phases of viral infections (Baccam et al, 2006;Beauchemin and Handel, 2011;Cho et al, 2014;Perelson et al, 1996;Smith and Perelson, 2011). A recent study shows that virions clearance rate is highly dependent on the density of infected cells (Smith et al, 2018). However, during the first day of infection, the virions either quickly infect cells or get cleared from the host.…”