Underwhelming the immune response: effect of slow virus growth on CD8+-T-lymphocyte responses

Abstract

The speed of virus replication has typically been seen as an advantage for a virus in overcoming the ability of the immune system to control its population growth. Under some circumstances, the converse may also be true: more slowly replicating viruses may evoke weaker cellular immune responses and therefore enhance their likelihood of persistence. Using the model of lymphocytic choriomeningitis virus (LCMV) infection in mice, we provide evidence that slowly replicating strains induce weaker cytotoxic-T-lymphocyte (CTL) responses than a more rapidly replicating strain. Conceptually, we show a "bell-shaped" relationship between the LCMV growth rate and the peak CTL response. Quantitative analysis of human hepatitis C virus infections suggests that a reduction in virus growth rate between patients during the incubation period is associated with a spectrum of disease outcomes, from fulminant hepatitis at the highest rate of viral replication through acute resolving to chronic persistence at the lowest rate. A mathematical model for virus-CTL population dynamics (analogous to predator [CTL]-prey [virus] interactions) is applied in the clinical data-driven analysis of acute hepatitis B virus infection. The speed of viral replication, through its stimulus of host CTL responses, represents an important factor influencing the pathogenesis and duration of virus persistence within the human host. Viruses with lower growth rates may persist in the host because they "sneak through" immune surveillance.

FIG. 1.

Kinetics of early LCMV replication and expansion of gp33-specific CD8⁺ T cells after infection with different LCMV strains. C57BL/6 mice were infected intravenously with 200 PFU of LCMV-ARM, WE-ARM, WE, Traub, or DOC. (A) LCMV titers in spleens were determined at the indicated times postinfection. (B and C) Total numbers of CD8⁺ tet-gp33⁺ CTLs were assessed in the spleen (B) and blood (C) at the indicated times by fluorescence-activated cell sorter analysis. The values represent means ± standard errors for two or three mice per group.

FIG. 2.

Bell-shaped relationship between initial virus growth rate and peak CTL responses in spleen (A) and blood (B) established using data on CTL expansion in C57BL/6 mice infected with distinct LCMV strains exhibiting different growth rates. The error bars indicate standard errors. Variation in the LCMV growth rate can have either an enhancing or a down-regulating effect on the clonal burst size of virus-specific CTLs. Virus replication above a threshold is required for strong CTL response. LCMV-WE appears to be an “optimally” replicating strain in C57BL/6 mice, as it induces the strongest CTL response.

FIG. 3.

Associations among the characteristics of HCV growth and the clinical outcomes resulting from hepatitis infection. (A) Peak serum HCV RNA level versus time posttransfusion in a well-defined cohort of prospectively followed patients (14). (B) Summary of virus doubling times and infection outcomes from data on HCV in humans and chimpanzees (5, 13, 14, 43). The hierarchy suggests that the kinetics of virus growth can affect the outcome of HCV infection, and slower replication is evident in patients with longer HCV persistence.

FIG. 4.

Schematic view of the predator-prey framework for the dynamic analysis of the CTL-virus interaction representing the amplification mode.

FIG. 5.

Model predictions of HBV-CTL dynamics for different virus population doubling times. (A) Clinical data for patient 1 (42) and the corresponding mathematical model simulation. d, days. (B and C) Viremia and CTL numbers in blood of a normal responder (B) and a high responder (C). A reduction in the HBV growth rate during the incubation period leads to a weaker CTL expansion and underwhelming of the host immune response.