Infectivity and host responses in Creutzfeldt-Jakob disease

Abstract

The relationship between viral titer and host responses was evaluated in Creutzfeldt-Jakob Disease (CJD). Rapid clearing of 97% of the virus from hamster brain occurred within 5 days, and residual virus was dispersed equally to both hemispheres. Exponential replication began only after a long eclipse phase of approximately 30 days, and by 100 days showed an > 3 log increase in titer. However, from 100 to 135 days, titers were restricted to plateau levels of approximately 10(8)/g. In comparison, previous studies show no appreciable eclipse phase and > or = 100-fold higher brain titers in hamster scrapie. Our calculations also revealed an effective doubling time (ti) of 7.6 days in CJD and a markedly different ti of approximately 3 days in scrapie. Thus different initiation and replication programs are encoded by each of these strains. The most pertinent host molecular responses included early astrocytic activity by 54 days, unaccompanied by morphological or behavioral changes. Changes in host PrP were minimal until 87 days when titers were already 2 x 10(7)/g. In the next 20 days 60% of brain PrP became resistant to limited proteolysis but total PrP did not increase. These fulminant PrP changes preceded viral arrest and subsequent spongiform degeneration. Because these and other data are not consistent with PrP itself being the infectious agent, we discuss a model in which progressive PrP and glial activation are part of a final host strategy to contain a virus that is innocuous at low titers. This strategy is flawed because PrP is an independent provocateur of self-destruction in the brain. However, in the periphery this strategy may eliminate rare infected cells.