Professor Richard Berry D. Phil.

Abstract:

The virological literature presents two broad types of defective virus mutants that can alter the outcome of viral infection. In some infections, defective interfering particles reduce the replication of wild-type virus and lead to an attenuated or persistent infection. In other cases, very specific and highly pathogenic defective mutants lead to virulent disease in the presence of a much less pathogenic but replication-competent helper virus. Here, we outline the theoretical possibility that defective mutants of HIV, which escape from some of the immune responses directed at the wild-type virus, can have a positive effect on total virus growth in HIV infections. The high error rate of HIV may generate many mutants that have some altered epitope (escape mutants), but at the cost of greatly reduced or completely impaired reproductive abilities. If these mutants retain some ability to impair immune cell function, then the production of such "defective escape" mutants may enhance overall virus reproduction. This will be illustrated by a mathematical model.

Abstract:

Many ion channels that normally gate fully open or shut have recently been observed occasionally to display well-defined subconductance states with conductances much less than those of the fully open channel. One model of this behavior is a channel consisting of several parallel pores with a strong correlation between the flux in each pore such that, normally, they all conduct together but, under special circumstances, the pores may transfer to a state in which only some of them conduct. This paper introduces a general technique for modeling correlated pores, and explores in detail by computer simulation a particular model based upon electric interaction between the pores. Correlation is obtained when the transient electric field of ions passing through the pores acts upon a common set of ionizable residues of the channel protein, causing transient changes in their effective pK and hence in their charged state. The computed properties of such a correlated parallel pore channel with single occupation of each pore are derived and compared to those predicted for a single pore that can contain more than one ion at a time and also to those predicted for a model pore with fluctuating barriers. Experiments that could distinguish between the present and previous models are listed.