Early HIV infection predictions: role of viral replication errors.

Abstract

In order to prevent and/or control infections it is necessary to understand their early-time dynamics. However this is precisely the phase of HIV about which the least is known. To investigate the initial stages of HIV infection within a host we have developed a multi-type, continuous-time branching process model. This model is a stochastic extension of the standard viral dynamics model, under the assumption that the number of cell targets for viral infection is constant, biologically reasonable since, during the earliest stages of HIV infection, very few cells are infected relative to their total population size. We use our model to investigate three important clinical characteristics of early HIV infection following intravenous challenge: risk of infection, time to infection clearance (assuming failed infection), and time to infection detection. Our focus is on the impact of errors in viral replication that result in non-infectious virus production on these characteristics. Only a small fraction of circulating virus in any chronically infected individual is capable of infecting susceptible cells: estimates range from 1/104 - 1/103. Characterization and quantification of the processes by which virus becomes defective remains incomplete. We consider two mechanisms that result in defective virus: (1) Copying errors, i.e., lethal errors in reverse transcription, which introduce mutations into the HIV-1 proviral genome, some of which may cripple the viral genome produced, and (2) Packaging errors, i.e., errors during viral packaging, at the end of the viral replication cycle, which cause defective virus by packaging new virions without, for example, viral RNA or key proteins required for infectivity. We show that assumptions on mechanisms of defective virus production can significantly impact early HIV infection model predictions. For example, the risk of infection is orders of magnitude higher if all defective virus is associated with packaging errors, but infection is predicted to be detectable sooner following HIV exposure if all defective virus is associated with copying errors. Thus, in order to make reliable predictions of risk, clearance time, and detection time, better characterization of viral replication is required.