HIV-1 fitness. The Apparent Interferon Resistance of Transmitted HIV-1 is Likely A Consequence of Enhanced Replicative Fitness

HIV-1 transmission via sexual exposure is an inefficient process. When successful transmission does occur, newly infected individuals are colonized by the descendants of either a single virion or a very small number of establishing virions. These transmitted founder (TF) viruses are more interferon (IFN)- resistant than chronic control (CC) viruses present 6 months after transmission. To identify the specific molecular defences that make CC viruses more susceptible to the IFN-induced ‘antiviral state’, we established a pair of fluorescent TF and CC viruses and used arrayed interferon-stimulated gene (ISG) expression screening to identify candidate antiviral effectors. However, we observed a relatively uniform ISG resistance of transmitted HIV-1, and this directed us to investigate the underlying mechanism. Our subsequent in silico simulations, modelling, and in vitro characterisation of a model TF/CC pair (closely matched in replicative fitness), revealed that small differences in replicative growth rates can explain the broad IFN resistance frequently associated with transmitted HIV-1. We propose that, when present, the apparent IFN resistance of transmitted HIV-1 can be explained by enhanced replicative fitness, as opposed to specific resistance to individual IFN-induced defences.