The Interferon Resistance of Transmitted HIV-1 is a Consequence of Enhanced Replicative Fitness

Sugrue, E.; Wickenhagen, A.; Mollentze, N.; Aziz, M. A.; Sreenu, V. B.; Truxa, S.; Tong, L.; da Silva Filipe, A.; Robertson, D. L.; Hughes, J.; Rihn, S. J.; Wilson, S. J.

doi:10.1101/2021.12.18.473292

bioRxiv · 10.1101/2021.12.18.473292

The Interferon Resistance of Transmitted HIV-1 is a Consequence of Enhanced Replicative Fitness

Sugrue, E.·Wickenhagen, A.·Mollentze, N.·Aziz, M. A.·Sreenu, V. B.·Truxa, S.·Tong, L.·da Silva Filipe, A.·Robertson, D. L.·Hughes, J.·Rihn, S. J.·Wilson, S. J.

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Abstract

HIV-1 transmission via sexual exposure is a relatively inefficient process. When successful transmission does occur, newly infected individuals are colonized by either a single or a very small number of establishing virion(s). 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 than TF viruses, we established a pair of fluorescent GFP-IRES-Nef TF and CC viruses and used arrayed interferon-stimulated gene (ISG) expression screening. The relatively uniform ISG resistance of transmitted HIV-1 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 displayed by transmitted HIV-1. We propose that the apparent IFN resistance of transmitted HIV-1 is a consequence of enhanced replicative fitness, as opposed to specific resistance to individual IFN-induced defences.

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Sugrue, E., Wickenhagen, A., Mollentze, N., Aziz, M. A., Sreenu, V. B., Truxa, S., Tong, L., da Silva Filipe, A., Robertson, D. L., Hughes, J., Rihn, S. J., Wilson, S. J.. 2021-12-19. The Interferon Resistance of Transmitted HIV-1 is a Consequence of Enhanced Replicative Fitness. https://doi.org/10.1101/2021.12.18.473292

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