Immuno-epidemiological Modeling of HIV-1 Predicts High Heritability of the Set-Point Virus Load, while Selection for CTL Escape Dominates Virulence Evolution

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Abstract
It has been suggested that HIV-1 has evolved its set-point virus load to be optimized for transmission. Previous epidemiological models and studies into the heritability of set-point virus load confirm that this mode of adaptation within the human population is feasible. However, during the many cycles of replication between infection of a host and transmission to the next host, HIV-1 is under selection for escape from immune responses, and not transmission. Here we investigate with computational and mathematical models how these two levels of selection, within-host and between-host, are intertwined. We find that when the rate of immune escape is comparable to what has been observed in patients, immune selection within hosts is dominant over selection for transmission. Surprisingly, we do find high values for set-point virus load heritability, and argue that high heritability estimates can be caused by the ‘footprints’ left by differing hosts' immune systems on the virus. HIV-1 is a relatively young virus, being introduced in the human population somewhere between 1884 and 1924. Yet, previous studies suggest that the virus has already evolved to be efficiently transmitted among humans. Efficient transmission occurs when the set-point virus load, the semi-stable number of virus particles in the blood during the asymptomatic phase, is intermediate (approximately particles/ml). At this virus load level, individuals remain asymptomatic for a long period (7.0 years on average), and still remain sufficiently infectious. In this study, we model the combined immunological and epidemiological dynamics of HIV-1 to explore whether population-level adaptation is feasible. We show that strong selective forces within the host are expected to dominate the much weaker population-level selection, unless the within-host dynamics of immune escape becomes exceedingly slow. Surprisingly, our analyses yield high levels of set-point virus load heritability, as observed in human populations. In the model, heritability of set-point virus load partially results from an immunological ‘footprint’ of the host-virus interaction in transmitting hosts, affecting the receiving hosts' virus load.

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