Modeling the immunological pre-adaptation of HIV-1

Abstract It is becoming increasingly evident that the evolution of HIV-1 is to a large extent determined by the immunological background of the host. On the population-level this results in associations between specific human leukocyte antigen (HLA) alleles and polymorphic loci of the virus. Furthermore, some HLA alleles that were previously associated with slow progression to AIDS have been shown to lose their protective effect, because HLA-specific immunological escape variants have spread through the population. This phenomenon is known as immunological pre-adaptation. Apart from adapting to human immune responses, the set-point virus load (SPVL) of HIV-1 is thought to have evolved to values that optimize the population-level fitness of the virus. This suggestion is supported by considerable heritability of the SPVL. Previous modeling studies show that whether or not SPVL optimization is expected to occur depends sensitively on the underlying assumptions with respect to the extent of within-versus between-host selection. Here we use a detailed and semi-realistic multi-level HIV-1 model in which immunological pre-adaptation and SPVL evolution can emerge from the underlying interactions of the virus with the immune system of the host. This enables us to study the effect of immunological escape on disease progression, and how disease progression may be molded by SPVL evolution. We find that the time to AIDS could decrease significantly (0.5-1.0 years) in a HLA-dependent manner by immunological pre-adaptation over the long-term course of the epidemic (> 100 years). We find that SPVL is not expected to evolve to optimize the population-level fitness of HIV-1, even though high heritability of the SPVL emerges from continual selection of immune-escape mutations.