RATIONALIZING HIV-1 REROUTING-RESISTANCE WITH STRUCTURAL SYSTEMS VIROLOGY

HIV-1 with its minimalist genome must hijack the host machinery for successful replication. We hypothesize that redundancies in cellular mechanisms may afford the virus with an important survival advantage by presenting variable routes through cellular pathways allowing flexibility to exploit alternative cellular machineries when the default pathway is blocked. Whereas current therapeutic strategies focus on key host-virus interactions, we suggest that virus flexibility in rerouting within essential cellular pathways will lead to a new type of stubborn resistance, ‘rerouting resistance,’ and that truly effective anti-AIDS drugs can only be designed with full knowledge of the rerouting landscape.

The high mutational rate of HIV-1 rarely provides direct survival adaptations and more often have deleterious effects by directly perturbing interfaces central to intrinsic protein folding and activity or extrinsic interactions essential for crafting protein assemblies of virus and viral-host complexes. Evolved virus strains usually accumulate auxiliary mutations that induce compensatory structural and functional changes in the mutant protein facilitating the maintenance of its native state together with the adaptive mutation. Investigating interspecies subtleties can highlight crucial conserved patterns for drug and vaccine targeting and can uncover conceivable latent escape patterns accessible to challenged HIV-1. Here we will discuss two mechanisms of protein fitness, namely intrinsic compensatory mutations and extrinsic buffering by cellular chaperons. Examples from the HIV-1 and feline immunodeficiency virus (FIV) integrase, capsid and Vif proteins will be discussed.

Pathway targeting is not unique to HIV–host interactions and not even an innovation of parasitic pathogens, but rather a common biologic principle meaning that the exploration of the pathway rerouting phenomena will have wide applicability for normal and diseased cellular states including cancer.