Mapping of the rerouting landscape uses interdisciplinary approaches including virology, X-ray crystallography and multi-omics tools and is facilitated by inter-species differences. Indeed, the intrinsic species-specific pathway preferences, which apparently hinge on variations as subtle as single residue mutations, highlight the importance of cross-species analysis to discover potential unknown alternative routes awaiting HIV-1 exploitation.
      In our recent publication in STRUCTURE, we  highlighted important distinctions between the  human HIV-1 and the cat FIV that can pave the way towards this goal:
  1.  Recombinant FIV integrase, unlike HIV-1 integrase, is inefficient for in vitro integration activity and we suggest that investigating this feature may highlight additional critical requirements for the integration step of FIV, perhaps elucidating alternative pathways to those used by HIV-1.
  2. We highlighted a single mutation in the FIV integrase that generated the first stable monomeric form of a retroviral integrase and we suggest that investigating such a monomeric form can reveal undiscovered cellular network manipulations that immunodeficiency viruses may exploit through successful replication.
    * Our recent discoveries utilizing this cross-species approach and investigating the FIV integrase has received excessive media coverage.
      To demonstrate the power and significance of “flexible pathway rerouting” Akram Alian and his team are mapping the rerouting landscape of HIV-1 Vif evasion of APOBEC3 innate immunity. APOBEC3 proteins are host cell cytidine deaminases that can introduce lethal C to U mutations into the viral genome. This activity however is inhibited by the HIV-1 virion-infectivity-factor (Vif) accessory protein, which orchestrates the degradation of APOBEC3 proteins via the proteasomal pathway. The E3-ligase complex (CRL5) is assembled by Vif and comprises cullin-5, Elongin-B/C, and in humans and rhesus macaque crucially requires cellular core-binding-factor-β (CBF-β) to tag APOBEC3 for the proteasomal degradation. Developing effective and long lasting therapeutic interventions which block Vif degradation of APOBEC3 requires complete characterization of interaction alternatives accessible to Vif variants.
      The limelight fell on cytidine deaminases after the 2003 discovery that a member of this family (APOBEC3G) acts as an innate immune factor restricting the replication of HIV-1. Cytidine deaminases catalyze the hydrolytic removal of amine group from C4 position of cytidine converting it to uridine. Their mutagenic ability to scramble the genetic code through hypermutation makes them not only powerful players in the immune response, but also potentially dangerous if left unregulated leading to cancer. Indeed,  accruing evidence has established their role in somatic mutations leading to various cancers including breast, bladder, cervix, lung, head and neck, and ovarian. Hence, persistent or uncontrolled infection- and inflammation-induced APOBEC3 expression and the subsequent editing of cellular genes may indeed contribute to oncogenic progression and tumor heterogeneity, offering a novel mechanism of infection-mediated cancer and a high priority topic in the whole infection and cancer field. Cytidine deamination is a powerful cellular tool and so likewise we seek to understand the mechanisms by which the different cytidine deaminase family members correctly select for and deaminate substrates and the ways in which the cell regulates this process, which is essential for future manipulation of these processes, especially for the benefit of rational and novel drug targeting in cancer.