Molecular and Structural Virology
Scientists in the Alian’s Lab investigate the molecular mechanisms by which HIV-1 reprogram and take over the host cell environment to replicate.
We use interdisciplinary approaches at different scales and levels including virology, molecular biology, biochemistry and structural biology.
Infectious diseases are the world’s leading cause of mortality, and in addition to their human toll, their financial burdens are enormous. They also pose research challenges of unparalleled complexity resulting from the unpredictable emergence of new or altered pathogens. The worldwide AIDS pandemic is but one example of a newly emergent viral disease.
Pathogens communicate with human cells through physical interactions with various human proteins on the surface of the cell and within the interior of the cell. Nearly all of the known human-pathogen protein-protein interactions are for viral systems (98.3%), with the majority belonging to the human–HIV system (77.9%). These interactions allow the pathogen to enter the host cell, manipulate important cellular processes, multiply, and invade other cells. Although viral pathogens may interact with different host-proteins, they share common infection strategies and use a number of important mechanisms to manipulate the human cell. These include the modulation of host cell surface molecules; inhibition of host cell restriction factors; and modulation of the intracellular environment to promote efficient virus replication. Defining these viral-host complexes biologically, biochemically and ultimately structurally, offers the potential to provide templates for the next generation of therapeutic and vaccine targets.
Resistance Through Flexibility: We hypothesize that redundancies in cellular pathways may actually present an important survival mechanism by presenting variable routes through cellular pathways allowing flexibility to exploit redundant cellular machineries when the default or favored pathway is blocked by antiviral cellular responses, therapeutic interventions or simply in order to circumvent challenges of the cellular environment and different replication stages.
The ability of viruses to readily mutate and gain resistance to traditional drugs, which target viral proteins, has driven a shift in the therapeutic intervention strategies towards targeting key host-virus interactions. This is because, unlike viral proteins which continue to mutate and develop resistance to drugs, host proteins are harder to mutate and develop resistance. However, we hypothesize that a new kind of viral resistance will emerge whereby the virus, taking advantage of cellular redundancies, can mutate to utilize unrestricted, functionally equivalent, cellular targets. Truly effective anti-AIDS drugs can only be designed with full knowledge of this rerouting landscape.
Detailing the HIV-1 rerouting landscape will require capturing fitness variants and defining the molecular and mechanistic basis underlining viral flexibility, which will especially be guided by cross-species nuances