Functional characterization of the HIV-1 Vpu accessory protein

DRAKE A; MAGADAN JG; GARRIDO FM; MORELLATTO RUGGIERI L; BONIFACINO JS

Paraná, Entre Ríos

Congreso; LIV Reunión anual de la Sociedad Argentina de Investigaciones en Bioquímica y Biología Molecular; 2018

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

The chronic and persistent viral replication that characterizes the Human Immunodeficiency Virus 1 (HIV-1) infection reflects the complex interplay between the host defenses and a number of viral factors whose primary function is to facilitate the evasion of such immune responses. In order to infect a new host, replicate on it for many years and spread to new individuals, HIV-1 should avoid not only the innate defenses, including the so-called ―antiviral restriction factors‖, but also the humoral and cellular adaptive defenses. To date, many restriction factors that actively act against HIV-1 have been identified, including APOBEC3G, TRIM5alpha, cyclophilin A, BST-2/tetherin, SAMHD1 and SERINC3/5. HIV-1 has evolved a variety of mechanisms to evade these factors, by either acquiring mutations in the viral proteins susceptible to their action or encoding specific proteins that neutralize them. Known as "accessory proteins" (Vif, Vpr, Vpu and Nef), those viral factors act as molecular adapters that connect specific cellular targets with proteolytic or alternative intracellular trafficking pathways. Our lab is currently focusing on Vpu, one of the more attractive HIV-1 proteins from both clinical and pharmacological points of view. Among its many functions, Vpu promotes the downregulation of its specific targets, including the viral receptor CD4 and the restriction factor BST-2/tetherin, through cellular mechanisms that are not fully understood. We sought to study them at a molecular level by creating a complete proteomic profile of cellular proteins that interact specifically with wild-type and well-characterized Vpu mutants. This information allowed us to identify and analyze 1) new Vpu substrates; 2) key cellular proteins important for its multiple actions; and 3) cellular factors that regulate the trafficking pathways followed by Vpu. On the other hand, viruses generally ―hijack‖ specific components of "normal" cellular pathways to facilitate the progression of their infectious cycle. Our analysis could eventually also define the participation of yet unknown factors in the complex cellular mechanisms that Vpu uses to perform each of its specific actions.