Vpr is the HIV‑1 acces­so­ry pro­tein with the high­est abun­dance in the viri­on and is deliv­ered direct­ly into the cyto­plasm of the infect­ed cell before de novo pro­duc­tion of viral pro­teins. Fur­ther­more, it has var­i­ous described but still enig­mat­ic func­tions relat­ed to the enhance­ment of HIV‑1 inte­gra­tion and increased viral gene expres­sion and new results sup­port a role for Vpr in eva­sion of HIV‑1 immune sens­ing. We here hypoth­e­size that coun­ter­ac­tion of innate sens­ing and retro­vi­ral restric­tion by HIV‑1 Vpr is a cru­cial deter­mi­nant of high viral loads and dis­eases pro­gres­sion in vivo. We will chal­lenge this hypoth­e­sis by the com­pre­hen­sive func­tion­al analy­ses of Vpr pro­teins iso­lat­ed from a cohort of ther­a­py naïve HIV‑1 infect­ed indi­vid­u­als dif­fer­ing in viral loads and CD4+ T cell counts. In detail, we will inves­ti­gate the abil­i­ty of pri­ma­ry Vpr alle­les to acti­vate the SLX4 com­plex, induce G2/​M arrest, asso­ciate with p21, coun­ter­act SamHD1, pro­mote HIV‑1 infec­tion of myeloid cells and to block inter­fer­on induc­tion. Recent­ly, these main­ly nov­el Vpr func­tions were pro­posed as impor­tant for Vprs puta­tive role in antag­o­nism of HIV‑1 immune sens­ing and expres­sion of antivi­ral restric­tion fac­tors. It is unknown if there is a mech­a­nis­tic link between these func­tions, if they syn­er­gize or whether these mech­a­nisms oper­ate inde­pen­dent­ly to sub­vert the innate immune response against HIV‑1. More­over, Vpr domains involved in medi­at­ing the var­i­ous activ­i­ties are elu­sive. Alto­geth­er, our com­pre­hen­sive analy­ses of pri­ma­ry patient derived Vpr alle­les sup­port­ed by a muta­ge­n­e­sis approach will give nov­el mech­a­nis­tic insights on the sub­ver­sion of innate immune sens­ing and retro­vi­ral restric­tion by Vpr. Fur­ther­more, we will reveal the rel­a­tive impor­tance of the inves­ti­gat­ed Vpr func­tions for HIV‑1 con­trol in vivo.