Compensatory mutations rescue the virus replicative capacity of VIRIP-resistant HIV-1

► Mutations conferring resistance to VIRIP/VIR-353 do not appear in the fusion peptide of gp41. ► Resistance to VIRIP induced a change in virus replicative capacity. ► Mutations in gp120 and gp41 restored virus replicative capacity maintaining the resistant phenotype. ► There is a high genetic barrier for resistance to VIRIP and its analogues.