HIV-1 Nef protein causes death in stressed yeast cells due to determinants near the N-terminus and elsewhere in Nef

The Human Immunodeficiency Virus type 1 (HIV-1) Nef protein is essential for AIDS pathogenesis. In order to determine more about the effects of Nef on basic cellular functions Nef was produced in yeast under a variety of conditions and in multiple cell types. Production of Nef caused cell death in acutely copper- or heat-stressed diploid cells. The N-terminal melittin-like region of Nef was involved in toxicity since a Trp5→Ala change within Nef change caused increased toxicity. However, another determinant was also involved in toxicity since production of Nef20-206 was also still toxic. In each of these Nef-producing cells there was coincident membrane permeabilisation. These results suggest the possibility of a novel yeast bioassay for Nef inhibitors and that cells producing high levels of Nef may be selectively killed by stress.