Requirement of Nef for HIV-1 infectivity is biased by the expression levels of Env in the virus-producing cells and CD4 in the target cells

The nef gene of human immunodeficiency virus type 1 (HIV-1) encodes a 27 to 34 kDa myristoylated protein, which enhances viral infectivity in a single -round infection assay. The level of Nef enhancement of HIV-1 infectivity d epends on the viral strains, on the target cells, and on the cells used for propagating the viruses. In this study, we aimed at clarifying the molecul ar basis of these differences in the requirement for Nef. We found that the requirement for Nef was increased when we decreased the quantity of Env pr otein in the virus-producing cells or the quantity of CD4 in the target cel ls. Both the wild-type and Nef-defective HIV-1 viruses were propagated in 2 93T cells, which did not express any CD4; therefore, Nef-induced CD4 down-r egulation did not explain this phenomenon. Moreover, we did not observe any increase in the viral entry or fusion activity of gp120(env) in the wild-t ype HIV-1 compared to that in the Nef-defective HIV-1. Thus, we propose tha t Env on the virion and CD4 on the target cells have inhibitory effects on the post-entry step of the HIV-1 replication cycle, and that Nef functions to counteract this negative effect.