T-tropic human immunodeficiency virus (HIV) type 1 Nef protein enters human monocyte-macrophages and induces resistance to HIV replication: a possible mechanism of HIV T-tropic emergence in AIDS

Increasing interest has been devoted to the role that monocyte-macrophages play in the pathogenesis of AIDS. The hypothesis of an involvement in AIDS pathogenesis of human/simian immunodeficiency virus (HIV/SIV) Nef also is c urrently under evaluation by many investigators. The original basis of this hypothesis came from evidence that monkeys infected with a nef-deleted SIV strain failed to develop simian AIDS. Here, we show that treatment of huma n monocyte-derived macrophages (MDM) with recombinant HIV-1 Nef protein (rN ef) induces a strong inhibition of the replication of either macrophage (M- ) or dual-tropic HIV-1 strains. Through cytofluorimetric analyses, we detec ted internalization of FITC-conjugated rNef in MDM as early as 6 h after tr eatment. Confocal microscope observations demonstrated that the intracellul ar distribution of internalized rNef was identical to that of endogenously produced Nef. Down-regulation of the CD4 HIV receptor detected upon rNef tr eatment of MDM suggested that the rNef-induced HIV inhibition occurred at t he virus entry step. This deduction was strengthened by the observation tha t CD4-independent infection was totally insensitive to rNef treatment. The specificity of all observed effects was demonstrated by immunodepletion of rNef. Finally, we showed that the resistance to HIV replication induced by rNef treatment in MDM favours the spread of T-tropic over M-tropic HIV stra ins in doubly infected CD4(+) lymphocyte-MDM co-cultures. We propose that e xtracellular Nef contributes to AIDS pathogenesis by inducing resistance to M-tropic HIV replication in MDM, thereby facilitating the switching from M - to T-tropic HIV prevalence that correlates frequently with AIDS progressi on.