Stumptner-Cuvelette, P., S. upregulation are genetically distinguishable. We have identified natural alleles that have lost one of the TC-E 5001 two functions but not the other one. Moreover, we have characterized Nef mutant forms possessing a similar phenotype in the context of HIV-1 infection. Therefore, the Nef-induced accumulation of Ii chain complexes at the cell surface probably results from a complex mechanism leading to the impairment of AP-2-mediated endocytosis rather than from direct competition between Nef and the Ii chain for binding AP-2. Nef is a highly conserved primate lentiviral accessory protein with diverse TC-E 5001 functions but with no enzymatic activity. Nef appears to be essential for human immunodeficiency virus (HIV) pathogenicity and viral replication in primary T cells (16) and helps to maintain the full infectivity of viral particles (41, 53). The capacity of Nef to modulate the surface expression of many immunoreceptors is likely to contribute to efficient viral spread, immune system escape, and disease progression. These receptors include major histocompatibility complex class I (MHC-I; in fact, HLA-A and HLA-B but not HLA-C) (8, 26), MHC-II and the class II-associated invariant (Ii) chain (50), CD4 (18), and CD28 (51), all of which play a role at the contact site between antigen-presenting cells and T cells. Nef expression in T lymphocytes prevents the correct formation of the immunological synapse at the interface with antigen-presenting cells (52). Thus, Nef-expressing cells can escape from the cytotoxic activities of antiviral CD8 T cells and NK and NKT cells. Nef-expressing cells may also compromise the antiviral T helper response. Indeed, Nef impairs MHC-II presentation by affecting MHC-II intracellular trafficking (50). Nef possesses a dual effect leading to (i) reduced surface levels of maturei.e., peptide-loadedMHC-II molecules and (ii) increased levels of immature MHC-II molecules, which are functionally incompetent due to their association with the chaperone, the Ii chain. These surface-displayed Ii chains are associated with MHC-II and chains (50). The upregulation of surface Ii chain complexes requires smaller amounts of Nef than the downregulation of mature MHC-II molecules. The two functions are genetically separable (50) and are well conserved among alleles from primary HIV type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (46). Accumulating data suggest that Nef-mediated surface upregulation of the Ii chain plays an important role in viral replication and persistence in vivo. First, the TC-E 5001 level of upregulation is very high, an increase in expression of up to 50-fold, in contrast to that of DC-SIGN, another molecule upregulated by Nef but only by 2- to 3-fold (47). Second, the Ii chain Rabbit Polyclonal to MRPS32 upregulation has been documented to occur not only in HeLa-CIITA and MelJuSo cell lines (50) but also in the monocytic cell line THP-1, as well as in primary CD4+ T cells (24) and monocyte-derived macrophages, leading to similarly high levels of Ii chain expression (45). Third, in a previous study, the function of Ii chain surface upregulation was conserved among many alleles derived from progressing HIV-1-infected individuals but among TC-E 5001 alleles from only two of four long-term nonprogressors (46). Fourth, it has been implied previously that Nef-mediated Ii chain upregulation may impact the clinical course of pediatric AIDS progression (45). In fact, HIV-specific helper-T-cell responses are impaired in progressing HIV-1-infected individuals and are strong in long-term nonprogressors (38, 42). Thus, the capacity of Nef to affect MHC-II antigen presentation may impact the virus-specific T helper response and, thus, the control of the infection. On the other hand, strong Ii chain upregulation may contribute to the low level of generalized immune activation that is observed in nonpathogenic lentiviral infections and HIV-2 infections (45). MHC-II molecules are synthesized in the endoplasmic reticulum, where their and subunits.