Official websites use. Share sensitive information only on official, secure websites. Corresponding author. Phone: 49 Fax: 49 E-mail: frank.
Nef is a multifunctional accessory protein of primate lentiviruses. Recently, it has been shown that the ability of Nef to downmodulate CD4, CD28, and class I major histocompatibility complex is highly conserved between most or all primate lentiviruses, whereas Nef-mediated downregulation of T-cell receptor-CD3 was lost in the lineage that gave rise to human immunodeficiency virus type 1 HIV Whether or not other Nef activities are preserved between different groups of primate lentiviruses remained to be determined.
Thus, most primate lentiviral Nefs enhance virion infectivity and stimulate viral replication. Moreover, our data show that SIVcpz and SIVsmm Nefs do not require adaptive changes to perform these functions in human cells or tissues and support the idea that nef alleles from other primate lentiviruses would also be capable of promoting efficient virus spread in humans.
The accessory nef gene is present in the genomes of all primate lentiviruses but absent in other retroviruses. Early studies have established that Nef accelerates progression to AIDS and is required for efficient viral replication and persistence of human immunodeficiency virus type 1 HIV-1 in humans 16 , 36 and of the simian immunodeficiency virus SIVmac in experimentally infected rhesus macaques Hence, Nef has been characterized as a key factor of primate lentiviral pathogenicity Subsequently, a striking number of Nef functions and interactions have been identified, including downregulation of CD4, CD28, and class I major histocompatibility complex MHC-I ; enhancement of virion infectivity; stimulation of viral replication; and alteration of T-cell activation pathways reviewed in references 3 , 14 , 33 , 56 , 57 , and Accumulating evidence suggests that the combination of these Nef activities is important for efficient viral persistence and accelerated disease progression in HIVinfected humans and in SIVmac-infected macaques 7 , 10 , 19 , 26 , 32 , 49 , 60 , Recently, however, it has been shown that some Nef activities, i.
HIV-2 and the majority of SIV nef alleles downmodulate TCR-CD3 with high efficiency, thereby suppressing the responsiveness of virally infected T cells to stimulation and activation-induced cell death 6 , 30 , The analysis of receptor modulation by different primate lentiviral Nef proteins revealed that the loss of one specific Nef function in the lineage that gave rise to HIV-1 may partly explain the different levels of immune activation observed in pathogenic and nonpathogenic HIV and SIV infections Possible lineage-specific differences in other Nef functions remained to be investigated.
