ReviewHuman immunodeficiency virus (HIV) type-1, HIV-2 and simian immunodeficiency virus Nef proteins
Introduction
Infection by the human immunodeficiency virus (HIV) originates from cross-species transmission of the simian immunodeficiency virus (SIV) from its monkey host to humans in the 20th century. Several transmissions must have occurred over time, without efficient propagation of the virus, before the socio-economical modifications that took place in some parts of Africa and served as a catalyst to the early spread of the epidemic. Phylogenetic studies traced the origin of HIV type-1 (HIV-1) and HIV-2 to different regions of Africa and divergent strains of SIV, thereby establishing a potential correlation between differential adaptation of simian viral strains and differences in the pathogenesis associated with these two viruses (reviewed in Gisselquist, 2003, Heeney et al., 2006). The close relationship between HIV and SIV has naturally established simian models as the most appropriate for in vivo studies of infection by immunodeficiency viruses; however, phenotypic differences between HIV and SIV revealed the limits of such models. Most importantly, SIV does not cause immunodeficiency in its natural host sooty mangabeys (SIVsm), African green monkeys (SIVagm) and chimpanzees (SIVcpz). On the contrary SIVmac which derived from SIVsm infection of Asian macaques is highly pathogenic in macaques and induces an immunodeficiency syndrome similar to that witnessed in humans infected by HIV. Strikingly, SIV natural hosts do harbor high viral titers but keep low levels of immune activation (Kirchhoff et al., 2008).
The differences that exist between the progression to AIDS of infected primates and humans should result from host-specific or virus specific factors or a combination of both. One of the key players that has been incriminated in the respective pathogenic and non-pathogenic consequences of HIV and SIV infection is the non-structural viral protein Nef, a 27–35 kDa myristylated protein than can interact with multiple factors in infected cells. In addition to genes that encode the elements that are essential to the assembly and budding of all infectious retroviral particles (gag, pol and env), the genome of primate lentiviruses encode non-structural proteins that regulate viral spread in hosts (reviewed in Li et al. (2005)). Early studies of the gene located at the 3′ end of HIV-1 genome (named 3′ORF) suggested that the corresponding protein could attenuate viral replication and be involved in the establishment of latency (Luciw et al., 1987). NEgative Factor (Nef) was thus coined in and replaced 3′ORF; however, soon thereafter, results indicating that Nef would to the contrary have a positive impact on the pathogenesis associated to HIV and SIV infection started accumulating (Hammes et al., 1989, Kim et al., 1989). It has thereon been known that Nef has a positive impact on viral replication in vitro and accelerates the progression towards immunodeficiency in both human hosts infected with HIV-1 and monkeys infected with pathogenic strains of SIV. Because HIV-2 prevalence is low and given the higher proportion of HIV-2 infected individuals who do not progress to AIDS as compared with individuals infected with HIV-1 (de Silva et al., 2008), data on HIV-2 Nef are scarce. On the contrary, SIV being the best animal model to study lentiviral infection in primates, SIV Nef has been thoroughly characterized. In this review, we will focus on the many functions of primate lentiviruses Nef proteins.
Section snippets
Impact of Nef on HIV- and SIV-associated pathogenesis
In 1991, Kestler et al. demonstrated that the presence of an intact nef allele was, at least in part, responsible for the maintenance of high viral loads and progression towards immunodeficiency in macaques infected with the pathogenic strain SIVmac239 (Kestler et al., 1991). Insertion of a stop codon in the nef ORF, abolishing Nef expression, resulted in a decrease of virulence and no or slower progression towards immunodeficiency in infected animals. Follow up of these animals revealed that
Nef down-regulates CD4 from the plasma membrane
Receptor down-regulation upon infection is a common mechanism used by many viruses in order to prevent super-infection that is toxic to cells and responsible for a decreased production of progeny virions (Breiner et al., 2001, Delwart and Panganiban, 1989, Schneider-Schaulies et al., 1995). CD4 is the primary receptor of primate lentiviruses (Dalgleish et al., 1984, Klatzmann et al., 1984). HIV and SIV Nef and Vpu, and to a lower extend Env, have the ability to decrease cell-surface expression
Avoiding immune surveillance: down-regulation of MHC molecules
Nef-mediated MHC-I down-regulation was first described by Schwartz et al. (1996). In vitro modulation of MHC-I cell-surface expression correlates with a protection of HIV and SIV infected cells from lysis mediated by cytotoxic T lymphocytes (Munch et al., 2001). While Nef causes a decrease of the cell-surface expression of HLA-A and -B molecules that are involved in the presentation of endogenous antigens to cytotoxic T lymphocytes, Nef does not affect the cell-surface expression of HLA-C and
Nef promotes virus release from infect cells
HIV-1 Nef alters the trafficking of various cell-surface proteins by connecting cargos to the clathrin-dependent or independent endocytic pathway. As discussed above, AP complexes play a major role in these mechanisms. In addition to prevent super-infection, CD4 down-regulation facilitates virion release by preventing HIV-1 Env to interact with cell-surface CD4 (Aiken et al., 1994, Lama et al., 1999). A connection between HIV-1 Nef and the multivesicular body was also shown to affect virions
Activation
The ability of HIV-1/2 and SIV Nef to promote T cell activation is generally admitted. Various models have been put forward to explain this effect of Nef. While some authors suggest that Nef primes T cells for TCR-dependent activation, others suggest that it might negatively interfere with TCR-dependent activation.
Efficient HIV and SIV proliferation in vitro requires mitogenic activation or engagement of the T cell receptor (Stevenson, 2003); however, replication in purified T cells, PBLs or
Increasing virus infectivity
CD4 down-regulation, together with down-regulation of the co-receptors CXCR4 and CCR5, contribute to prevent super-infection of the cells that would be deleterious to the virus (Michel et al., 2005). There also is a correlation between the ability of Nef to down-regulate CD4 and its ability to increase viral replication in vitro and HIV-1 associated pathogenesis in vivo (Glushakova et al., 2001, Lundquist et al., 2002, Stoddart et al., 2003). Viruses produced from cells that express wild type
Effect of Nef on bystander cells: a soluble form of Nef
Nef expression achieved by infecting cells with HIV or SIV, or upon transfection profoundly alters the host cell biology. In addition, evidence have accumulated showing that Nef can be released from Nef-expressing cells, either as vesicles or as a soluble protein, and affect bystander cells (Campbell et al., 2008, Fujii et al., 1996, Guy et al., 1987, Lenassi et al., 2010, Muratori et al., 2009) (Fig. 4). The cell-free pool of Nef was shown to play a role in HIV-1 pathogenesis in a recent
Conclusions
HIV and SIV Nef proteins have the ability to interfere with many cellular pathways with the ultimate consequence of favoring virus persistence in infected individuals and its transmission. Such properties are accomplished by the interaction of Nef with an increasing number of cellular targets through multiple binding motifs on Nef.
Major Nef functions fall into four distinct categories. Nef makes a connection between cellular proteins and the endocytic machinery, thereby altering their basal
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Nef homodimers down-regulate SERINC5 by AP-2–mediated endocytosis to promote HIV-1 infectivity
2020, Journal of Biological ChemistryCommensal pathogens as a source of a coexistence mechanism
2015, Journal of Theoretical BiologyCitation Excerpt :A seemingly contradicting observation is that many organisms carry commensal viruses that are hostile to similar species, competing for a similar niche (Hudson and Greenman, 1998; Tompkins et al., 2002). For example, among SIV viruses, there is good evidence of non-pathogenicity for African green monkeys and sooty mangabeys (Laguette et al., 2010). The chimpanzee virus (SIVcpz) appears to cause AIDS in chimpanzees (Apetrei et al., 2004) (chimpanzees acquired this virus recently from other monkeys); and obviously does (as HIV-1) in humans (Sharp and Hahn, 2010; Huet et al., 1990), the sooty mangabey virus causes AIDS in humans (Apetrei et al., 2004) (as HIV-2), and in macaques (as SIVmac, SIVstm, SIVmne).
Understanding HIV infection for the design of a therapeutic vaccine. Part I: Epidemiology and pathogenesis of HIV infection
2015, Annales Pharmaceutiques FrancaisesCitation Excerpt :The nef gene encodes the accessory protein Nef (negative factor) and although its name suggests differently, Nef accelerates progression to immunodeficiency and viral replication. Nef decreases the expression of viral co-receptors at the cell surface, such as CD4, CCR5, and to a lesser extent CXCR4, to prevent superinfection [32,33]. Nef mediated downregulation of HLA class I decreases the efficiency of cytotoxic T lymphocytes (CTL) mediated killing of infected cells, suggesting that it plays a central role in immune evasion [34–36].
- 1
Present address: Institut de Génétique Humaine, CNRS UPR1142, Montpellier, France.
- 2
Present address: Institut de Recherche Necker-Enfants Malades, INSERM U781, Paris, France.