Dataset Information

The Potency of Nef-Mediated SERINC5 Antagonism Correlates with the Prevalence of Primate Lentiviruses in the Wild.

ABSTRACT: The cellular factor serine incorporator 5 (SERINC5) impairs HIV-1 infectivity but is antagonized by the viral Nef protein. We analyzed the anti-SERINC5 activity of Nef proteins across primate lentiviruses and examined whether SERINC5 represents a barrier to cross-species transmissions and/or within-species viral spread. HIV-1, HIV-2, and SIV Nefs counteract human, ape, monkey, and murine SERINC5 orthologs with similar potency. However, HIV-1 Nefs are more active against SERINC5 than HIV-2 Nefs, and chimpanzee SIV (SIVcpz) Nefs are more potent than those of their monkey precursors. Additionally, Nefs of HIV and most SIVs rely on the dileucine motif in the C-terminal loop for anti-SERINC5 activity, while the Nef from colobus SIV (SIVcol) evolved different inhibitory mechanisms. We also found a significant correlation between anti-SERINC5 potency and the SIV prevalence in the respective ape and monkey species. Thus, Nef-mediated SERINC5 antagonism may determine the ability of primate lentiviruses to spread within natural hosts.

SUBMITTER: Heigele A

PROVIDER: S-EPMC5098270 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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The Potency of Nef-Mediated SERINC5 Antagonism Correlates with the Prevalence of Primate Lentiviruses in the Wild.

Heigele Anke A Kmiec Dorota D Regensburger Kerstin K Langer Simon S Peiffer Lukas L Stürzel Christina M CM Sauter Daniel D Peeters Martine M Pizzato Massimo M Learn Gerald H GH Hahn Beatrice H BH Kirchhoff Frank F

Cell host & microbe 20160901 3

The cellular factor serine incorporator 5 (SERINC5) impairs HIV-1 infectivity but is antagonized by the viral Nef protein. We analyzed the anti-SERINC5 activity of Nef proteins across primate lentiviruses and examined whether SERINC5 represents a barrier to cross-species transmissions and/or within-species viral spread. HIV-1, HIV-2, and SIV Nefs counteract human, ape, monkey, and murine SERINC5 orthologs with similar potency. However, HIV-1 Nefs are more active against SERINC5 than HIV-2 Nefs, ...[more]

PMID: 27631701

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Project description:Nef is an accessory protein critical for the ability of human and simian immunodeficiency viruses (HIV and SIV) to replicate efficiently in their respective hosts. Previous analyses of members of 15 different primate lentivirus lineages revealed a link between Nef function and the presence of a vpu gene. In particular, Nef proteins of all vpu-containing viruses had lost their ability to downmodulate the T cell (TCR-CD3) receptor. Here we examined Nef proteins from eight additional SIV lineages, including SIVgor, SIVwrc, SIVolc, SIVgri, SIVdrl, SIVlho, SIVden, and SIVasc, from western lowland gorillas, western red colobus monkeys, olive colobus monkeys, grivet monkeys, drills, L'Hoest's monkeys, Dent's mona monkeys, and red-tailed monkeys, respectively. We found that except for the nef gene of SIVdrl, all of them were efficiently expressed and modulated CD4, major histocompatibility complex class I (MHC-I), CD28, CXCR4, and Ii cell surface expression and/or enhanced viral infectivity and replication. Furthermore, the Nef proteins of SIVgri, SIVlho, SIVwrc, SIVolc, and SIVgor antagonized tetherin. As expected, the Nef protein of SIVgor, which carries vpu, failed to downmodulate CD3, whereas those of SIVwrc, SIVgri, SIVlho, and SIVasc, which lack vpu, were capable of performing this function. Surprisingly, however, the Nef protein of the vpu-containing SIVden strain retained the ability to downmodulate TCR-CD3, whereas that of SIVolc, which does not contain vpu, was unable to perform this function. Although the SIVden Vpu is about 20 amino acids shorter than other Vpu proteins, it degrades CD4 and antagonizes tetherin. Our data show that there are exceptions to the link between the presence of a vpu gene and nef alleles deficient in CD3 modulation, indicating that host properties also affect the selective pressure for Nef-mediated disruption of TCR-CD3 signaling. Our results are also further evidence that tetherin antagonism is a common function of primate lentivirus Nef proteins and that the resistance of human tetherin to Nef represents a relevant barrier to cross-species transmission of SIVs to humans.

Project description:The primate lentiviral accessory protein Nef downregulates CD4 and major histocompatibility complex class I (MHC-I) from the cell surface via independent endosomal trafficking pathways to promote viral pathogenesis. In addition, Nef antagonizes a novel restriction factor, SERINC5 (Ser5), to increase viral infectivity. To explore the molecular mechanism of Ser5 antagonism by Nef, we determined how Nef affects Ser5 expression and intracellular trafficking in comparison to CD4 and MHC-I. We confirm that Nef excludes Ser5 from human immunodeficiency virus type 1 (HIV-1) virions by downregulating its cell surface expression via similar functional motifs required for CD4 downregulation. We find that Nef decreases both Ser5 and CD4 expression at steady-state levels, which are rescued by NH4Cl or bafilomycin A1 treatment. Nef binding to Ser5 was detected in living cells using a bimolecular fluorescence complementation assay, where Nef membrane association is required for interaction. In addition, Nef triggers rapid Ser5 internalization via receptor-mediated endocytosis and relocalizes Ser5 to Rab5+ early, Rab7+ late, and Rab11+ recycling endosomes. Manipulation of AP-2, Rab5, Rab7, and Rab11 expression levels affects the Nef-dependent Ser5 and CD4 downregulation. Moreover, although Nef does not promote Ser5 polyubiquitination, Ser5 downregulation relies on the ubiquitination pathway, and both K48- and K63-specific ubiquitin linkages are required for the downregulation. Finally, Nef promotes Ser5 colocalization with LAMP1, which is enhanced by bafilomycin A1 treatment, suggesting that Ser5 is targeted to lysosomes for destruction. We conclude that Nef uses a similar mechanism to downregulate Ser5 and CD4, which sorts Ser5 into a point-of-no-return degradative pathway to counteract its restriction.IMPORTANCE Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) express an accessory protein called Nef to promote viral pathogenesis. Nef drives immune escape in vivo through downregulation of CD4 and MHC-I from the host cell surface. Recently, Nef was reported to counteract a novel host restriction factor, Ser5, to increase viral infectivity. Nef downregulates cell surface Ser5, thus preventing its incorporation into virus particles, resulting in disruption of its antiviral activity. Here, we report mechanistic studies of Nef-mediated Ser5 downregulation in comparison to CD4 and MHC-I. We demonstrate that Nef binds directly to Ser5 in living cells and that Nef-Ser5 interaction requires Nef association with the plasma membrane. Subsequently, Nef internalizes Ser5 from the plasma membrane via receptor-mediated endocytosis, and targets ubiquitinated Ser5 to endosomes and lysosomes for destruction. Collectively, these results provide new insights into our ongoing understanding of the Nef-Ser5 arms race in HIV-1 infection.

Project description:Primate lentiviruses have evolved sophisticated strategies to suppress the immune response of their host species. For example, HIV-2 and most simian immunodeficiency viruses (SIVs) use their accessory protein Nef to prevent T cell activation and antiviral gene expression by downmodulating the T cell receptor CD3. This Nef function was lost in HIV-1 and other vpu-encoding viruses suggesting that the acquisition of Vpu-mediated NF-?B inhibition reduced the selection pressure for inhibition of T cell activation by Nef. To obtain further insights into the modulation of NF-?B activity by primate lentiviral accessory factors, we analyzed 32 Vpr proteins from a large panel of divergent primate lentiviruses. We found that those of SIVcol and SIVolc infecting Colobinae monkeys showed the highest efficacy in suppressing NF-?B activation. Vpr-mediated inhibition of NF-?B resulted in decreased IFN? promoter activity and suppressed type I IFN induction in virally infected primary cells. Interestingly, SIVcol and SIVolc differ from all other primate lentiviruses investigated by the lack of both, a vpu gene and efficient Nef-mediated downmodulation of CD3. Thus, primate lentiviruses have evolved at least three alternative strategies to inhibit NF-?B-dependent immune activation. Functional analyses showed that the inhibitory activity of SIVolc and SIVcol Vprs is independent of DCAF1 and the induction of cell cycle arrest. While both Vprs target the IKK complex or a factor further downstream in the NF-?B signaling cascade, only SIVolc Vpr stabilizes I?B? and inhibits p65 phosphorylation. Notably, only de-novo synthesized but not virion-associated Vpr suppressed the activation of NF-?B, thus enabling NF-?B-dependent initiation of viral gene transcription during early stages of the replication cycle, while minimizing antiviral gene expression at later stages. Our findings highlight the key role of NF-?B in antiviral immunity and demonstrate that primate lentiviruses follow distinct evolutionary paths to modulate NF-?B-dependent expression of viral and antiviral genes.

Dataset Information

The Potency of Nef-Mediated SERINC5 Antagonism Correlates with the Prevalence of Primate Lentiviruses in the Wild.

Publications

The Potency of Nef-Mediated SERINC5 Antagonism Correlates with the Prevalence of Primate Lentiviruses in the Wild.

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