Nef Proteins of Epidemic HIV-1 Group O Strains Antagonize Human Tetherin

Kluge, Silvia F.; Mack, Katharina; Iyer, Shilpa S.; Pujol, François M.; Heigele, Anke; Learn, Gerald H.; Usmani, Shariq M.; Sauter, Daniel; Joas, Simone; Hotter, Dominik; Bibollet-Ruche, Frédéric; Plenderleith, Lindsey J.; Peeters, Martine; Geyer, Matthias; Sharp, Paul M.; Fackler, Oliver T.; Hahn, Beatrice H.; Kirchhoff, Frank

doi:10.1016/j.chom.2014.10.002

Cited by 77 publications

(110 citation statements)

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“…The natural history of group O infection appears to be similar to the natural history of group M infection (43), and it is thus likely that a roughly similar number of people have died as are currently infected. Therefore, it is reasonable to estimate that HIV-1 group O may have infected around 100,000 people (14).…”

Section: Sivgor Resulted From a Single Introduction Of Sivcpz From Symentioning

confidence: 99%

“…Both lineages also had to acquire resistance to the potent restriction factor tetherin: SIVcpz and SIVgor antagonize tetherin via their Nef proteins, but the tetherin motif that these proteins target was deleted in a human ancestor. In group M viruses, Vpu adapted to acquire antitetherin activity (50), whereas in the ancestor of group O, the Nef protein evolved to use a different target within tetherin (14). The fact that group O viruses have not spread even more widely in the human population is thus unlikely to be due to a lack of adaptation to the human host, but may simply reflect the absence of epidemiological opportunity during the early stages of the pandemic expansion of AIDS starting a little over 50 y ago.…”

Section: Sivgor Resulted From a Single Introduction Of Sivcpz From Symentioning

confidence: 99%

“…Africa, group O viruses have spread through Cameroon, Gabon, Nigeria, and other neighboring countries, and are estimated to have infected about 100,000 individuals (13,14).…”

Section: Significancementioning

confidence: 99%

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Origin of the HIV-1 group O epidemic in western lowland gorillas

D’arc

Ayouba

Esteban

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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134

149

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HIV-1, the cause of AIDS, is composed of four phylogenetic lineages, groups M, N, O, and P, each of which resulted from an independent cross-species transmission event of simian immunodeficiency viruses (SIVs) infecting African apes. Although groups M and N have been traced to geographically distinct chimpanzee communities in southern Cameroon, the reservoirs of groups O and P remain unknown. Here, we screened fecal samples from western lowland (n = 2,611), eastern lowland (n = 103), and mountain (n = 218) gorillas for gorilla SIV (SIVgor) antibodies and nucleic acids. Despite testing wild troops throughout southern Cameroon (n = 14), northern Gabon (n = 16), the Democratic Republic of Congo (n = 2), and Uganda (n = 1), SIVgor was identified at only four sites in southern Cameroon, with prevalences ranging from 0.8–22%. Amplification of partial and full-length SIVgor sequences revealed extensive genetic diversity, but all SIVgor strains were derived from a single lineage within the chimpanzee SIV (SIVcpz) radiation. Two fully sequenced gorilla viruses from southwestern Cameroon were very closely related to, and likely represent the source population of, HIV-1 group P. Most of the genome of a third SIVgor strain, from central Cameroon, was very closely related to HIV-1 group O, again pointing to gorillas as the immediate source. Functional analyses identified the cytidine deaminase APOBEC3G as a barrier for chimpanzee-to-gorilla, but not gorilla-to-human, virus transmission. These data indicate that HIV-1 group O, which spreads epidemically in west central Africa and is estimated to have infected around 100,000 people, originated by cross-species transmission from western lowland gorillas.

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Section: Sivgor Resulted From a Single Introduction Of Sivcpz From Symentioning

confidence: 99%

Section: Sivgor Resulted From a Single Introduction Of Sivcpz From Symentioning

confidence: 99%

See 1 more Smart Citation

Origin of the HIV-1 group O epidemic in western lowland gorillas

D’arc

Ayouba

Esteban

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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134

149

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“…This species barrier is believed to have led the predominant HIV-1 group M and, less effectively, the minor group N strains to adapt and use Vpu to antagonize BST2 (6,17), while HIV-2 adopted the envelope (Env) glycoproteins as a BST2 countermeasure (18). Although initial studies failed to identify a human BST2 viral antagonist in HIV-1 groups O and P (6,19,20), recent evidence reveals that HIV-1 O Nef can counteract human BST2, thus providing a potential explanation for the epidemic spread of HIV-1 group O in western central Africa (21,22).…”

mentioning

confidence: 99%

Differential Control of BST2 Restriction and Plasmacytoid Dendritic Cell Antiviral Response by Antagonists Encoded by HIV-1 Group M and O Strains

Bego

Cong

Mack

et al. 2016

J Virol

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BST2/tetherin is a type I interferon (IFN-I)-stimulated host factor that restricts the release of HIV-1 by entrapping budding virions at the cell surface. This membrane-associated protein can also engage and activate the plasmacytoid dendritic cell (pDC)-specific immunoglobulin-like transcript 7 (ILT7) inhibitory receptor to downregulate the IFN-I response by pDCs. Pandemic HIV-1 group M uses Vpu (M-Vpu) to counteract the two BST2 isoforms (long and short) that are expressed in human cells. MVpu efficiently downregulates surface long BST2, while it displaces short BST2 molecules away from viral assembly sites. We recently found that this attribute is used by M-Vpu to activate the BST2/ILT7-dependent negative-feedback pathway and to suppress pDC IFN-I responses during sensing of infected cells. However, whether this property is conserved in endemic HIV-1 group O, which has evolved Nef (O-Nef) to counteract specifically the long BST2 isoform, remains unknown. In the present study, we validated that O-Nefs have the capacity to downregulate surface BST2 and enhance HIV-1 particle release although less efficiently than M-Vpu. In contrast to M-Vpu, O-Nef did not efficiently enhance viral spread in T cell culture or displace short BST2 from viral assembly sites to prevent its occlusion by tethered HIV-1 particles. Consequently, O-Nef impairs the ability of BST2 to activate negative ILT7 signaling to suppress the IFN-I response by pDC-containing peripheral blood mononuclear cells (PBMCs) during sensing of infected cells. These distinctive features of BST2 counteraction by O-Nefs may in part explain the limited spread of HIV-1 group O in the human population. IMPORTANCEThe geographical distributions and prevalences of different HIV-1 groups show large variations. Understanding drivers of distinctive viral spread may aid in the development of therapeutic strategies for controlling the spread of HIV-1 pandemic strains. The differential spread of HIV-1 groups appears to be linked to their capacities to antagonize the long and short isoforms of the BST2 restriction factor. We found that the endemic HIV-1 group O-encoded BST2 antagonist Nef is unable to counteract the restriction mediated by short BST2, a condition that impairs its ability to activate ILT7 and suppress pDC antiviral responses. This is in contrast to the pandemic HIV-1 group M-specified BST2 countermeasure Vpu, which displays a diverse array of mechanisms to counteract short and long BST2 isoforms, an attribute that allows the effective control of pDC antiviral responses. These findings may help explain the limited spread of HIV-1 group O as well as the continued predominance of HIV-1 group M throughout the world. BST2/tetherin is a type I interferon (IFN-I)-inducible surface protein with an unusual topology. The protein consists of a N-terminal cytosolic tail followed by a transmembrane domain (TMD) and an ectodomain that is membrane associated through a C-terminal glycosylphosphatidylinositol (GPI) anchor (1). BST2 inhibits the release of a broad arr...

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“…However, recent reports on BST-2 antagonism suggest that this is not always the case. For instance, Vpu + SIVs such as SIV from greater spot-nosed monkeys (SIVgsn) can utilize their Nef protein to antagonize BST-2 (41), some HIV-2 Env variants also fail to antagonize BST-2 (35), and HIV-1 group O -which lacks Vpu expression -antagonizes BST-2 using its Nef protein (42). In addition, we demonstrated in this study that SIVsmE543-3 and SIVmac239 utilize distinct strategies to antagonize BST-2, despite being closely related to each other.…”

Section: Discussionmentioning

confidence: 99%