Tetherin-Driven Adaptation of Vpu and Nef Function and the Evolution of Pandemic and Nonpandemic HIV-1 Strains

Sauter, Daniel; Schindler, Michael; Specht, Anke; Landford, Wilmina N.; Münch, Jan; Kim, Kyeong-Ae; Votteler, Jörg; Schubert, Ulrich S.; Bibollet-Ruche, Frédéric; Keele, Brandon F.; Takehisa, Jun; Ogando, Yudelca; Ochsenbauer, Christina; Kappes, John C.; Ayouba, Ahidjo; Peeters, Martine; Learn, Gerald H.; Shaw, George M.; Sharp, Paul M.; Bieniasz, Paul D.; Hahn, Beatrice H.; Hatziioannou, Théodora; Kirchhoff, Frank

doi:10.1016/j.chom.2009.10.004

Cited by 383 publications

(752 citation statements)

References 49 publications

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“…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%

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%

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.

Self Cite

134

149

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“…The majority of primate lentiviruses, including phylogenetically diverse SIVs endemic to chimpanzees (SIV cpz ), sooty mangabeys (SIV smm ), and African green monkeys (SIV agm ), use Nef (negative regulatory factor) to counteract the tetherin proteins of their non-human primate hosts (61,67,68). In fact, the anti-tetherin activities of HIV-1 Vpu and HIV-2 Env appear to have been acquired after the respective cross-species transmission of SIV cpz and SIV smm into humans due to the absence of a five-amino acid sequence in human tetherin required for susceptibility to Nef (61,68).…”

Section: Restriction By Particle Tethering: Bst-2/tetherin Integral Mmentioning

confidence: 99%

The Restriction Factors of Human Immunodeficiency Virus

Harris

Hultquist

Evans

2012

Journal of Biological Chemistry

243

255

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Cellular proteins called "restriction factors" can serve as powerful blockades to HIV replication, but the virus possesses elaborate strategies to circumvent these barriers. First, we discuss general hallmarks of a restriction factor. Second, we review how the viral Vif protein protects the viral genome from lethal levels of cDNA deamination by promoting APOBEC3 protein degradation; how the viral Vpu, Env, and Nef proteins facilitate internalization and degradation of the virus-tethering protein BST-2/tetherin; and how the viral Vpx protein prevents the premature termination of reverse transcription by degrading the dNTPase SAMHD1. These HIV restriction and counter-restriction mechanisms suggest strategies for new therapeutic interventions. Restriction Factor HallmarksRestriction factors have at least four defining characteristics (see Fig. 1A). First and foremost, a restriction factor must directly and dominantly cause a significant decrease in HIV infectivity. This is often determined by cotransfecting cell lines such as HEK293 and HeLa with a molecular clone of the virus, with or without a plasmid expressing the restriction factor, and measuring the amount and infectivity of virus recovered in the cell culture medium after 1-2 days of incubation. Such assays are ideally done over a range of restriction factor expression, with the highest levels often imposing log-scale drops in viral infectivity (see Fig. 1B). This "single-cycle" assay for viral replication is useful for testing the impact of viral mutations and/or restriction factor variations.Second, if a restriction factor is a true threat to viral replication, then the predecessors of HIV invariably evolved an equally potent counter-restriction mechanism that still exists in the present day virus. For instance, titrating a counter-restriction factor into the aforementioned single-cycle infectivity experiment can result in a full recovery of viral infectivity despite the presence of an active restriction factor (Fig. 1B). Viruses lacking these various countermeasures are able to replicate in some, but not all, cell types depending on the expression level of the relevant restriction factor. Cell lines that support replication are termed "permissive," and those that do not are termed "nonpermissive." This life/death dichotomy has been elegantly exploited to identify several restriction factors and their corresponding viral antagonists.Third, because the interactions between restriction and counter-restriction factors occur through direct protein-protein interactions, the restriction factor often shows signatures of rapid evolution. In general, mutations are maintained in a population only if they confer a selective advantage. If a host species experiences iterative rounds of pathogenic pressure, altered variants of host restriction factors that are no longer susceptible to the pathogen's counteraction mechanism are selected. Over evolutionary time, this results in an overabundance of amino acid substitution mutations in these genes relative to non-amino acid...

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“…Whereas most simian immunodeficiency viruses (SIVs) use Nef to counteract the tetherin proteins of their nonhuman primate hosts (12)(13)(14), HIV-1 and HIV-2 use their Vpu and Env proteins, respectively, to counteract human tetherin because of the absence of sequences in the cytoplasmic domain of the protein required for susceptibility to Nef (5,6,15). Tetherin has therefore had a significant impact on shaping the course of lentiviral evolution in primates.…”

mentioning

confidence: 99%

Tetherin antagonism by Vpu protects HIV-infected cells from antibody-dependent cell-mediated cytotoxicity

Arias

Heyer

Bredow

et al. 2014

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

145

161

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Significance HIV-1 viral protein U (Vpu) facilitates virus release from infected cells by down-regulating and degrading tetherin, a transmembrane protein upregulated by IFN that impedes the detachment of enveloped viruses from infected cells. Here we show that this activity of Vpu protects HIV-infected cells from antibodies that are capable of directing their elimination by antibody-dependent cell-mediated cytotoxicity. A direct implication of these observations is that tetherin serves as a link between innate and adaptive immunity to enhance the susceptibility of virus-infected cells to antibodies. Thus, the antiviral activity of tetherin may be much greater than previously appreciated based on its ability to inhibit virus release in cell culture assays.

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Tetherin-Driven Adaptation of Vpu and Nef Function and the Evolution of Pandemic and Nonpandemic HIV-1 Strains

Cited by 383 publications

References 49 publications

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

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

The Restriction Factors of Human Immunodeficiency Virus

Tetherin antagonism by Vpu protects HIV-infected cells from antibody-dependent cell-mediated cytotoxicity

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