Research Article: Human Tetherin Exerts Strong Selection Pressure on the HIV-1 Group N Vpu Protein

Date Published: December 20, 2012

Publisher: Public Library of Science

Author(s): Daniel Sauter, Daniel Unterweger, Michael Vogl, Shariq M. Usmani, Anke Heigele, Silvia F. Kluge, Elisabeth Hermkes, Markus Moll, Edward Barker, Martine Peeters, Gerald H. Learn, Frederic Bibollet-Ruche, Joëlle V. Fritz, Oliver T. Fackler, Beatrice H. Hahn, Frank Kirchhoff, Christopher Aiken.


HIV-1 groups M and N emerged within the last century following two independent cross-species transmissions of SIVcpz from chimpanzees to humans. In contrast to pandemic group M strains, HIV-1 group N viruses are exceedingly rare, with only about a dozen infections identified, all but one in individuals from Cameroon. Poor adaptation to the human host may be responsible for this limited spread of HIV-1 group N in the human population. Here, we analyzed the function of Vpu proteins from seven group N strains from Cameroon, the place where this zoonosis originally emerged. We found that these N-Vpus acquired four amino acid substitutions (E15A, V19A and IV25/26LL) in their transmembrane domain (TMD) that allow efficient interaction with human tetherin. However, despite these adaptive changes, most N-Vpus still antagonize human tetherin only poorly and fail to down-modulate CD4, the natural killer (NK) cell ligand NTB-A as well as the lipid-antigen presenting protein CD1d. These functional deficiencies were mapped to amino acid changes in the cytoplasmic domain that disrupt putative adaptor protein binding sites and an otherwise highly conserved ßTrCP-binding DSGxxS motif. As a consequence, N-Vpus exhibited aberrant intracellular localization and/or failed to recruit the ubiquitin-ligase complex to induce tetherin degradation. The only exception was the Vpu of a group N strain recently discovered in France, but originally acquired in Togo, which contained intact cytoplasmic motifs and counteracted tetherin as effectively as the Vpus of pandemic HIV-1 M strains. These results indicate that HIV-1 group N Vpu is under strong host-specific selection pressure and that the acquisition of effective tetherin antagonism may lead to the emergence of viral variants with increased transmission fitness.

Partial Text

HIV-1 is the result of at least four independent cross-species transmissions of SIVs from chimpanzees or gorillas to humans [1]. The resulting pathogens, termed HIV-1 groups M, O, N and P, differ greatly in their spread within the human population. The main group M was introduced from a chimpanzee early in the last century and is responsible for the global AIDS epidemic [1]. In contrast, the rare group N, which is also of chimpanzee origin, has thus far only been identified in about a dozen people, all but one from Cameroon [2]–[7]. The remaining two groups O and P are more closely related to SIVgor infecting gorillas [1], [8]. HIV-1 O has infected tens of thousands of individuals, but is geographically restricted to Cameroon and surrounding countries, while group P has only been found in two individuals from Cameroon [8], [9].

HIV-1 group N is an example of a (thus far) poorly successful SIVcpz zoonosis, which until recently has only been detected in about a dozen individuals from Cameroon [2]–[4]. In the present study, we analyzed the function of Vpu proteins from these viruses to elucidate to what extent they are impaired in tetherin antagonism and down-modulation of CD4, CD1d and NTB-A. We also examined the Vpu protein of one unusual group N strain that was only recently discovered in a French patient who most likely became infected in Togo [3]. This N strain represents a very recent infection and the only documented transmission case outside of Cameroon. We thus reasoned that this strain may provide insights into whether Vpu, which has been implicated as a determinant of viral transmission fitness [12], [45], continues to be under strong host specific selection. Our data show that N-Vpus have evolved a transmembrane domain that efficiently interacts with human tetherin. However, most also contain disruptive changes in their cytoplasmic region, which are not only responsible for their inability to down-modulate CD4, but also attenuate their anti-tetherin activity. Only the most recently identified HIV-1 N strain from Togo expressed a Vpu that was fully active against tetherin, yet remained inactive against CD4 because it fails to interact with this receptor. These findings indicate that group N viruses are still in the process of adaptation, with strong host selection pressures shaping the function of their Vpu proteins, especially their ability to clear the tetherin barrier.




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