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.
HIV-1 is the result of at least four independent cross-species transmissions of SIVs from chimpanzees or gorillas to humans . 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 . 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 –. The remaining two groups O and P are more closely related to SIVgor infecting gorillas , . 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 , .
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 –. 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 . 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 , , 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.