Abstract
BackgroundThe acquisition of effective Vpu-mediated anti-tetherin activity to promote virion release following transmission of SIVcpzPtt from central chimpanzees (Pan troglodytes troglodytes) to humans distinguishes pandemic HIV-1 group M strains from non-pandemic group N, O and P viruses and may have been a prerequisite for their global spread. Some functional motifs in the cytoplasmic region of HIV-1 M Vpus proposed to be important for anti-tetherin activity are more frequently found in the Vpu proteins of SIVcpzPtt than in those of SIVcpzPts infecting eastern chimpanzees (P. t. schweinfurthii), that have not been detected in humans, and SIVgor from gorillas, which is closely related to HIV-1 O and P. Thus, SIVcpzPtt strains may require fewer adaptive changes in Vpu than SIVcpzPts or SIVgor strains to counteract human tetherin.ResultsTo examine whether SIVcpzPtt may only need changes in the transmembrane domain (TMD) of Vpu to acquire anti-tetherin activity, whereas SIVcpzPts and SIVgor may also require changes in the cytoplasmic region, we analyzed chimeras between the TMD of an HIV-1 M Vpu and the cytoplasmic domains of SIVcpzPtt (n = 2), SIVcpzPts (n = 2) and SIVgor (n = 2) Vpu proteins. Unexpectedly, all of these chimeras were capable of counteracting human tetherin to enhance virion release, irrespective of the presence or absence of the putative adaptor protein binding sites and the DSGxxS β-TrCP binding motif reported to be critical for effective anti-tetherin activity of M Vpus. It was also surprising that in three of the six chimeras the gain of anti-tetherin function was associated with a loss of the CD4 degradation activity since this function was conserved among all parental HIV-1, SIVcpz and SIVgor Vpu proteins.ConclusionsOur results show that changes in the TMD of SIVcpzPtt, SIVcpzPts and SIVgor Vpus are sufficient to render them active against human tetherin. Thus, several previously described domains in the extracellular region of Vpu are not absolutely essential for tetherin antagonism but may be required for other Vpu functions.
Highlights
The acquisition of effective Vpu-mediated anti-tetherin activity to promote virion release following transmission of SIVcpzPtt from central chimpanzees (Pan troglodytes troglodytes) to humans distinguishes pandemic human immunodeficiency virus type 1 (HIV-1) group M strains from non-pandemic group N, O and P viruses and may have been a prerequisite for their global spread
In the present study, we examined whether differential adaptive hurdles of SIVcpz Vpu could explain why only one of two infected subspecies of chimpanzees served as a zoonotic reservoir for humans and why HIV-1 groups O and P that are most closely related to SIVgor [25] failed to acquire Vpu-mediated anti-tetherin activity (Figure 1A)
To examine whether the SIVcpzPtt Vpus may only require alterations in the transmembrane domain (TMD) to counteract human tetherin, whereas the SIVcpzPts and SIVgor Vpus may need additional changes in cytoplasmic part (CP), we generated a set of chimeras between the TMD of the HIV-1 M NL4-3 Vpu, which is a well characterized antagonist of human tetherin, and the CP of these simian immunodeficiency viruses (SIVs) Vpus (Figure 1B; Additional file 1: Table S1)
Summary
The acquisition of effective Vpu-mediated anti-tetherin activity to promote virion release following transmission of SIVcpzPtt from central chimpanzees (Pan troglodytes troglodytes) to humans distinguishes pandemic HIV-1 group M strains from non-pandemic group N, O and P viruses and may have been a prerequisite for their global spread. SIVcpz and (most likely) SIVgor Vif are capable of antagonizing the human APOBEC3G orthologue because it is highly homologous to the corresponding ape proteins [8] Adaptation of these SIVs to our closest non-human relatives has already disarmed two potent human defense factors. HIV-1 group O and P strains, which resulted from independent zoonotic transmissions and are closely related to SIVgor [13,14] have apparently not yet evolved an effective antagonist of human tetherin [9,15]. Vpus of the rare HIV-1 N strains acquired some antitetherin activity in humans, but lost the second key function of Vpu, i.e. degradation of CD4, the primary viral receptor [9,16]
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