Tetherin Antagonism by HIV-1 Group M Nef Proteins

Abstract

Although Nef is the viral gene product used by most simian immunodeficiency viruses to overcome restriction by tetherin, this activity was acquired by the Vpu protein of HIV-1 group M due to the absence of sequences in human tetherin that confer susceptibility to Nef. Thus, it is widely accepted that HIV-1 group M uses Vpu instead of Nef to counteract tetherin. Challenging this paradigm, we identified Nef alleles of HIV-1 group M isolates with significant activity against human tetherin. These Nef proteins promoted virus release and tetherin downmodulation from the cell surface and, in the context of vpu-deleted HIV-1 recombinants, enhanced virus replication and resistance to antibody-dependent cell-mediated cytotoxicity (ADCC). Further analysis revealed that the Vpu proteins from several of these viruses lack antitetherin activity, suggesting that under certain circumstances, HIV-1 group M Nef may acquire the ability to counteract tetherin to compensate for the loss of this function by Vpu. These observations illustrate the remarkable plasticity of HIV-1 in overcoming restriction by tetherin and challenge the prevailing view that all HIV-1 group M isolates use Vpu to counteract tetherin. IMPORTANCEMost viruses of HIV-1 group M, the main group of HIV-1 responsible for the global AIDS pandemic, use their Vpu proteins to overcome restriction by tetherin (BST-2 or CD317), which is a transmembrane protein that inhibits virus release from infected cells. Here we show that the Nef proteins of certain HIV-1 group M isolates can acquire the ability to counteract tetherin. These results challenge the current paradigm that HIV-1 group M exclusively uses Vpu to counteract tetherin and underscore the importance of tetherin antagonism for efficient viral replication.

The Nef Protein of the Macrophage Tropic HIV-1 Strain AD8 Counteracts Human BST-2/Tetherin

“…Instead, we show that both Nand C-terminal domains in AD8 Nef contribute to the reduction in the cell surface levels of human tetherin ( Figure 5). Anti-tetherin activity has been reported for several M group subtype C HIV-1 Nef proteins [42]. In agreement with our findings, these Nef proteins downregulated cell surface l-tetherin, which correlated with enhanced virus release and replication.…”

“…Moreover, 1.24% of primary isolates in the HIV database encode a Vpu start codon mutation [45]; it will be intriguing to investigate whether some of these viruses use their Nef proteins to overcome tetherin restriction. Interestingly, Arias et al observed that in viral strains with Nef anti-tetherin activity, the corresponding Vpu proteins displayed diminished or no anti-tetherin activity [42]. In conclusion, HIV-1 viruses appear to have retained some flexibility to use either Vpu and/or Nef to antagonize tetherin, thus ensuring that by one mechanism or another, the virus is able to antagonise this key restriction factor.…”

TIM-mediated inhibition of HIV-1 release is antagonized by Nef but potentiated by SERINC proteins

“…For example, the Nef proteins of HIV-1 group O and most SIV strains are capable of counteracting tetherin by downregulating or sequestrating this antiviral protein, thereby enhancing lentiviral particle release (45)(46)(47)(48). Recently, the Nef proteins of some HIV-1 M group strains were also shown to counteract tetherin (49). Here, we provide evidence that the Nef proteins of primate lentiviruses are capable of overcoming the inhibitory effect of TIM proteins on the release of HIV-1, HIV-2, and SIVs.…”

Severe acute respiratory syndrome coronavirus spike protein counteracts BST2‐mediated restriction of virus‐like particle release

“…The transmembrane protein SARS‐CoV ORF7a has been shown to counteract BST2 tethering by interfering with BST2 glycosylation . In addition to the likelihood that BST2‐associated restriction of SARS‐CoV virion release is mitigated by SARS‐CoV S, it is possible that a number of enveloped viruses have developed supplementary anti‐BST2 factors over time—note that in addition to Vpu, HIV‐1 Nef is capable of overcoming BST2 restrictions on virus release under certain conditions . SIV Nef and Env are capable of antagonizing BST2, and influenza neuraminidase and M2 proteins both possess anti‐BST2 capabilities.…”