Cell-Cell Spread of Human Immunodeficiency Virus Type 1 Overcomes Tetherin/BST-2-Mediated Restriction in T cells

Abstract

Direct cell-to-cell spread of human immunodeficiency virus type 1 (HIV-1) between T cells at the virological synapse (VS) is an efficient mechanism of viral dissemination. Tetherin (BST-2/CD317) is an interferoninduced, antiretroviral restriction factor that inhibits nascent cell-free particle release. The HIV-1 Vpu protein antagonizes tetherin activity; however, whether tetherin also restricts cell-cell spread is unclear. We performed quantitative cell-to-cell transfer analysis of wild-type (WT) or Vpu-defective HIV-1 in Jurkat and primary CD4 ؉ T cells, both of which express endogenous levels of tetherin. We found that Vpu-defective HIV-1 appeared to disseminate more efficiently by cell-to-cell contact between Jurkat cells under conditions where tetherin restricted cell-free virion release. In T cells infected with Vpu-defective HIV-1, tetherin was enriched at the VS, and VS formation was increased compared to the WT, correlating with an accumulation of virus envelope proteins on the cell surface. Increasing tetherin expression with type I interferon had only minor effects on cell-to-cell transmission. Furthermore, small interfering RNA (siRNA)-mediated depletion of tetherin decreased VS formation and cell-to-cell transmission of both Vpu-defective and WT HIV-1. Taken together, these data demonstrate that tetherin does not restrict VS-mediated T cell-to-T cell transfer of Vpu-defective HIV-1 and suggest that under some circumstances tetherin might promote cell-to-cell transfer, either by mediating the accumulation of virions on the cell surface or by regulating integrity of the VS. If so, inhibition of tetherin activity by Vpu may balance requirements for efficient cell-free virion production and cell-to-cell transfer of HIV-1 in the face of antiviral immune responses.

Role of retroviral restriction factors in the interferon-α–mediated suppression of HIV-1 in vivo

“…However, recent data reveal that increased APOBEC3G and APOBEC3F expression levels in rhesus monkeys are associated with lower simian immunodeficiency virus viral loads and prolonged survival, reinforcing the concept that induction of these factors ultimately has beneficial effects on lentiviral disease progression (47). In regards to the antiretroviral effects of BST-2 induction, the impact of BST-2 surface expression on the cell to cell spread of HIV-1 may differ from its effect on the dissemination of free virus, and some reported data suggest that cell to cell transmission may, in fact, be enhanced by this restriction mechanism (48,49). In addition, ISG15, our marker of IFN exposure in this study, has an emerging antiviral role in vitro.…”

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

“…However, in contrast to other restriction factors, such as the TRIM5 and APOBEC3 proteins, which often impose a complete block to virus replication, vpu-deleted HIV-1 and nef-deleted SIV still replicate in primary CD4 + T cells under conditions of IFN-induced up-regulation of tetherin (17,36). Moreover, under certain conditions, tetherin may actually enhance virus replication by facilitating cell-to-cell virus transmission (19). A role for tetherin in increasing the susceptibility of HIV-infected cells to antibodies NKR-CCR5 -sLTR-Luc cells treated with a nontargeting (n.t.)…”

“…Instances of lentiviral adaptation to tetherin, including the acquisition of compensatory changes in gp41 of a nef-deleted strain of SIV passaged in rhesus macaques (17), and changes that restore the anti-tetherin activity of Nef in HIV-1-infected chimpanzees (18), further underscore the importance of tetherin antagonism for efficient virus replication in vivo. However, under certain circumstances, tetherin can also facilitate virus replication by enhancing cell-to-cell transmission (19). Indeed, a role for tetherin in promoting cell-to-cell transmission probably accounts for the selection of vpu-deficient HIV-1 under cell culture conditions designed to mimic rapid T-cell turnover (20).…”

Interferon-Induced Tetherin Restricts Vesicular Stomatitis Virus Release in Neurons

“…The coimmunoprecipitation of HIV-1 vpu and tetherin results from the interaction of their transmembrane domains, and this association was found to be critical for reducing cellsurface tetherin expression (Dube et al, 2010;Jolly et al, 2010). Tetherin and HIV-1 Gag accumulate at the contact zone between infected and target cells, but tetherin cannot prevent the formation of viral synapses; together, tetherin and HIV-1 virions are transferred to target cells as abnormally large patches that are impaired in their fusion capacities (Casartelli et al, 2010).…”