Abstract
The plasma membrane is a site of conflict between host defenses and many viruses. One aspect of this conflict is the host’s attempt to eliminate infected cells using innate and adaptive cell-mediated immune mechanisms that recognize features of the plasma membrane characteristic of viral infection. Another is the expression of plasma membrane-associated proteins, so-called restriction factors, which inhibit enveloped virions directly. HIV-1 encodes two countermeasures to these host defenses: The membrane-associated accessory proteins Vpu and Nef. In addition to inhibiting cell-mediated immune-surveillance, Vpu and Nef counteract membrane-associated restriction factors. These include BST-2, which traps newly formed virions at the plasma membrane unless counteracted by Vpu, and SERINC5, which decreases the infectivity of virions unless counteracted by Nef. Here we review key features of these two antiviral proteins, and we review Vpu and Nef, which deplete them from the plasma membrane by co-opting specific cellular proteins and pathways of membrane trafficking and protein-degradation. We also discuss other plasma membrane proteins modulated by HIV-1, particularly CD4, which, if not opposed in infected cells by Vpu and Nef, inhibits viral infectivity and increases the sensitivity of the viral envelope glycoprotein to host immunity.
Highlights
The host–pathogen relationship typically involves a conflict between host-defenses and viral countermeasures, which over time and consequent to cross-species transmission often leaves telltale genetic signatures [1]
Despite causing the net removal of BST-2 from the cell surface, Vpu enables HIV-1 infected T cells to inhibit the production of interferons by plasmacytoid dendritic cells (pDCs) in a manner dependent on BST-2 [40]
We have focused here on SERINC5, other cell-specific factors might contribute to the virologic phenotype of nef, raising the possibility that restriction factor(s) antagonized by Nef remain to be discovered [61]
Summary
The host–pathogen relationship typically involves a conflict between host-defenses and viral countermeasures, which over time and consequent to cross-species transmission often leaves telltale genetic signatures [1]. The host cell can express, either constitutively or in response to interferons, various proteins with direct antiviral activity, some of which act on HIV-1 virions as they assemble and bud from the plasma membrane [4,5,6,7]. Despite causing the net removal of BST-2 from the cell surface, Vpu enables HIV-1 infected T cells to inhibit the production of interferons by pDCs in a manner dependent on BST-2 [40] It apparently does this by directing a subpopulation of residual BST-2 away from virion-assembly sites, where it remains free to interact directly with ILT-7. It co-localizes with virions in large virion-containing compartments, but the significance of this is unclear [41]
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