Upregulation of BST-2/Tetherin by HIV Infection In Vivo

Abstract

The interferon-inducible antiviral factor BST-2 prevents several enveloped viruses, including HIV, from escaping infected cells. The HIV protein Vpu antagonizes this host defense. Little is known about the expression of BST-2 during HIV infection in vivo and whether it can be modulated to the host's advantage. We studied the expression of BST-2 on blood cells from HIV-infected patients during the acute and chronic phases of disease as well as after antiretroviral treatment (ART). The expression of BST-2 was increased on mononuclear leukocytes, including CD4-positive T lymphocytes from HIV-positive patients, compared to that on cells of uninfected controls. The expression of BST-2 was highest during acute infection and decreased to levels similar to those of uninfected individuals after ART. Treatment of primary blood mononuclear cells in vitro with alpha interferon or with Toll-like receptor (TLR) agonists increased the expression of BST-2 to levels similar to those found during infection in vivo. The interferon-induced levels were sufficient to overcome the Vpu protein in vitro, reducing the release of wild-type HIV. These data show that BST-2 is upregulated during HIV infection, consistent with its role as an interferon-stimulated gene. The data further suggest that this upregulation is sufficient to saturate the activity of Vpu and inhibit wild-type HIV.

The role of BST‐2/Tetherin in host protection and disease manifestation

“…However, using patient‐derived specimens, it was shown that pandemic HIV‐1 group M express a Vpu variant that antagonizes BST‐2 and CD4 whereas Vpu from non‐pandemic HIV‐1 strains does not antagonize BST‐2 187. Additionally, the neutralizing effect of BST‐2 by Vpu is not absolute in HIV‐1 infected patients 162 and BST‐2 has developed an immune sensing function for HIV‐1 clearance in vivo 41. These data point to the Vpu‐BST‐2 antagonistic interaction as a significant determinant of the ability of either HIV‐1 to promote its spread or of the host to restrict the virus.…”

“…This observation was made in macrophages derived from rhesus macaques where TLR3 induces the expression of BST‐2 and other restriction factors 161, 162. Although the elements of TLR3‐mediated induction of BST‐2 are yet to be determined, TLR3 induces BST‐2 expression in peripheral blood mononuclear cells (PBMCs) independent of IFN signaling during early immune responses 145 and treatment of PBMCs with poly(I · C), a TLR3 agonist increased BST‐2 levels 162. BST‐2 promoter contains IRF binding elements and a single IRF binding site renders the BST‐2 promoter responsive to induction by IFNα 145.…”

“…Signaling through TLR3 mediates restriction of virus infection and replication in MDMs 160. This observation was made in macrophages derived from rhesus macaques where TLR3 induces the expression of BST‐2 and other restriction factors 161, 162. Although the elements of TLR3‐mediated induction of BST‐2 are yet to be determined, TLR3 induces BST‐2 expression in peripheral blood mononuclear cells (PBMCs) independent of IFN signaling during early immune responses 145 and treatment of PBMCs with poly(I · C), a TLR3 agonist increased BST‐2 levels 162.…”

“…Stimulation of TLR7 or TLR9 by nucleic acids in relevant cell types triggers signal transduction cascades that result in secretion of inflammatory molecules including type I IFNs 169, 170, 171. In PBMCs and not CD4+ T cells, activation of TLR9 with the agonist ODN2216 (type A CpG DNA) induces BST‐2 expression 162. The lack of BST‐2 induction in CD4+ T cells was attributed to absence of TLR9 expression 162.…”

“…In PBMCs and not CD4+ T cells, activation of TLR9 with the agonist ODN2216 (type A CpG DNA) induces BST‐2 expression 162. The lack of BST‐2 induction in CD4+ T cells was attributed to absence of TLR9 expression 162. On the other hand, the relationship between TLR7/9 and BST‐2 in pDCs is one of a negative regulation 150, 172, that may result in manifestation of diseases, such as lupus and cancer 122, 173.…”