BST-2 Expression Modulates Small CD4-Mimetic Sensitization of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity

Abstract

Antibodies recognizing conserved CD4-induced (CD4i) epitopes on human immunodeficiency virus type 1 (HIV-1) Env and able to mediate antibodydependent cellular cytotoxicity (ADCC) have been shown to be present in sera from most HIV-1-infected individuals. These antibodies preferentially recognize Env in its CD4-bound conformation. CD4 downregulation by Nef and Vpu dramatically reduces exposure of CD4i HIV-1 Env epitopes and therefore reduce the susceptibility of HIV-1-infected cells to ADCC mediated by HIV-positive (HIVϩ) sera. Importantly, this mechanism of immune evasion can be circumvented with small-molecule CD4 mimetics (CD4mc) that are able to transition Env into the CD4-bound conformation and sensitize HIV-1-infected cells to ADCC mediated by HIVϩ sera. However, HIV-1 developed additional mechanisms to avoid ADCC, including Vpu-mediated BST-2 antagonism, which decreases the overall amount of Env present at the cell surface. Accordingly, BST-2 upregulation in response to alpha interferon (IFN-␣) was shown to increase the susceptibility of HIV-1-infected cells to ADCC despite the activity of Vpu. Here we show that BST-2 upregulation by IFN-␤ and interleukin-27 (IL-27) also increases the surface expression of Env and thus boosts the ability of CD4mc to sensitize HIV-1-infected cells to ADCC by sera from HIV-1-infected individuals.IMPORTANCE HIV-1 evolved sophisticated strategies to conceal Env epitopes from ADCC-mediating antibodies present in HIVϩ sera. Vpu-mediated BST-2 downregulation was shown to decrease ADCC responses by limiting the amount of Env present at the cell surface. This effect of Vpu was shown to be attenuated by IFN-␣ treatment. Here we show that in addition to IFN-␣, IFN-␤ and IL-27 also affect Vpumediated BST-2 downregulation and greatly enhance ADCC responses against HIV-1-

Antibody-Induced Internalization of HIV-1 Env Proteins Limits Surface Expression of the Closed Conformation of Env

“…3A). This phenomenon has been well established and is due to the accumulation of BST-2trapped viral particles at the cell surface, which results in Env accumulation (9,12,14). In agreement with their CD4-induced nature, the recognition of infected cells by the nNAbs tested (A32, 17b, N12-i2, and N5-i5) was dramatically enhanced by deletion of Nef and Vpu.…”

“…It is becoming increasingly clear that several factors contribute to ADCC responses against HIV-1-infected cells, i.e., Env conformation (38), CD4 (8,9,11) and BST-2 (12)(13)(14) downregulation, gp120 shedding (37,59), and the stability of Env-Ab complexes at the cell surface (60), which are driven by the affinity of Abs for Env (61), Env internalization (15), cell surface expression of stress ligands (56,62), and now antibody-induced Env internalization. Additional work will be required to tease apart the differential contribution of each of these factors in ADCC.…”

“…BST-2 (9,(12)(13)(14) through its Vpu accessory protein. In addition to these evasion mechanisms, the virus minimizes Env accumulation at the cell surface by internalizing Env (15).…”

Comprehensive Cross-Clade Characterization of Antibody-Mediated Recognition, Complement-Mediated Lysis, and Cell-Mediated Cytotoxicity of HIV-1 Envelope-Specific Antibodies toward Eradication of the HIV-1 Reservoir

“…Previous reports have also described only limited efficacy, typically Ͻ30%, of ADCML (67) and ADCC of HIV-1-infected cell lines by NK effector cells (40,42). Blockade of CD59 yields increased complement-mediated lysis (67, 68), whereas attenuated viruses, deficient for Nef and Vpu expression, displayed enhanced susceptibility to ADCC of infected cells in a tetherin-dependent manner (40,63). Consistent with this, we found that ADCML-and ADCC-sensitive HIV-1-infected CD4 T cells were phenotypically in the early stage of infection, i.e., displayed high CD4 expression.…”

“…This protective role of ADCC in elite controllers highlights the importance of ADCC in vivo and identifies it as a correlate of control in HIV-1 infection. Vpu and Nef also downregulate BST2 (tetherin), a restriction factor that anchors virions onto the surface of infected CD4 T cells, thus increasing surface density of viral antigens and leading to enhancement of antibody-antigen interactions (40,58,63). Additionally, both HIV-1 virions and infected cells utilize surface regulators of complement activation, such as CD55 and CD59, to resist complement-mediated lysis (34,(64)(65)(66).…”