Journal
JOURNAL OF VIROLOGY
Volume 91, Issue 11, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.00219-17
Keywords
HIV-1; BST-2; envelope glycoproteins; gp120; CD4; CD4-bound conformation; nonneutralizing antibodies; ADCC; CD4 mimetics; IFN-alpha; Env; IL-27; interferons
Categories
Funding
- CIHR foundation [352417]
- amfAR [109343-59-RGRL]
- FRQS AIDS and Infectious Diseases Network grant
- Canada Research Chair on Retroviral Entry
- CIHR [135349]
- Research Scholar Career Award of the Quebec Health Research Fund (FRQS)
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health
- Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) [UM1-AI100645, AI100663]
- National Institutes of Health [GM56550]
- NIH [R01AI116274, HL-092565, R01 AI114266, AI121135, AI098485, AI095098]
- DFG
- ERC
- state Baden-Wuerttemberg, Germany
- FAIR
- MRC [G0801937] Funding Source: UKRI
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Antibodies recognizing conserved CD4-induced (CD4i) epitopes on human immunodeficiency virus type 1 (HIV-1) Env and able to mediate antibody-dependent 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 (HIV+) 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 HIV+ 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-alpha) 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-alpha 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 HIV+ 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-alpha treatment. Here we show that in addition to IFN-alpha, IFN-alpha and IL-27 also affect Vpu-mediated BST-2 downregulation and greatly enhance ADCC responses against HIV-1-infected cells in the presence of CD4mc. These findings may inform strategies aimed at HIV prevention and eradication.
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