Fab-based inhibitors reveal ubiquitin independent functions for HIV Vif neutralization of APOBEC3 restriction factors
Year: 2018
Type: article
Abstract: The lentiviral protein Viral Infectivity Factor (Vif) counteracts the antiviral effects of host APOBEC3 (A3) proteins and contributes to persistent HIV infection. Vif targets A3 restriction factors for ubiquitination and proteasomal degradation by recruiting them to a multi-protein ubiquitin E3 ligase complex. Here, we describe a degradation-independent mechanism of Vif-mediated antagonism that was revealed through detailed structure-function studies of antibody antigen-binding fragments (Fabs) to the Vif complex. Two Fabs were found to inhibit Vif-mediated A3 neutralization through distinct mechanisms: shielding A3 from ubiquitin transfer and blocking Vif E3 assembly. Combined biochemical, cell biological and structural studies reveal that disruption of Vif E3 assembly inhibited A3 ubiquitination but was not sufficient to restore its packaging into viral particles and antiviral activity. These observations establish that Vif can neutralize A3 family members in a degradation-independent manner. Additionally, this work highlights the potential of Fabs as functional probes, and illuminates how Vif uses a multi-pronged approach involving both degradation dependent and independent mechanisms to suppress A3 innate immunity.
Source: PLoS Pathogens
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
Funders: amfAR, The Foundation for AIDS Research, University of Minnesota, University of Washington, Houston Advanced Research Center, University of Oxford, China Scholarship Council, National Institutes of Health, Center for AIDS Research, University of Washington, University of California, San Francisco, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases
Awards: G1255407591, Evolution of the Vif E3 Ubiquitin Ligase, HARC Center: HIV Accessory and Regulatory Complexes, G2502458181, G26840534, G2839755957, Global innate immune responses to HIV-1 infection, G2976896075, G3181090803, Developing Small Molecule Screens for Vif-APOBEC3 antagonists, Structure and Function of the Decapping Enzyme Complex, Structural Investigation into the HIV RNA Nuclear Export Complex, TAT Transactivation, G6129755832, G6138831382, G6335145789, G6734531460, Linux cluster for near atomic resolution single particle cryo-EM, Multiscale analysis of influenza host-pathogen interactions: Fluomics, G9000078127, G9000177694, Integrative Microbiology Program, UCSF-Bay Area Center for AIDS Research
OpenAlex ID: W2782324548