Abstract
APOBEC3 family DNA cytosine deaminases provide overlapping defenses against pathogen infections. However, most viruses have elaborate evasion mechanisms such as the HIV-1 Vif protein, which subverts cellular CBF-β and a polyubiquitin ligase complex to neutralize these enzymes. Despite advances in APOBEC3 and Vif biology, a full understanding of this direct host-pathogen conflict has been elusive. We combine virus adaptation and computational studies to interrogate the APOBEC3F-Vif interface and build a robust structural model. A recurring compensatory amino acid substitution from adaptation experiments provided an initial docking constraint, and microsecond molecular dynamic simulations optimized interface contacts. Virus infectivity experiments validated a long-lasting electrostatic interaction between APOBEC3F E289 and HIV-1 Vif R15. Taken together with mutagenesis results, we propose a wobble model to explain how HIV-1 Vif has evolved to bind different APOBEC3 enzymes and, more generally, how pathogens may evolve to escape innate host defenses.
Highlights
The APOBEC3 (A3) family of DNA cytosine deaminases comprises a powerful arm of the innate immune defense system in mammals
Taken together with mutagenesis results, we propose a “wobble model” to explain how human immunodeficiency virus type 1 (HIV-1) virion infectivity factor (Vif) has evolved to bind different APOBEC3 enzymes and, more generally, explain how pathogens may evolve to escape innate host defenses
We hypothesized that cells expressing this simianized form of human A3F (huA3F) or the naturally restrictive rhesus macaque A3F (rhA3F) (Hultquist et al, 2011; Virgen and Hatziioannou, 2007) would provide selective pressure to force HIV-1 to adapt by making compensatory changes in Vif, analogous to the way that ancestral simian immunodeficiency virus (SIV) strains may have adapted in order to transmit into the human population (Figure 1A)
Summary
The APOBEC3 (A3) family of DNA cytosine deaminases comprises a powerful arm of the innate immune defense system in mammals. Four A3 enzymes, APOBEC3D (A3D), APOBEC3F (A3F), APOBEC3G (A3G), and APOBEC3H (A3H), each act to suppress human immunodeficiency virus type 1 (HIV-1) replication by packaging into newly synthesized viral particles, directly interfering with reverse transcription, and mutating nascent cDNA cytosines to uracils [reviewed by (Desimmie et al, 2014; Harris and Dudley, 2015)]. The Vif protein of primate lentiviruses HIV-1, HIV-2, and simian immunodeficiency virus (SIV) has evolved to dimerize with the transcription cofactor CBF-β [(Anderson and Harris, 2015) and references therein] This complex enables Vif to bind ELOC and CUL5 and, through these partners, to ELOB and RBX2. A crystal structure of HIV-1 Vif-CBF-β-ELOB-ELOC-CUL5 has helped rationalize prior results (Guo et al, 2014)
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